EP4634175A1 - Benzimidazole derivatives - Google Patents

Abstract

Disclosed are benzimidazole derivatives, pharmaceutical compositions comprising them, and methods of using them.

Description

BENZIMIDAZOLE DERIVATIVES BACKGROUND OF THE DISCLOSURE Field of the Disclosure [0001] This disclosure relates generally to benzimidazole derivatives, pharmaceutical compositions comprising them, and methods of using them. Technical Background [0002] Oxidative stress, characterized by elevated levels of reactive oxygen species (ROS) within the cell, is counteracted by cellular anti-oxidant responses to maintain homeostasis. Aberrant ROS production, left unchecked, can result in damage to cellular components including lipids and nucleic acids. Excessive and prolonged oxidative stress within the cell is linked to chronic diseases including, but not limited to, autoimmune, pulmonary, neuroinflammatory, neurodegenerative, blood, cardiovascular, renal, metabolic, and cancer. Hence, therapeutic strategies to restore a homeostatic oxidative state within the cell are of significant therapeutic interest. [0003] The Bach1 (BTB and CNC homology 1)/Nrf2 (nuclear factor erythroid 2-related factor 2) axis is a master regulator of the cellular antioxidant response, and a proven therapeutic target to counteract diseases driven by oxidative stress (e.g., Nrf2 activator dimethyl fumarate is approved in the U.S. for use in treating relapsing remitting multiple sclerosis and psoriasis). Under homeostatic conditions, Bach1 occupies antioxidant response elements (AREs) in the promoters of diverse genes involved in cellular antioxidant responses, preventing their transcription. In response to oxidative stress, Bach1 dissociates from the AREs allowing binding by the transcription factor Nrf2. This drives the expression of antioxidant response genes including, but not limited to, heme oxygenase-1 (Hmox1). Activation of the Bach1/Nrf2, and consequent Hmox1 expression, is associated with positive outcomes in numerous epidemiological association studies, genetic models and animal models of disease. [0004] One pathway regulated by the Bach1/Nrf2 pathway is inflammasomes. These are large multiprotein complexes that play an important role in both sterile tissue injury and infection. However, due to the potently inflammatory nature of inflammasome derived mediators, complex regulatory mechanisms have evolved to suppress inflammasome activation in the absence of injury or infection. The importance of such mechanisms is highlighted by activating mutations in the inflammasome pathway that leads to an array of autoinflammatory diseases which can be life threatening. Chronic and acute aberrant activation of the inflammasome pathway also contributes to the pathology of a wide range of arthritic, neurodegenerative, neurological, cardiovascular, hematological, dermatological, fibrotic, metabolic, renal, ocular, pulmonary, and systemic inflammatory conditions. [0005] Assembly of the inflammasome complex is under the control of a ‘two-hit’ system whereby two independent signals are required for activation. Signal 1 stimulates transcription of inflammasome related genes, leading to upregulation of the individual components of the inflammasome, as well as the production of the pro-form of the inflammasome substrates interleukin-1ȕ (IL-1ȕ), interleukin-18 (IL-18), and Gasdermin-D within the cytosol. Signal 2 is provided by an array of pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) that are sensed by a family of cytosolic pattern recognition receptors termed nucleotide-binding oligomerization domain-like receptors (NLRs), as well as a few additional inflammasome forming sensors. Binding of the DAMP to its corresponding NLR leads to conformational changes in the NLR allowing self-oligomerization of the receptor. These NLR oligomers then recruit the adapter protein, apoptosis-associated speck-like protein containing a CARD (ASC). This NLR-ASC complex then nucleates formation of an ASC filament, mediated through ASC’s pyrin domain (PYD). The ASC filaments in turn creates a platform for recruitment of caspase-1 leading autocatalytic cleavage and activation, as well nucleating subsequent caspase-1 filament formation mediated through the caspase-1 CARD domain, which is thought to amplify caspase-1 activation. Active caspase-1 then cleaves pro-IL-1ȕ, pro-IL-18, and Gasdermin D into their active forms, releasing the inflammatory mediators from the cell and inducing Gasdermin-D mediated pyroptotic cell death. [0006] Inflammasome formation can be initiated by at least 11 different sensors including Pyrin, numerous NLRs including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4, and NLRC5, the PYHIN family members IFI-16 and AIM2, as well as RIG-I. Conventional approaches to inflammasome inhibition have targeted individual receptors, such as NLRP3, to inhibit a subset of inflammasomes. However, emerging evidence clearly demonstrates that activation of multiple different inflammasome forming receptors is a common pathological feature of many diseases including inflammatory bowel disease, arthritic diseases, and neurodegenerative disorders, among others. Hence, broader pharmaceutical approaches capable of simultaneously inhibiting multiple species of inflammasomes are needed to address pathological inflammasome-dependent inflammation. [0007] One way to achieve broader inflammasome inhibition is to target the shared components of the inflammasome, such as caspase-1 or ASC filaments. Assembly of the inflammasome is induced by a cytosolic sensor (e.g., NLRP3 or AIM2) which detects danger signals associated with infection or sterile injury. Upon sensing these signals, the sensor nucleates formation of long filaments composed of repeating units of the inflammasome adapter protein ASC. These filaments form a scaffold for the recruitment of caspase-1 leading to autoproteolytic activation of the enzyme. The development of active site inhibitors against caspase-1, however, has been significantly hindered by a highly conserved active site shared by all caspases. This feature, combined with the diverse and essential biological roles of other caspase family members, lead to a high degree of cross-reactivity with off-target caspase proteins, leading to unacceptable toxicity. [0008] While the inflammasome plays a protective role against infection and injury, aberrant activation of the complex in the absence of infection or injury contributes to a wide range of inflammatory conditions. Accordingly, the development of compositions and methods that prevent inflammasome driven inflammation is an important challenge. SUMMARY OF THE DISCLOSURE [0009] One aspect of the disclosure provides compounds having the structural formula (I): and pharmaceutically acceptable salts, tautomers, solvates and hydrates thereof, wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; R is H, C₁-C₆ alkyl, phenyl, -(C₁-C₃ alkyl)-phenyl, heteroaryl optionally substituted with methyl, C₃-C₈ cycloalkyl, or -(C₁-C₃ alkyl)-C₃-C₈ cycloalkyl; R¹ is independently halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkoxy), alkoxy(C₁-C₆ alkyl), alkoxy(C₁-C₆ alkoxy), or amino(C₁-C₆ alkyl); R² is H or C₁-C₆ alkyl; each R³ is independently halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -OH, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -C₁-C₆ alkyl-NR⁴R⁵, -CN, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, -(C₁-C₆ alkyl)-aryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heteroaryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R₇, -(C₁-C₆ alkyl)-C₃-C₈ cycloalkyl optionally substituted with one or more R₇, -COH, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), or -CONR⁸R⁹ wherein R⁸ and R⁹ are independently H or C₁-C₆ alkyl wherein each alkyl within R⁸ and R⁹ is independently substituted with one, two or three halogen, cyano, hydroxy, C₁-C₃ alkoxy, amino or mono- or di(C₁-C₃ alkyl)amino, amino-C₁- C₃ alkoxy, mono- or di(C₁-C₃ alkyl)amino-C₁-C₃ alkoxy, hydroxy-C₁-C₃ alkoxy, or C₁- C₆ alkoxy-C₁-C₆ alkoxy, or two R³ together with the atoms to which they are attached, form a heterocycle, the heterocycle optionally substituted with one or more R₇, wherein R⁴ is H or C₁-C₆ alkyl; R⁵ is H, C₁-C₆ alkyl optionally substituted with one or more R₇, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C1-C6 haloalkyl, –(C1-C6 alkyl)-O-C1-C6 alkyl, –(C1-C6 alkyl)-O-C2-C6 alkenyl, or –(C₁-C₆ alkyl)-O-C₂-C₆ alkynyl; each R⁶ is independently halogen, -NO₂, -CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -OH, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -CO₂H, alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁- each R⁷ is independently halogen, -NO₂, -CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -OH, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁- C₆ alkyl)₂, or two R⁷ groups, together with the carbon to which they are attached, form a =O. [0010] In certain embodiments, the compound of formula (I) is not 2-[(1-methyl-1H- benzimidazol-2-yl)amino]-5-benzoxazolecarboxylic acid. [0011] In another aspect, the disclosure provides pharmaceutical compositions comprising a compound (e.g., a compound of formula (I)) as described herein. [0012] In another aspect, the present disclosure provides compounds described herein bind to the transcriptional repressor Bach1. For example, the present disclosure provides for a method of inhibiting Bach1 activity, the method comprising administering to a human subject an effect amount of the compound as otherwise described herein. [0013] Accordingly, in various embodiments as otherwise described herein, the compounds are HO-1 inducers. Accordingly, in another aspect, the present disclosure provides a method of increasing the activity or the amount of HO-1 in a human subject comprising: administering to a human subject an effective amount of the compounds as otherwise described herein, or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition thereof. [0014] Nrf 2 is a transcription factor that regulates HO-1 expression. In another aspect, the present disclosure provides methods of activating transcription factor Nrf2 in human subjects comprising: administering to a human subject an effective amount of the compounds as otherwise described herein, or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition thereof. [0015] In another aspect, the present disclosure provides methods of reducing the amount of reactive oxygen species in human subjects comprising: administering to a human subject an effective amount of the compounds as otherwise described herein, or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition thereof. In various embodiments, the compounds as otherwise described herein are not intrinsically reductive. For example, the compounds may function to reduce the amount of reactive oxygen species through enhancing or suppressing a biological target involved with a natural oxidative stress response. [0016] In another aspect, the disclosure provides methods for treating inflammatory conditions or disorders in a subject, particularly a mammalian subject, and more particularly a human subject. The methods include administering to the subject an effective amount of a compound as described herein. [0017] In another aspect, the disclosure provides intermediates useful to prepare the compounds of formula (I). [0018] Other aspects and embodiments of the disclosure are evident in view of the detailed description provided herein. BRIEF DESCRIPTION OF THE DRAWINGS [0019] The accompanying drawings are included to provide a further understanding of the methods and compositions of the disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiment(s) of the disclosure and, together with the description, serve to explain the principles and operation of the disclosure. [0020] Figure 1 shows inflammasome inhibition activity of the compounds of the disclosure as compared to a control compound, MCC950. DETAILED DESCRIPTION [0021] The disclosure provides compounds, pharmaceutical compositions, methods and uses for treating a variety of diseases associated with inhibiting inflammasome formation. [0022] Accordingly, one aspect of the disclosure provides compounds of formula (I) as described above: [0023] In certain embodiments, the compound of formula (I) is not: 2-[(1-methyl-1H- benzimidazol-2-yl)amino]-5-benzoxazolecarboxylic acid. [0024] In various embodiments, R is H, C₁-C₃ alkyl, phenyl, benzyl, methylpyrazolyl, cyclopropyl, or cyclopropylmethyl. For example, in certain embodiments, R is H or methyl or ethyl, e.g., H or CH₃. In particular embodiments, R is CH₃. [0025] In certain embodiments, each R² is independently H or methyl. For example, in some embodiments, the disclosure provides compounds of formula (I) as described herein, such as of formula: . [0026] One embodiment of the disclosure provides compounds of formula (I) as described herein, wherein m is 1 or 2. In one embodiment, m is 1. For example, such compounds may be of formula: [0027] In certain embodiments, the disclosure provides compounds of formula: . [0028] In certain embodiments, the disclosure provides compounds of formula: . [0029] Another embodiment of the disclosure provides compounds of formula (I) as described herein, wherein R¹ is independently halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl. In certain embodiments, R¹ is independently halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In certain embodiments, R¹ is independently halo, C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In certain embodiments, R¹ is independently halo. [0030] In certain embodiments, the disclosure provides compounds of formula (I) as described herein wherein at least one R¹ is halo (such as fluoro). [0031] In certain embodiments, the disclosure provides compounds of formula: [0032] Another embodiment of the disclosure provides compounds of formula (I) as described herein, wherein R² is H or C₁-C₃ alkyl. In certain embodiments, R² is H or methyl. In certain embodiments, R² is H. [0033] In certain embodiments, the disclosure provides compounds of formula: [0034] One embodiment of the disclosure provides compounds of formula (I) as described herein, wherein n is 1 or 2. In one embodiment, n is 1. For example, such compounds may be of formula: [0035] In certain embodiments, the disclosure provides compounds of formula: [0036] In certain embodiments, the disclosure provides compounds of formula: [0037] Another embodiment of the disclosure provides compounds of formula (I) as described herein, wherein R³ is -C₁-C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, -(C₁-C₆ alkyl)-aryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heteroaryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R₇, -(C₁-C₆ alkyl)-C₃-C₈ cycloalkyl optionally substituted with one or more R₇, -COH, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁-C₆ alkyl)₂, or two R³ together with the atoms to which they are attached, form a heterocycle, the heterocycle optionally substituted with one or more R₇. [0038] In certain embodiments, R³ is -C₁-C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, - (C₁-C₆ alkyl)-aryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heteroaryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R₇, -(C₁-C₆ alkyl)-C₃-C₈ cycloalkyl optionally substituted with one or more R₇, -COH, - CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁-C₆ alkyl)₂. [0039] In certain embodiments, R³ is -C₁-C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, - (C1-C6 alkyl)-heterocyclyl optionally substituted with one or more R7, -COH, -CO2H, -CO2(C1- C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁-C₆ alkyl)₂; or two R³ together with the atoms to which they are attached, form a heterocycle, the heterocycle optionally substituted with one or more R₇. In certain embodiments, R³ is -C₁-C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R₇, -COH, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁-C₆ alkyl)₂. [0040] In certain embodiments of the compounds of formula (I) as described herein, R³ is --C1- C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-OR⁴, or -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R₇. In certain embodiments, R³ is -C₁-C₆ alkyl-NR⁴R⁵. [0041] In certain embodiments of the compounds of formula (I) as described herein, R³ is -CONR⁸R⁹ wherein R⁸ and R⁹ are independently H or C₁-C₆ alkyl wherein each alkyl within R⁸ and R⁹ is independently substituted with one, two or three halogen, cyano, hydroxy, C₁-C₃ alkoxy, amino, mono- or di(C₁-C₃ alkyl)amino, amino-C₁-C₃ alkoxy, mono- or di(C₁-C₃ alkyl)amino-C1-C3 alkoxy, hydroxy-C1-C3 alkoxy, or C1-C6 alkoxy-C1-C6 alkoxy. [0042] In certain embodiments of the compounds of formula (I) as described herein, R³ is -CONR⁸R⁹ wherein R⁸ and R⁹ are independently H or C₁-C₆ alkyl wherein each alkyl within R⁸ and R⁹ is independently substituted with one, two or three halogen, cyano, hydroxy, C₁-C₃ alkoxy, amino, mono- or di(C₁-C₃ alkyl)amino, hydroxy-C₁-C₃ alkoxy, or C₁-C₆ alkoxy-C₁-C₆ alkoxy. [0043] In certain embodiments of the compounds of formula (I) as described herein, R³ is -CONHR⁹ wherein R⁹ is H or C₁-C₆ alkyl wherein the alkyl is substituted with one, two or three halogen, cyano, hydroxy, C₁-C₃ alkoxy, amino, mono- or di(C₁-C₃ alkyl)amino, hydroxy-C₁-C₃ alkoxy, or C₁-C₆ alkoxy-C₁-C₆ alkoxy. [0044] In certain embodiments of the compounds of formula (I) as described herein, R³ is -CONHR⁹ wherein R⁹ is C₁-C₆ alkyl substituted with one, two or three halogen, cyano, hydroxy, C₁-C₃ alkoxy, amino or mono- or di(C₁-C₃ alkyl)amino., [0045] In certain embodiments of the compounds of formula (I) as described herein, R³ is -CONHR⁹ wherein R⁹ is C₁-C₆ alkyl substituted with hydroxy-C₁-C₃ alkoxy or C₁-C₆ alkoxy-C₁- C₆ alkoxy. [0046] In certain embodiments of the compounds of formula (I) as described herein, R³ is -CONHR⁹ wherein R⁹ is C₁-C₆ alkyl substituted with hydroxy-C₁-C₃ alkoxy. [0047] In certain embodiments of the compounds of formula (I) as described herein, R³ is -CONHR⁹ wherein R⁹ is C1-C6 alkyl substituted with C1-C6 alkoxy-C1-C6 alkoxy. [0048] In certain embodiments of the compounds of formula (I) as described herein, R³ is -CONHR⁹ wherein R⁹ is C₁-C₆ alkyl substituted with amino-C₁-C₃ alkoxy. [0049] In certain embodiments of the compounds of formula (I) as described herein, R³ is -CONHR⁹ wherein R⁹ is C₁-C₆ alkyl substituted with mono- or di(C₁-C₃ alkyl)amino-C₁-C₃ alkoxy. [0050] In certain embodiments of the compounds of formula (I) as described herein, R⁴ is C₁- C6 alkyl and R⁵ is C1-C6 alkyl optionally substituted with one or more R7, C2-C6 alkenyl, C2-C6 alkynyl, C₁-C₆ haloalkyl, –(C₁-C₆ alkyl)-O-C₁-C₆ alkyl, –(C₁-C₆ alkyl)-O-C₂-C₆ alkenyl, or –(C₁- C₆ alkyl)-O-C₂-C₆ alkynyl. In certain embodiments, R⁴ is C₁-C₆ alkyl and R⁵ is C₁-C₆ alkyl optionally substituted with one or more R7. In certain embodiments, R⁴ is C1-C3 alkyl and R⁵ is C₁-C₃ alkyl. In certain embodiments, R⁴ is methyl and R⁵ is methyl optionally substituted with one or more R₇. [0051] In certain embodiments of the compounds of formula (I) as described herein, two R³ together with the atoms to which they are attached, form a heterocycle, the heterocycle optionally substituted with one or more R₇. [0052] In particular embodiments of the compounds of formula (I) as described herein, R³ is selected from: [0053] In particular embodiments, the compounds described herein are of formula: , where R is H or CH3; R¹ is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; and R² is H or C1-C3 alkyl. [0054] In particular embodiments, the compounds described herein are of formula: , where R is H or CH₃; R¹ is independently halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and R² is H or C₁-C₃ alkyl. [0055] In other embodiments, the compounds have the formula: . wherein R¹ is fluoro or hydrogen; and R⁴ and R⁵ are independently hydrogen, methyl, ethyl, propyl, isopropyl, propargyloxyethyl, propargyloxymethyl, or propargyl; or R⁴ and R⁵ together with the nitrogen to which they are attached form a 3-7 membered heterocycloalkyl group. [0056] In certain embodiments of the compounds as otherwise described herein, the compound is in the form of a pharmaceutically acceptable salt of a compound as described herein. The person of ordinary skill in the art will appreciate that a variety of pharmaceutically- acceptable salts may be provided, as described in additional detail below. In certain embodiments of the compounds as otherwise described herein, a compound is in the form of a solvate (e.g., a hydrate) of a compound or salt as described herein. The person of ordinary skill in the art will appreciate that a variety of solvates and/or hydrates may be formed. The person of ordinary skill in the art will appreciate that the phrase “optionally in the form of a pharmaceutically acceptable salt thereof, and/or a solvate or hydrate thereof” includes compounds in the form of solvates and hydrates of base compounds or pharmaceutically acceptable salts as described above. But in certain embodiments as described above, the compound is not in the form of a solvate or hydrate. [0057] In certain embodiments, the compound of Formula (I) is: Table 1 or a pharmaceutically acceptable salt thereof. Therapeutic Applications [0058] The disclosure also provides methods of treating various inflammatory conditions, i.e., inflammatory diseases and disorders. These methods include administering to a subject in need of such treatment an effective amount of one or more compounds of the disclosure as described herein (e.g., compounds of formula (I)) or a pharmaceutical composition of the disclosure as described herein. [0059] In certain embodiments, the disclosure provides methods of treating inflammatory condition in a subject thereof, wherein the methods include providing to the subject a compound as otherwise described herein. In certain embodiments as otherwise described herein, the inflammatory condition is an inflammatory bowel disease, an arthritic disease, or a neurodegenerative disorder. In certain embodiments, the inflammatory condition is an infectious disease, autoimmune disease, cancer, metabolic disorder, or neurological disease. [0060] In other embodiments, the inflammatory condition is an autoinflammatory syndrome. In still other embodiments, the inflammatory condition is an inflammasome-related condition. Some conditions and/or diseases may be combinations of the above embodiments, or otherwise fall into multiple categories simultaneously. [0061] In certain embodiments, the diseases and disorders that can be treated according to the methods disclosed herein include, but are not limited to, Adult-Onset Still’s Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Macrophage Activation Syndrome (MAS), Autoinflammation with Infantile Enterocolitic (AIFEC), Bullous Pemphigoid, Pemphigus Vulgaris, Idiopathic Pulmonary Fibrosis (IPF), Non-Alcoholic Steatohepatitis (NASH), Systemic Lupus Erythematosus (SLE), Multiple Sclerosis, Amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease, Parkinson’s Disease, Epilepsy, Traumatic Brain Injury (TBI), Inflammatory Bowel Disease (IBD), Rheumatoid Arthritis (RA), Cryopyrin-Associated Periodic Syndromes (CAPS), Vitiligo, Multiple Self-Healing Palmoplantar Carcinoma (MSPC), Autoimmune Addison’s Disease, Familial Mediterranean Fever (FMF), Autoimmune Thyroiditis, Stroke, Type 2 Diabetes (T2D), Osteoarthritis, Gout, Atherosclerosis, Hidradenitis Suppurativa, Psoriasis, Pyrin Diseases, Sickle Cell Disease, and Autosomal dominant polycystic kidney disease (ADPKD). [0062] In certain embodiments, the disclosure provides methods for treating one or more diseases selected from the following categories: (i) fibrotic diseases, such as those related to the lung (COPD, idiopathic pulmonary fibrosis, sarcoidosis), liver (alcoholic cirrhosis, steatosis, cholestasis, drug induced fibrosis, viral infection), or skin (Scleroderma, psoriasis); (ii) neurodegenerative diseases, such as Friedreich’s ataxia, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis and Charcot-Marie-Tooth syndrome; (iii) cardiovascular disease, such as hypertension, heart failure, hypercholesterolemia, atherosclerosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease, congestive heart failure, acute coronary syndrome, failure of arterial fistula for dialysis and primary pulmonary hypertension, ischemia-reperfusion events; (iv) renal disease, such as diabetic nephropathy, glomerular nephritis, acute tubular necrosis and Autosomal dominant polycystic kidney disease; (v) liver disease, such as drug induced liver toxicity, nonalcoholic steatohepatitis, hepatitis C infection; (vi) eye diseases, such as glaucoma, uveitis, wound healing (after surgery), eye trauma, corneal grafts, macular degeneration, cataracts, light retinopathy, retinopathy of prematurity; (vii) thyroid diseases, such as Graves’ disease, follicular adenoma and papillary and follicular carcinomas; (viii) viral infections, such as HIV, hepatitis B, Hepatitis C, herpesvirus, coronaviruses (e.g., SARS-CoV 2, SARS-CoV, or MERS); and (ix) diabetic conditions, such as type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, pre-diabetes, hyperglycemia and metabolic syndrome as well as pancreatic beta cell loss. [0063] In certain embodiments, the disclosure provides methods of treating inflammatory conditions that result from a viral, e.g., coronavirus (e.g., SARS-CoV 2, SARS-CoV, or MERS) infection, bacterial infection, fungal infection, parasitic infection, or other type of infection, in a human subject and consequently causes cell death, or release of pro-inflammatory cytokines or other inflammatory mediators. [0064] The invention also provides for the use of a compound as described herein in combination with one or more medically effective active compounds for simultaneous, subsequent or sequential administration. Examples of such medically effective ingredients include, but are not limited to, Nrf2 activators, antioxidants, detoxification agents (e.g., metformin). In one embodiment, the invention provides a pharmaceutical composition comprising a compound as described herein and at least one other medically effective ingredients selected from Nrf2 activators, antioxidants, detoxification agents, anti-inflammatory agents, and antidiabetic agents (e.g., metformin). In another embodiment, the invention provides for the use of a compound as described herein in combination with at least one other medically effective ingredients selected from Nrf2 activators, antioxidants, detoxification agents, anti-inflammatory agents, and antidiabetic agents (e.g., metformin) for simultaneous, subsequent or sequential administration. [0065] Examples of Nrf2 activators include sulforaphane, avicins, 15dPGJ2, xanthohumol, curcumin, carnosol, zerumbone, isothiocyanate, Į-lipoic acid, olipraz (4-methyl-5-[2-pyrazinyl]- 1,2-dithiole-3-thione), 1,2-dithiole-3-thione, 2,3-butyl-4-hydroxuanisole, monomethyl fumarate, and dimethyl fumarate (Tefidera). [0066] Examples of antioxidants include vitamin C, vitamin E, carotenoids, retinoids, polyphenols, falvanoids, lignan, selenium, butylated hydroxyanisole, ethylene diamine tetra- acetate, calcium disodium, acetylcysteine, probucol, and tempo. [0067] Examples of the detoxification agents include dimethyl caprol, glutathione, acetylcysteine, methionine, sodium hydrogen carbonate, deferoxamine mesylate, calcium disodium edetate, trientine hydrochloride, penicillamine, and pharmaceutical charcoal. [0068] Without wishing to be bound by theory, it is presently believed that certain compounds of the present disclosure may aid in the treatment of inflammatory conditions by inhibiting caspase-1. Accordingly, in certain embodiments, the present disclosure provides for a method for inhibiting caspase-1 in a subject, wherein the method includes administering a compound as otherwise described herein. In particular, in some embodiments, the inhibition may be through interacting with the CARD domain of caspase-1. Pharmaceutical Compositions and Dosage Forms [0069] A compound as described herein can usefully be provided in the form of a pharmaceutical composition. Such compositions include the compound according to any one of the preceding aspects or embodiments described herein, together with a pharmaceutically acceptable excipient, diluent, or carrier. [0070] The compounds may be formulated in the pharmaceutical composition per se, or in the form of a hydrate, solvate, or pharmaceutically acceptable salt, as previously described. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed. [0071] The pharmaceutical composition can be, for example, in the form of a tablet, a capsule, or a parenteral formulation, but the person of ordinary skill in the art will appreciate that the compound can be provided in a wide variety of pharmaceutical compositions. [0072] The compounds of the disclosure can be administered, for example, orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing one or more pharmaceutically acceptable carriers, diluents or excipients. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. A medicament including a compound of the disclosure can be provided in any appropriate of the formulations and dosage forms as described herein. [0073] Pharmaceutical compositions can be made using the presently disclosed compounds. For example, in one embodiment, a pharmaceutical composition includes a pharmaceutically acceptable carrier, diluent or excipient, and compound as described above with reference to any one of structural formulae. [0074] In the pharmaceutical compositions disclosed herein, one or more compounds of the disclosure may be present in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and, if desired, other active ingredients. The pharmaceutical compositions containing compounds of the disclosure may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. [0075] Compositions intended for oral use can be prepared according to any suitable method for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or coated by known techniques. In some cases, such coatings can be prepared by suitable techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material, such as, glyceryl monostearate or glyceryl distearate, can be employed. [0076] Formulations for oral use can also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Formulations for oral use can also be presented as lozenges. [0077] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. [0078] Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin, or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti- oxidant such as ascorbic acid. [0079] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, can also be present. [0080] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example, gum acacia or gum tragacanth, naturally- occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents. [0081] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not water. In other embodiments, the water comprises less than 50% of the composition. In some embodiments, compositions comprising less than 50% water have at least 1%, 2%, 3%, 4% or 5% water. In other embodiments, the water content is present in the composition in a trace amount. [0082] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not alcohol. In other embodiments, the alcohol comprises less than 50% of the composition. In some embodiments, compositions comprising less than 50% alcohol have at least 1%, 2%, 3%, 4% or 5% alcohol. In other embodiments, the alcohol content is present in the composition in a trace amount. [0083] Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring, and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [0084] Compounds of the disclosure can also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. [0085] Compounds of the disclosure can also be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. [0086] The compositions can be formulated in a unit dosage form of the active ingredient. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. [0087] The compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. [0088] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein. [0089] The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [0090] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. [0091] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. [0092] The therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose response curves derived from in vitro or animal model test systems. [0093] The compounds described herein can also be formulated in combination with or administered sequentially with one or more additional active ingredients which can include any pharmaceutical agent such as antiviral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like. [0094] The person of ordinary skill in the art will formulate a compound as described into pharmaceutical formulations herein. For example, based on the physicochemical properties of the compound, one of ordinary skill in the art will recognize a pharmaceutically effective amount of the compound, and the desired route of administration. Definitions [0095] Terms used herein may be preceded and/or followed by a single or a double dash, to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond or a pair of single bonds in the case of a spiro-substituent. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “left to right” with reference to the chemical structure referred to unless a dash indicates otherwise. For example, arylalkyl, arylalkyl-, and -alkylaryl indicate the same functionality. [0096] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety can refer to a monovalent radical (e.g., CH₃-CH₂-), in some circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH₂- CH₂-), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene). All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S). Nitrogens in the presently disclosed compounds can be hypervalent, e.g., an N-oxide or tetrasubstituted ammonium salt. On occasion a moiety may be defined, for example, as -B-(A)_a, wherein a is 0 or 1. In such instances, when a is 0 the moiety is -B and when a is 1 the moiety is -B-A. [0097] As used herein, the term “alkyl” includes a saturated hydrocarbon having a designed number of carbon atoms, such as 1 to 10 carbons (i.e., inclusive of 1 and 10), 1 to 8 carbons, 1 to 6 carbons, 1 to 3 carbons, or 1, 2, 3, 4, 5 or 6. Alkyl group may be straight or branched and depending on context, may be a monovalent radical or a divalent radical (i.e., an alkylene group). For example, the moiety “-(C₁C₆ alkyl)-O-” signifies connection of an oxygen through an alkylene bridge having from 1 to 6 carbons and C₁-C₃ alkyl represents methyl, ethyl, and propyl moieties. Examples of “alkyl” include, for example, methyl, ethyl, propyl, isopropyl, butyl (including iso-, sec- and tert-butyl), pentyl, and hexyl. [0098] The term “alkoxy” represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of “alkoxy” include, for example, methoxy, ethoxy, propoxy, and isopropoxy. [0099] The term “alkenyl” as used herein, unsaturated hydrocarbon containing from 2 to 10 carbons (i.e., inclusive of 2 and 10), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5 or 6, unless otherwise specified, and containing at least one carbon-carbon double bond. Alkenyl group may be straight or branched and depending on context, may be a monovalent radical or a divalent radical (i.e., an alkenylene group). For example, the moiety “-(C₂-C₆ alkenyl)-O-” signifies connection of an oxygen through an alkenylene bridge having from 2 to 6 carbons. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2- methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3- decenyl, and 3,7-dimethylocta-2,6-dienyl. [0100] The term “alkynyl” as used herein, unsaturated hydrocarbon containing from 2 to 10 carbons (i.e., inclusive of 2 and 10), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5 or 6 unless otherwise specified, and containing at least one carbon-carbon triple bond. Alkynyl group may be straight or branched and depending on context, may be a monovalent radical or a divalent radical (i.e., an alkynylene group). For example, the moiety “-(C₂-C₆ alkynyl)-O-” signifies connection of an oxygen through an alkynylene bridge having from 2 to 6 carbons. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. [0101] The term “aryl” represents an aromatic ring system having a single ring (e.g., phenyl) which is optionally fused to other aromatic hydrocarbon rings or nonaromatic hydrocarbon or heterocycle rings. “Aryl” includes ring systems having multiple condensed rings and in which at least one is carbocyclic and aromatic, (e.g., 1,2,3,4tetrahydronaphthyl, naphthyl). Examples of aryl groups include phenyl, 1naphthyl, 2naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl, and 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. “Aryl” also includes ring systems having a first carbocyclic, aromatic ring fused to a nonaromatic heterocycle, for example, 1H-2,3dihydrobenzofuranyl and tetrahydroisoquinolinyl. The aryl groups herein are unsubstituted or, when specified as “optionally substituted”, can unless stated otherwise be substituted in one or more substitutable positions with various groups as indicated. [0102] The terms “halogen” or "halo" indicate fluorine, chlorine, bromine, and iodine. In certain embodiments of each and every embodiment as otherwise described herein, the term “halogen” or “halo” refers to fluorine or chlorine. In certain embodiments of each and every embodiment described herein, the term “halogen” or “halo” refers to fluorine. The term “fluoroalkyl” indicates an alkyl group (i.e., as otherwise described herein) that is substituted with at least one fluorine. “Fluoroalkyl” or “fluorinated alkyl” includes alkyl groups substituted with one or multiple fluorines, such as perfluoroalkyl groups. Examples of fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoroprop-2-yl and 2,2,3,3,3-pentafluoroprop-1-yl. [0103] The term “heteroaryl” refers to an aromatic ring system containing at least one aromatic heteroatom selected from nitrogen, oxygen and sulfur in an aromatic ring. Most commonly, the heteroaryl groups will have 1, 2, 3, or 4 heteroatoms. The heteroaryl may be fused to one or more non-aromatic rings, for example, cycloalkyl or heterocycloalkyl rings, wherein the cycloalkyl and heterocycloalkyl rings are described herein. In one embodiment of the present compounds the heteroaryl group is bonded to the remainder of the structure through an atom in a heteroaryl group aromatic ring. In another embodiment, the heteroaryl group is bonded to the remainder of the structure through a non-aromatic ring atom. Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, isoindolinyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, benzisoxazinyl, benzoxazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridinyl-N-oxide, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. In certain embodiments, each heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N- oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. The heteroaryl groups herein are unsubstituted or, when specified as “optionally substituted”, can unless stated otherwise be substituted in one or more substitutable positions with various groups, as indicated. [0104] The term “heterocycloalkyl” refers to a non-aromatic ring or ring system containing at least one heteroatom that is preferably selected from nitrogen, oxygen and sulfur, wherein said heteroatom is in a non-aromatic ring. The heterocycloalkyl may have 1, 2, 3 or 4 heteroatoms. The heterocycloalkyl may be saturated (i.e., a heterocycloalkyl) or partially unsaturated (i.e., a heterocycloalkenyl). Heterocycloalkyl includes monocyclic groups of three to eight annular atoms as well as bicyclic and polycyclic ring systems, including bridged and fused systems, wherein each ring includes three to eight annular atoms. The heterocycloalkyl ring is optionally fused to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings. In certain embodiments, the heterocycloalkyl groups have from 3 to 7 members in a single ring. In other embodiments, heterocycloalkyl groups have 5 or 6 members in a single ring. In some embodiments, the heterocycloalkyl groups have 3, 4, 5, 6 or 7 members in a single ring. Examples of heterocycloalkyl groups include, for example, azabicyclo[2.2.2]octyl (in each case also “quinuclidinyl” or a quinuclidine derivative), azabicyclo[3.2.1]octyl, 2,5- diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, 3,4-dihydroisoquinolin-2(1H)-yl, isoindolindionyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. Especially desirable heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl, tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl, Ȗ-butyrolactonyl (i.e., an oxo-substituted tetrahydrofuranyl), Ȗ-butryolactamyl (i.e., an oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindionyl, piperazinonyl. The heterocycloalkyl groups herein are unsubstituted or, when specified as “optionally substituted”, can unless stated otherwise be substituted in one or more substitutable positions with various groups, as indicated. [0105] The term “cycloalkyl” refers to a nonaromatic carbocyclic ring or ring system, which may be saturated (i.e., a cycloalkyl) or partially unsaturated (i.e., a cycloalkenyl). The cycloalkyl ring optionally fused to or otherwise attached (e.g., bridged systems) to other cycloalkyl rings. Certain examples of cycloalkyl groups present in the disclosed compounds have from 3 to 7 members in a single ring, such as having 5 or 6 members in a single ring. In some embodiments, the cycloalkyl groups have 3, 4, 5, 6 or 7 members in a single ring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl and bicyclo[2.2.1]heptane. The cycloalkyl groups herein are unsubstituted or, when specified as “optionally substituted”, may be substituted in one or more substitutable positions with various groups, as indicated. [0106] The term “ring system” encompasses monocycles, as well as fused and/or bridged polycycles. [0107] The term “oxo” means a doubly bonded oxygen, sometimes designated as =O or for example in describing a carbonyl “C(O)” may be used to show an oxo substituted carbon. [0108] The term “substituted,” when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below, unless specified otherwise. [0109] As used herein, the phrase “pharmaceutically acceptable salt” refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC(CH₂)_nCOOH where n is 0-4, and the like. Nontoxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art will recognize a wide variety of nontoxic pharmaceutically acceptable addition salts. [0110] As used herein, "tautomer" refers to isomers of a compound that exist in equilibrium and differ from one another in the position and/or electron distribution of the protons. Certain compounds disclosed herein may exist in tautomeric form and all tautomeric forms of such compounds are within the scope of this disclosure. [0111] One of ordinary skill in the art of medicinal chemistry also will appreciate that the disclosed structures are intended to include isotopically enriched forms of the present compounds. As used herein “isotopes” includes those atoms having the same atomic number but different mass numbers. As is known to those of skill in the art, certain atoms, such as hydrogen occur in different isotopic forms. For example, hydrogen includes three isotopic forms, protium, deuterium and tritium. As will be apparent to those of skill in the art upon consideration of the present compounds, certain compounds can be enriched at a given position with a particular isotope of the atom at that position. For example, compounds having a fluorine atom, may be synthesized in a form enriched in the radioactive fluorine isotope ¹⁸F. Similarly, compounds may be enriched in the heavy isotopes of hydrogen: deuterium and tritium; and similarly can be enriched in a radioactive isotope of carbon, such as ¹³C. Such isotopic variant compounds undergo different metabolic pathways and can be useful, for example, in studying the ubiquitination pathway and its role in disease. Of course, in certain embodiments, the compound has substantially the same isotopic character as naturally- occurring materials. [0112] One of ordinary skill in the art of chemistry will also appreciate that the disclosed structures, unless otherwise indicated are intended to include all possible stereoisomers of the claimed molecule, including mixtures of certain or all stereoisomers. However, compounds drawn with certain stereochemistry at one or more stereocenters are intended to have the indicated stereochemistry. Compounds and stereocenters drawn with ambiguous stereochemistry are meant to convey any stereoisomer or mixture thereof, e.g., a racemic mixture of compounds or a purified subset of stereoisomers. [0113] As used herein, the terms “individual,” “patient,” or “subject” are used interchangeably, refers to any animal, including mammals, preferably humans. [0114] As used herein, the phrase “therapeutically effective amount” or “effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. [0115] In certain embodiments, an effective amount can be an amount suitable for (i) inhibiting the progression the disease; (ii) prophylactic use for example, preventing or limiting development of a disease, condition or disorder in an individual who may be predisposed or otherwise at risk to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (iii) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; (iv) ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease; or (v) eliciting the referenced biological effect. [0116] As used here, the terms “treatment” and “treating” mean (i) ameliorating the referenced disease state, condition, or disorder (or a symptom thereof), such as, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease or symptom thereof, or inhibiting the progression of disease; or (ii) eliciting the referenced biological effect (e.g., inhibiting inflammasome formation or function, or inhibition of IL-1ȕ). Methods of Preparation [0117] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978). [0118] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as HPLC, preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically, the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, New York, 1969. [0119] During any of the processes for preparation of the subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry,” Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis,” Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie,” Houben-Weyl, 4.sup.th edition, Vol.15/l, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine,” Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and/or in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate,” Georg Thieme Verlag, Stuttgart 1974. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. [0120] A “leaving group” as used herein (e.g., suitable as LG) refers to a moiety of a reactant (e.g., the alkylhalogenide of the disclosure) that is displaced from the first reactant in the chemical reaction. A comprehensive list of suitable leaving groups can be found in J. March, Advanced Organic Chemistry, John Wiley and Sons, N.Y. (2013). Examples of suitable leaving groups include, but are not limited to, halogen (such as Cl or Br), acetoxy, and sulfonyloxy groups (such as methyl sulfonyloxy, trifluoromethylsulfonyloxy (“triflate”), p-toluenesulfonyloxy (“tosylate”)). EXAMPLES [0121] The compounds as disclosed herein can be prepared using procedures and methods known to the person of ordinary skill in the art and, for example, the General Reaction Schemes and Examples as described herein. One of skill in the art can adapt the reaction sequences of the schemes and as provided herein to fit the desired target molecule. Of course, in certain situations, one of skill in the art will use different reagents to affect one or more of the individual steps or to use protected versions of certain of the substituents. Additionally, one skilled in the art would recognize that compounds of the disclosure can be synthesized using different routes altogether. For example, the person of ordinary skill in the art may adapt the procedures described herein and/or other procedures familiar to the person of ordinary skill in the art to make the compounds described herein. [0122] General Reaction Scheme 1: Preparation of Benzimidazole Derivatives [0123] General Reaction Scheme 2: Preparation of Benzimidazole-Benzoxazole Derivatives [0124] The preparation of the compounds of the disclosure is illustrated further by the following examples, which are not to be construed as limiting the disclosure in scope or spirit to the specific procedures and compounds described therein. [0125] Example 1 Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine [0126] Step 1: Synthesis of 4-fluoro-N-methyl-2-nitroaniline [0127] To 1,4-difluoro-2-nitrobenzene (20 g, 126 mmol) is added aqueous methylamine (120 mL, 377 mmol) at room temperature and allowed to stir for 5 h in a sealed tube. The progress of the reaction is monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture is quenched with ice-cold water (100 mL) and stirred for 10 min. Solid precipitates out and is filtered and dried over vacuum to afford crude 4-fluoro-N-methyl-2- nitroaniline (18 g, 84%) as an orange solid. [0128] Step 2: Synthesis of 4-fluoro-N1-methylbenzene-1,2-diamine [0129] To a stirred solution of 4-fluoro-N-methyl-2-nitroaniline (18 g, 106 mmol) in ethyl acetate (90 mL) and DM water (90 mL) at room temperature are added zinc dust (69.2 g, 1.06 mol) and ammonium chloride (84.9 g, 1.59 mol). The resulting reaction mixture is stirred for 3 h at room temperature. The progress of the reaction is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is filtered through a celite bed, and the celite bed is washed with ethyl acetate (2 x 50 mL). The resulting filtrate is diluted in demineralized (DM) water (300 mL) and extracted with ethyl acetate (2 x 250 mL). The organic layer is separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford crude compound 4-fluoro-N1-methylbenzene-1,2-diamine (14 g, 94%) as a brown solid. [0130] Step 3: Synthesis of 5-fluoro-1-methyl-1H-benzo[d]imidazol-2-amine [0131] To a stirred solution of 4-fluoro-N1-methylbenzene-1,2-diamine (10 g, 71.3 mmol) in acetonitrile (30 mL) and water (10 mL) at room temperature is added cyanogen bromide (18.9 g, 178 mmol). The reaction mixture is stirred for 16 h at room temperature. The progress of the reaction is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is concentrated to obtain a crude product, which is diluted with DM water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The aqueous layer is basified to pH ~12-14 using 1N sodium hydroxide solution (30 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers are separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford 5-fluoro-1-methyl-1H-1,3-benzodiazol-2-amine (11.5 g, 97%) as brown solid. [0132] Step 4: Synthesis of methyl benzo[d]oxazole-5-carboxylate [0133] To a stirred solution of methyl 3-amino-4-hydroxybenzoate (5 g, 29.9 mmol) in triethyl orthoformate (50 mL) is added 4-methylbenzene-1-sulfonic acid (0.5 g, 2.9 mmol) at room temperature. The reaction mixture is heated to 100 °C for 16 h in a sealed tube. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to afford a crude product. The crude product is purified by flash column chromatography using 0-30% ethyl acetate in n-heptane as eluent to afford methyl 1,3-benzoxazole-5-carboxylate (4 g, 75%) as a white solid. [0134] Step 5: Synthesis of methyl 2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)amino)benzo[d]oxazole-5-carboxylate [0135] To a stirred solution of methyl 1,3-benzoxazole-5-carboxylate (2.4 g, 13.5 mmol) in tetrahydrofuran (24 mL) are added lithium(1+) 2-methylpropan-2-olate (3.25 g, 40.6 mmol) and iodine (2.58 g, 20.3 mmol) at room temperature. The reaction mixture is allowed to stir for 10 min, and then 5-fluoro-1-methyl-1H-1,3-benzodiazol-2-amine (3.36 g, 20.3 mmol) is added, after which the reaction mixture is stirred for 2 h at room temperature. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers are washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford a crude compound. The crude compound is purified by flash column chromatography using 0-60% ethyl acetate in n-heptane as eluent to afford methyl 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol- 2-yl)amino]-1,3-benzoxazole-5-carboxylate (1.6 g, Crude). [0136] Step 6: Synthesis of (2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)amino)benzo[d]oxazol-5-yl) methanol [0137] To a stirred solution of methyl 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]- 1,3-benzoxazole-5-carboxylate (1.6 g, 4.7 mmol) in tetrahydrofuran (20 mL) is added 1M lithium aluminum hydride in THF (7.05 mL, 7.05 mmol) at room temperature. The reaction mixture is stirred for 2 h at room temperature. The progress of the reaction is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers are washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 0-10% methanol in dichloromethane as eluent to afford {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2- yl)amino]-1,3-benzoxazol-5-yl}methanol (1.2 g, 82%) as an off-white solid. [0138] Step 7: Synthesis of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine [0139] To a stirred solution of {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3- benzoxazol-5-yl}methanol (1.2 g, 3.84 mmol) in dimethylformamide (12 mL) is added thionyl chloride (307 μL, 4.23 mmol) at 0 °C, and the reaction mixture is stirred for 2 h at 0 °C. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is basified (pH ~ 8) using saturated potassium carbonate solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers are washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- 1,3-benzoxazol-2-amine (950 mg, Crude) as a pale yellow solid. [0140] Step 8: Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H- benzo[d]imidazol-2-yl)benzo [d]oxazol-2-amine [0141] To a stirred solution of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- 1,3-benzoxazol-2-amine (950 mg, 2.87 mmol) in dimethylformamide (15 mL) are added dimethylamine hydrogen chloride (351 mg, 4.31 mmol) and potassium carbonate (1.19 g, 8.62 mmol) at room temperature. The reaction mixture is stirred at 60 °C for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is diluted with DM water (60 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers are washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by reverse phase prep HPLC: [Column: ZORBAX Eclipse C18 (150 mm x 21.2 mm; 7 μm); Flow: 19 mL/min; mobile phase (A) 0.1% ammonia in water; mobile phase (B) acetonitrile] to afford Example 1 (5-[(dimethylamino)methyl]-N-(5- fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine) (380 mg, 38%) as an off- white solid. LCMS (ES) m/z = 340.3 [M+H]⁺. [0142] Example 2 Synthesis of 5-{[ethyl(methyl)amino]methyl}-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- 1,3-benzoxazol-2-amine [0143] Example 2 is synthesized in an analogous manner to Example 1, except that N- methylaminoethane is used in Step 8. LCMS (ES) m/z = 352.2 [M-H]^–. [0144] Example 3 Synthesis of 5-[(diethylamino)methyl]-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3- benzoxazol-2-amine [0145] Example 3 is synthesized in an analogous manner to Example 1, except that N,N- diethylamine is used in Step 8. LCMS (ES) m/z = 366.3 [M-H]^–. [0146] Example 4 Synthesis of 5-[(dimethylamino)methyl]-N-[5-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-1,3-benzoxazol-2-amine [0147] Example 4 is synthesized in an analogous manner to Example 1, except that 1- methyl-1H-pyrazol-4-amine is used in Step 1. LCMS (ES) m/z = 406.3 [M+H]⁺. [0148] Example 5 Synthesis of 5-(azetidin-1-ylmethyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine [0149] Example 5 is synthesized in an analogous manner to Example 1, except that azetidine is used in Step 8. LCMS (ES) m/z = 352.2 [M+H]⁺. [0150] Example 6 Synthesis of 5-[(dimethylamino)methyl]-N-(1-methyl-1H-1,3-benzodiazol-2-yl)-1,3- benzoxazol-2-amine [0151] Example 6 is synthesized in an analogous manner to Example 1, except that 1-fluoro- 2-nitrobenzene is used in Step 1. LCMS (ES) m/z = 322.3 [M+H]⁺. [0152] Example 7 Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine [0153] Example 7 is synthesized in an analogous manner to Example 1, except that methyl 4-amino-3-hydroxybenzoate is used in Step 4. LCMS (ES) m/z = 340.2 [M+H]⁺. [0154] Example 8 Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-[(pyrrolidin-1-yl)methyl]-1,3- benzoxazol-2-amine [0155] Example 8 is synthesized in an analogous manner to Example 1, except that pyrrolidine is used in Step 8. LCMS (ES) m/z = 366.2 [M+H]⁺. [0156] Example 9 Synthesis of 5-[(dimethylamino)methyl]-N-(5-fluoro-1-phenyl-1H-1,3-benzodiazol-2-yl)-1,3- benzoxazol-2-amine [0157] Example 9 is synthesized in an analogous manner to Example 1, except that phenylamine is used in Step 1. LCMS (ES) m/z = 402.3[M+H]⁺. [0158] Example 10 Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-({methyl[2-(prop-2-yn-1- yloxy)ethyl]amino}methyl)-1,3-benzoxazol-2-amine [0159] Step 1: Synthesis of tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate [0160] To a stirred solution of 2-(methylamino)ethan-1-ol (0.5 g, 6.66 mmol) in dichloromethane (5 mL) are added triethylamine (1.86 mL, 13.3 mmol) and di-tert-butyl dicarbonate (1.45 g, 6.66 mmol) at 0 °C. The resulting reaction mixture is allowed to stir at room temperature for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude. The crude is diluted with DM water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers are separated and washed with DM water (10 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford a crude. The crude is purified by flash column chromatography using 30-40% ethyl acetate in n-heptane as eluents to afford tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (0.8 g, 69%) as a colorless liquid. [0161] Step 2: Synthesis of tert-butyl N-methyl-N-[2-(prop-2-yn-1-yloxy)ethyl]carbamate [0162] To a solution of sodium hydride (60% dispersion in mineral oil) (21.9 mg, 571 μmol) in dimethylformamide (3 mL) at 0 °C is added tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (0.8 g, 4.57 mmol) (diluted in dimethylformamide 4 mL) dropwise to the reaction mixture. After 20 min, 3-bromoprop-1-yne (815 mg, 6.85 mmol) is added dropwise to the reaction mixture at 0 °C. The resulting reaction mixture is allowed to stir from 0 °C to room temperature over 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is quenched slowly with saturated ammonium chloride solution (10 mL) at 0 °C and extracted with ethyl acetate (2 x 20 mL). The combined organic layers are separated, dried over sodium sulphate, and concentrated to afford a crude compound. The crude compound is purified by flash column chromatography using 10-15% ethyl acetate in n- heptane as eluents to afford tert-butyl N-methyl-N-[2-(prop-2-yn-1-yloxy)ethyl]carbamate (750 mg, 77%) as a yellow oil. [0163] Step 3: Synthesis of methyl[2-(prop-2-yn-1-yloxy)ethyl]amine hydrochloride [0164] To a stirred solution of tert-butyl N-methyl-N-[2-(prop-2-yn-1-yloxy)ethyl]carbamate (0.7 g, 4.22 mmol) in dichloromethane (8 mL, 125 mmol) is added 4.0 M hydrogen chloride in 1,4- dioxane (615 mg, 16.9 mmol) at 0 °C. The resulting reaction mixture is allowed to stir from 0 °C to room temperature over 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude compound. The crude compound is washed with n-pentane (5 mL) followed by diethyl ether (5 mL) and acetonitrile (5 mL) to afford methyl[2-(prop-2-yn-1- yloxy)ethyl]amine hydrochloride (510 mg, 81%) as a white solid. [0165] Step 4: Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-({methyl[2-(prop- 2-yn-1-yloxy)ethyl]amino}methyl)-1,3-benzoxazol-2-amine [0166] To a stirred solution of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- 1,3-benzoxazol-2-amine (i.e., the intermediate product in Step 7 of the synthesis of Example 1) (0.2 g, 605 μmol) in N,N-dimethylformamide (3 mL) are added potassium carbonate (167 mg, 1.21 mmol) and methyl[2-(prop-2-yn-1-yloxy)ethyl]amine hydrochloride (136 mg, 907 μmol) in a sealed tube at room temperature. The resulting reaction mixture is allowed to stir at 80 °C for 2 h in a sealed tube. The progress of the reaction is monitored with TLC and LCMS. After completion of the reaction, the reaction mixture is quenched with DM water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford a crude compound. The crude compound is purified by flash column chromatography using 7-10% methanol in dichloromethane as eluents to afford Example 10 (N-(5-fluoro-1-methyl-1H-1,3- benzodiazol-2-yl)-5-({methyl[2-(prop-2-yn-1-yloxy)ethyl]amino}methyl)-1,3-benzoxazol-2- amine) as a brown solid (50 mg, 20%). LCMS (ES) m/z = 408.3 [M+H]⁺. [0167] Example 11 Synthesis of 5-((dimethylamino)methyl)-N-(6-fluoro-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine [0168] Example 11 can be synthesized essentially according to procedures set forth in the preceding examples and Reaction Schemes 1 and 2. [0169] Example 12 Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-{[methyl(propyl)amino]methyl}- 1,3-benzoxazol-2-amine [0170] Example 12 is synthesized in an analogous manner to Example 1, except that N- methylpropan-1-amine is used in Step 8. LCMS (ES) m/z = 368.3 [M+H]⁺. [0171] Example 13 Synthesis of (2-((5-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2- yl)amino)benzo[d]oxazol-5-yl)methanol

[0172] Example 13 is synthesized in Step 6 of the synthesis of Example 4. LCMS (ES) m/z = 379.2 [M+H]⁺. [0173] Example 14 Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-propyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine [0174] Example 14 is synthesized in an analogous manner to Example 1, except that 1- aminopropane is used in Step 1. LCMS (ES) m/z = 367.2 [M-H]^–. [0175] Example 15 Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-[(morpholin-4-yl)methyl]-1,3- benzoxazol-2-amine [0176] Example 15 is synthesized in an analogous manner to Example 1, except that morpholine is used in Step 8. LCMS (ES) m/z = 380.2 [M-H]-. [0177] Example 16 and Example 20 Synthesis of N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-7-methyl-7,8-dihydro-6H- oxazolo[4,5-e]isoindol-2-amine (Example 16) and N-(5-fluoro-1-methyl-1H-benzo[d]imidazol- 2-yl)-6-methyl-6,7-dihydro-5H-oxazolo[4,5-f]isoindol-2-amine (Example 20) p Example 20 [0178] Step 1: Synthesis of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindoline-2-carboxylate [0179] To a stirred solution of tert-butyl 5-bromo-2,3-dihydro-1H-isoindole-2-carboxylate (5 g, 16.8 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (8.52 g, 33.5 mmol) in 1,4-dioxane (100 mL) is added potassium acetate (6.58 g, 67.1 mmol) at room temperature. The reaction mixture is degassed with nitrogen atmosphere for 10 min, and then tetrakis(triphenylphosphane) palladium (1.94 g, 1.68 mmol) is added. The reaction mixture is stirred at 80 °C for 16 h. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is filtered through celite bed, and the solvent is concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 0-20% ethyl acetate in n-heptane as eluents to afford tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,3-dihydro-1H-isoindole-2-carboxylate (5.5 g, 95%) as a white solid. [0180] Step 2: Synthesis of tert-butyl 5-hydroxyisoindoline-2-carboxylate [0181] To a stirred solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3- dihydro-1H-isoindole-2-carboxylate (5 g, 14.5 mmol) in ethyl acetate (60 mL) is added hydrogen peroxide (5.66 mL, 72.4 mmol) at room temperature and stirred for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is quenched with saturated sodium thiosulphate solution (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers are washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 0-30% ethyl acetate in n-heptane as eluents to afford tert-butyl 5-hydroxy-2,3-dihydro-1H-isoindole-2-carboxylate (3.4 g, 100%) as a white solid. [0182] Step 3: Synthesis of regioisomeric mixtures of 4-nitro-2,3-dihydro-1H-isoindol-5-ol, trifluoroacetic acid; and 6-nitro-2,3-dihydro-1H-isoindol-5-ol, trifluoroacetic acid [0183] To a stirred solution of tert-butyl 5-hydroxy-2,3-dihydro-1H-isoindole-2-carboxylate (3.4 g, 14.5 mmol) in trifluoroacetic acid (40 mL) is added sodium nitrate (3.07 g, 36.1 mmol) portion wise at 0 °C. The reaction mixture is warmed to room temperature and stirred for 1 h. The progress of the reaction is monitored by LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain regioisomeric mixtures of 4-nitro- 2,3-dihydro-1H-isoindol-5-ol, trifluoroacetic acid; and 6-nitro-2,3-dihydro-1H-isoindol-5-ol, trifluoroacetic acid (4.0 g, crude) as a brown liquid. The crude material is used in the next step without purification. [0184] Step 4: Synthesis of a regioisomeric mixture of 2-methyl-4-nitroisoindolin-5-ol and 2- methyl-6-nitroisoindolin-5-ol [0185] To a stirred solution of regioisomeric mixtures of 4-nitro-2,3-dihydro-1H-isoindol-5-ol, trifluoroacetic acid; and 6-nitro-2,3-dihydro-1H-isoindol-5-ol, trifluoroacetic acid (4.0 g, 13.6 mmol) in methanol (40 mL) are added 37% formaldehyde in water (2.02 mL, 27.2 mmol), sodium acetate (2.23 g, 27.2 mmol), and acetic acid (0.5 mL) at 0 °C. The reaction mixture is stirred for 15 min, and sodium cyanoborohydride (1.71 g, 27.2 mmol) is added to the reaction mixture. The reaction mixture is then stirred for 2 h at room temperature. The progress of the reaction is monitored by LCMS. After completion of the reaction, the reaction mixture is quenched with DM water (100 mL) and extracted with 5% methanol in dichloromethane (2 x 100 mL). The combined organic layers are washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 0-10% methanol in dichloromethane as eluents to afford a regioisomeric mixture of 2- methyl-4-nitro-2,3-dihydro-1H-isoindol-5-ol and 2-methyl-6-nitro-2,3-dihydro-1H-isoindol-5-ol (2.0 g, 76%) as a brown solid. [0186] Step 5: Synthesis of regioisomeric mixture of 6-amino-2-methyl-2,3-dihydro-1H- isoindol-5-ol and 4-amino-2-methyl-2,3-dihydro-1H-isoindol-5-ol [0187] To a stirred solution of a regioisomeric mixture 2-methyl-6-nitro-2,3-dihydro-1H- isoindol-5-ol and 2-methyl-4-nitro-2,3-dihydro-1H-isoindol-5-ol (1.0g, 5.15 mmol) in methanol (15 mL) is added 10% palladium on carbon (0.4 g, 3.76 mmol) under nitrogen atmosphere. The reaction mixture is degassed with H₂ atmosphere and stirred under H₂ atmosphere for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is filtered through celite bed, and the filtrate is concentrated under reduced pressure to afford a regioisomeric mixture of 6-amino-2-methyl-2,3-dihydro-1H- isoindol-5-ol and 4-amino-2-methyl-2,3-dihydro-1H-isoindol-5-ol (0.8 g, 95%) as a brown solid. [0188] Step 6: Synthesis of regioisomeric mixture 6-methyl-5H,6H,7H-[1,3]oxazolo[4,5- f]isoindol-2-amine and 7-methyl-6H,7H,8H-[1,3]oxazolo[4,5-e]isoindol-2-amine [0189] To a stirred solution of 6-amino-2-methyl-2,3-dihydro-1H-isoindol-5-ol and 4-amino-2- methyl-2,3-dihydro-1H-isoindol-5-ol (0.8 g, 4.87 mmol) in methanol (6 mL) and DM water (2 mL) is added cyanogen bromide (1.03 g, 9.74 mmol) at 0 °C. The reaction mixture is stirred for 16 h at room temperature. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure, diluted with DM water (20 mL), and extracted with ethyl acetate (2 x 30 mL). The combined aqueous layers are basified with 1N sodium hydroxide solution (20 mL) and extracted with 5% methanol in dichloromethane (2 x 50 mL). The combined organic layers are washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford a regioisomeric mixture of 6-methyl-6,7- dihydro-5H-oxazolo[4,5-f]isoindol-2-amine and 7-methyl-7,8-dihydro-6H-oxazolo[4,5- e]isoindol-2-amine (0.5 g, 54%) as an off-white solid. [0190] Step 7: Synthesis of N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-7-methyl-7,8- dihydro-6H-oxazolo [4,5-e]isoindol-2-amine, trifluoroacetic acid salt and N-(5-fluoro-1-methyl- 1H-benzo[d]imidazol -2-yl)-6-methyl-6,7-dihydro-5H-oxazolo[4,5-f]isoindol-2-amine, trifluoroacetic acid salt [0191] To a stirred solution of a regioisomeric mixture of 7-methyl-7,8-dihydro-6H-oxazolo[4,5- e]isoindol-2-amine and 6-methyl-6,7-dihydro-5H-oxazolo[4,5-f]isoindol-2-amine (250 mg, 1.32 mmol) in dimethyl sulfoxide (6 mL) is added 2-chloro-5-fluoro-1-methyl-1H-benzo[d]imidazole (268 mg, 1.45 mmol), cesium fluoride (602 mg, 3.96 mmol) at room temperature. The reaction mixture is stirred at 100 °C for 16 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is quenched with DM water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers are washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude compound. The crude compound purified by reverse phase prep HPLC [column: Inertsil ODS C18 (250x20)mm;5mic; flow:- 19ml/min; mobile phase (A): 0.1% TFA in water; mobile phase (B): acetonitrile; RT = 11.3 and 10.44] to afford N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-7-methyl-7,8-dihydro-6H- oxazolo[4,5-e]isoindol-2-amine, trifluoroacetic acid salt (40 mg, 7%) as a light brown solid. LCMS (ES) m/z = 338.3 [M+H]⁺ (Example 16) and N-(5-fluoro-1-methyl-1H-benzo[d]imidazol- 2-yl)-6-methyl-6,7-dihydro-5H-oxazolo[4,5-f]isoindol-2-amine; trifluoroacetic acid salt (45 mg, 7.5%) as off white solid. LCMS (ES) m/z = 338.2 [M+H]⁺ (Example 20) [0192] Example 17 Synthesis of {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl) amino]-1,3-benzoxazol-5-yl} methanol [0193] Example 17 is synthesized in Step 6 of the synthesis of Example 1. LCMS (ES) m/z = 313.2 [M+H]⁺. [0194] Example 18 Synthesis of N-(1-cyclopropyl-5-fluoro-1H-1,3-benzodiazol-2-yl)-5-[(dimethylamino)methyl] - 1,3-benzoxazol-2-amine [0195] Example 18 is synthesized in an analogous manner to Example 1, except that 1- aminocyclopropane is used in Step 1. LCMS (ES) m/z = 366.29 [M+H]⁺. [0196] Example 19 Synthesis of N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5-((4-methylpiperazin-1-yl) methyl) benzo[d]oxazol-2-amine trifluoro acetic acid [0197] Example 19 is synthesized in an analogous manner to Example 1, except that 1- methylpiperazine is used in Step 8. LCMS (ES) m/z = 393.2 [M+H]⁺. Synthesis of N-[1-(cyclopropylmethyl)-5-fluoro-1H-1,3-benzodiazol-2-yl]-5- [(dimethylamino)methyl]-1,3-benzoxazol-2-amine [0199] Example 21 is synthesized in an analogous manner to Example 1, except that 1- cyclopropylmethylamine is used in Step 1. LCMS (ES) m/z = 380.2 [M+H]⁺. [0200] Example 22 Synthesis of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol- 2-amine [0201] Example 22 is synthesized in Step 7 of the synthesis of Example 1. LCMS (ES) m/z = 329.1 [M-H]^–. [0202] Example 23 Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(methoxymethyl)-1,3- benzoxazol-2-amine [0203] To a stirred solution of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- 1,3-benzoxazol-2-amine (i.e., the intermediate product in Step 7 of the synthesis of Example 1) (20 mg, 0.060 mmol) in tetrahydrofuran (2 mL) at room temperature is added sodium methanolate (7.26 μL, 0.012 mmol). The reaction mixture is stirred at room temperature for 16 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (10 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers are washed with DM water (2 x 10 mL), dried over sodium sulphate, and concentrated under reduced pressure to afford a crude compound. The crude compound is purified by flash column chromatography using 0-5% methanol in DCM as eluents to afford Example 23 (N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5- (methoxymethyl)-1,3-benzoxazol-2-amine) (5 mg, 25%) as an off-white solid. LCMS (ES) m/z = 327.2 [M+H]⁺. [0204] Example 24 Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-{[methyl(prop-2-yn-1-yl) amino]methyl}-1,3-benzoxazol-2-amine [0205] Step 1: Synthesis of tert-butyl N-methyl-N-(prop-2-yn-1-yl)carbamate [0206] To a solution of sodium hydride (60% dispersion in mineral oil) (247 mg, 6.44 mmol) in tetrahydrofuran (3 mL) at 0 °C in a sealed tube is added dropwise tert-butyl N-(prop-2-yn-1- yl)carbamate (0.5 g, 3.22 mmol) solution in tetrahydrofuran. After 20 min, iodomethane (401 μL, 6.44 mmol) is added at 0 °C dropwise to the reaction mixture. The resulting reaction mixture is allowed to stir at room temperature for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is quenched slowly with saturated ammonium chloride solution (25 mL) at 0 °C and extracted with ethyl acetate (2 x 20 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 10-15% ethyl acetate in n-heptane as eluents to afford tert-butyl N-methyl-N-(prop-2-yn-1-yl)carbamate as a yellow oil (450 mg, 83%). [0207] Step 2: Synthesis of methyl(prop-2-yn-1-yl)amine hydrochloride [0208] To a stirred solution of tert-butyl N-methyl-N-(prop-2-yn-1-yl)carbamate (450 mg, 2.66 mmol) in dichloromethane (4 mL) is added 4.0 M hydrogen chloride in dioxane (388 mg, 10.6 mmol) at 0 °C. The resulting reaction mixture is allowed to stir from 0 °C to room temperature over 2 h. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude compound. The crude compound is washed with n-pentane (5 mL), diethyl ether (5 mL), and acetonitrile (5 mL), and then dried under reduced pressure to afford methyl(prop-2-yn-1-yl)amine hydrochloride as a white solid (240 mg, 85%). [0209] Step 3: Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-{[methyl(prop-2- yn-1-yl)amino]methyl}-1,3-benzoxazol-2-amine [0210] To a stirred solution of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- 1,3-benzoxazol-2-amine (i.e., the intermediate product in Step 7 of the synthesis of Example 1) (0.2 g, 605 μmol) in N,N-dimethylformamide (5 mL) are added potassium carbonate (167 mg, 1.21 mmol) and methyl(prop-2-yn-1-yl)amine hydrochloride (128 mg, 1.21 mmol) in a sealed tube at room temperature. The resulting reaction mixture is allowed to stir at 75 °C for 2 h in a sealed tube. The progress of the reaction monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is quenched with DM water (25 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford a crude compound. The crude compound is purified with reverse phase prep HPLC: [column: Inertsil ODS C18 (250x20)mm;5mic; flow:-19ml/min; mobile phase (A): 0.1% ammonia in water; mobile phase (B): acetonitrile] to afford Example 24 (N-(5-fluoro-1-methyl-1H-1,3-benzodiazol- 2-yl)-5-{[methyl(prop-2-yn-1-yl)amino]methyl}-1,3-benzoxazol-2-amine) as a white solid (78 mg, 35%). LCMS (ES) m/z = 364.2 [M+H]⁺. [0211] Example 25 Synthesis of N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl) benzo[d]oxazol-2-amine [0212] To a stirred solution of 1,3-benzoxazole (0.1 g, 0.839 mmol) in tetrahydrofuran at room temperature (4 mL) are added lithium tert-butoxide (202 mg, 2.52 mmol) and iodine (160 mg, 1.26 mmol). The reaction mixture is allowed to stir for 10 min. After 10 min, 5-fluoro-1-methyl- 1H-1,3-benzodiazol-2-amine (i.e., the intermediate product in Step 3 of the synthesis of Example 1) (277 mg, 1.68 mmol) is added to the reaction mixture and stirred for additional 1 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (50 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford a crude compound. The crude compound is purified by Prep-HPLC: [column: Inertsil ODS-3 (250 mm x 20 mm x 5 μm); mobile phase (A): 0.1% ammonia in water; mobile phase (B): acetonitrile; flow rate: 19.0 ml/min; % of B: 0/50,1/50,10/80,13/80,13.1/98,17/98,17.1/50, 19/50). The product fractions are concentrated to afford Example 25 (N-(5-fluoro-1-methyl-1H-benzo[d] imidazol-2-yl)benzo[d]oxazol-2- amine) (38 mg, 13%) as an off-white solid. LCMS (ES) m/z = 283.2 [M+H]⁺. [0213] Example 26 Synthesis of 2-{2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5- yl}acetonitrile [0214] To a stirred solution of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- 1,3-benzoxazol-2-amine (i.e., the intermediate product in Step 7 of the synthesis of Example 1) (250 mg, 756 μmol) in tetrahydrofuran (25 mL) and acetonitrile (25 mL) are added tetrabutylammonium fluoride (0.1 mL, 756 μmol) and trimethylsilyl cyanide (0.3 mL, 756 μmol) slowly at room temperature under nitrogen atmosphere. The resulting reaction mixture is allowed to stir at room temperature for 48 h in a sealed tube. The progress of the reaction monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is quenched with DM water (30 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers are separated, dried over sodium sulphate, and concentrated under reduced pressure to afford a crude compound. The crude compound is purified by flash column chromatography using 5-15% methanol in dichloromethane as eluents to afford Example 26 (2-{2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5-yl}acetonitrile) as a brown solid (94 mg, 39%). LCMS (ES) m/z = 322.2 [M+H]⁺. [0215] Example 27 Synthesis of {2-[(1-cyclopropyl-5-fluoro-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5- yl}methanol [0216] Example 27 is synthesized in Step 6 of the synthesis of Example 18. LCMS (ES) m/z = 339.2 [M+H]⁺. [0217] Example 28 Synthesis of 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl) amino]-1,3-benzoxazole-5- carbaldehyde [0218] To a stirred solution of {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3- benzoxazol-5-yl}methanol (i.e., the intermediate product in Step 6 of the synthesis of Example 1) (80 mg, 0.256 mmol) in dichloromethane (5 mL) at 0 °C is added 1,1-bis(acetyloxy)-3-oxo- 3H-1^^,2-benziodaoxol-1-yl acetate (163 mg, 0.384 mmol). The reaction mixture is allowed to bring to room temperature and stir for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layers are separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford a crude compound. The crude compound is purified using Prep-HPLC [column: Inertsil ODS C18 (250 x 20)mm; 5mic; flow: - 19ml/min; mobile phase (A): 0.1% ammonia in water; mobile phase (B): acetonitrile) to afford Example 28 (2-[(5-fluoro-1-methyl-1H-1,3- benzodiazol-2-yl)amino]-1,3-benzoxazole-5-carbaldehyde) (22 mg, 28%) as an off-white solid. LCMS (ES) m/z: 311.2 [M+H]⁺. [0219] Example 29 Synthesis of N-(1-benzyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-5-((dimethylamino) methyl) benzo[d]oxazol-2-amine [0220] Example 29 is synthesized in an analogous manner to Example 1, except that benzylamine is used in Step 1. LCMS (ES) m/z = 416.3 [M+H]⁺. [0221] Example 30 Synthesis of 5-((dimethylamino)methyl)-N-(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-N- methylbenzo[d]oxazol-2-amine [0222] Example 30 can be synthesized essentially according to procedures set forth in the preceding examples and Reaction Schemes 1 and 2. [0223] Example 31 Synthesis of 5-[(dimethylamino)methyl]-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-N- methyl-1,3-benzoxazol-2-amine [0224] Step 1: Synthesis of 5-fluoro-2-iodo-1-methyl-1H-1,3-benzodiazole [0225] To a stirred solution of 5-fluoro-1-methyl-1H-1,3-benzodiazol-2-amine (0.5 g, 3.03 mmol) in dimethylformamide (5 mL), diiodomethane (1.02 mL, 12.1 mmol) and 3-methylbutyl nitrite (1.24 mL, 9.08 mmol) are added at 0 °C. The reaction mixture is stirred at 60 °C for 4 h. The progress of the reaction is monitor by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 0-50% ethyl acetate in n-heptane as eluents to afford 5-fluoro-2-iodo-1-methyl-1H-1,3-benzodiazole (250 mg, 30%) as an off-white solid. [0226] Step 2: Synthesis of methyl 1,3-benzoxazole-5-carboxylate [0227] To a stirred solution of methyl 3-amino-4-hydroxybenzoate (5 g, 29.9 mmol) in triethylorthoformate (50 mL) is added 4-methylbenzene-1-sulfonic acid (515 mg, 2.99 mmol) at room temperature. The reaction mixture is stirred at 120 °C for 16 h in a sealed tube. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude residue. The crude residue is diluted with DM water (100 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford methyl 1,3-benzoxazole-5-carboxylate (3.3 g, crude) as a light yellow solid. [0228] Step 3: Synthesis of methyl 2-iodo-1,3-benzoxazole-5-carboxylate [0229] To a stirred solution of methyl 1,3-benzoxazole-5-carboxylate (1 g, 5.64 mmol) in tetrahydrofuran (10 mL) is added lithium(1+) bis(trimethylsilyl)azanide (2.83 g, 16.9 mmol) dropwise at -78 °C under an inert condition and allowed to stir for 1h. After 1 h, iodine (1.07 g, 8.47 mmol) in tetrahydrofuran (5 ml) is added dropwise at -78 °C. The reaction mixture is stirred at the same temperature for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (40 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers are dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 0- 40% ethyl acetate in n-heptane as eluents to afford methyl 2-iodo-1,3-benzoxazole-5- carboxylate (0.6 g, 35%) as a light yellow solid. [0230] Step 4: Synthesis of methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate [0231] To a stirred solution of methyl 2-iodo-1,3-benzoxazole-5-carboxylate (0.6 g, 2.97 mmol) in 30% methyl amine in ethanol (366 μL, 8.91 mmol) is stirred for 30 min at room temperature. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 0-10% methanol in DCM as eluents to afford methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate (0.550 g, 98%) as a white solid. [0232] Step 5: Synthesis of [2-(methylamino)-1,3-benzoxazol-5-yl]methanol [0233] To a stirred solution of methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate (550 mg, 2.67 mmol) in tetrahydrofuran (20 mL) is added 1M Lithium aluminium hydride in THF (152 mg, 4 mmol) at 0 °C. The reaction mixture is stirred at room temperature for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford [2-(methylamino)-1,3- benzoxazol-5-yl]methanol (350 mg, Crude) as a brown solid. [0234] Step 6: Synthesis of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methyl-1,3-benzoxazol-2- amine [0235] To a stirred solution of [2-(methylamino)-1,3-benzoxazol-5-yl]methanol (0.350 g, 1.68 mmol) in dimethylformamide (2 mL), 1H-imidazole (172 mg, 2.53 mmol) and tert- butyl(chloro)dimethylsilane (381 mg, 2.53 mmol) are added at 0 °C. The reaction mixture is stirred at room temperature for 1.5 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 0-20% ethyl acetate in n-heptane as eluents to afford 5-{[(tert-butyldimethylsilyl)oxy]methyl}-N- methyl-1,3-benzoxazol-2-amine (450 mg, 91%) as a brown oil. [0236] Step 7: Synthesis of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-N-(5-fluoro-1-methyl-1H- 1,3-benzodiazol-2-yl)-N-methyl-1,3-benzoxazol-2-amine [0237] To a stirred solution of 5-fluoro-2-iodo-1-methyl-1H-1,3-benzodiazole (150 mg, 513 μmol) and 6-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methyl-1,3-benzoxazol-2-amine (0.1 g, 342 μmol) in 1,4-dioxane (4 mL) is added cesium carbonate (223 mg, 684 μmol) at room temperature. The reaction mixture is degassed with nitrogen atmosphere for 5 min. After 5 min, tris(1,5-diphenylpenta-1,4-dien-3-one) dipalladium (31.3 mg, 34.2 μmol) and 5-{[(tert- butyldimethylsilyl)oxy]methyl}-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-N-methyl-1,3- benzoxazol-2-amine (120 mg, 272 μmol) are added to the reaction mixture. The reaction mixture is stirred at 120 °C for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers are dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford §s (120 mg, 80%) as an off-white solid. [0238] Step 8: Synthesis of {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)(methyl)amino]- 1,3-benzoxazol-5-yl}methanol [0239] To a stirred solution of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-N-(5-fluoro-1-methyl-1H- 1,3-benzodiazol-2-yl)-N-methyl-1,3-benzoxazol-2-amine (120 mg, 159 μmol) in tetrahydrofuran (1 mL) is added tetrabutylazanium fluoride (125 mg, 477 μmol) in 0 °C. The reaction mixture is stirred at room temperature for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)(methyl)amino]-1,3-benzoxazol-5- yl}methanol (80 mg, Crude) as an off-white solid. [0240] Step 9: Synthesis of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-N- methyl-1,3-benzoxazol-2-amine [0241] To a stirred solution of {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)(methyl)amino]- 1,3-benzoxazol-5-yl}methanol (80 mg, 245 μmol) in N,N-dimethylformamide (0.2 mL) is added sulfuryl dichloride (43.7 mg, 368 μmol) at 0 °C. The reaction mixture is stirred at room temperature for 1 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a solid. The solid is washed with ether (15 mL) and dried under reduced pressure to afford 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-N-methyl-1,3- benzoxazol-2-amine (50 mg, Crude) as an off-white solid. [0242] Step 10: Synthesis of 5-[(dimethylamino)methyl]-N-(5-fluoro-1-methyl-1H-1,3- benzodiazol-2-yl)-N-methyl-1,3-benzoxazol-2-amine [0243] To a stirred solution of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- N-methyl-1,3-benzoxazol-2-amine (50 mg, 145 μmol) in N,N-dimethylformamide (2 mL), potassium carbonate (60.1 mg, 435 μmol) and dimethylamine hydrochloride (17.7 mg, 218 μmol) are added. The reaction mixture is stirred at 80 °C for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is diluted with DM water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by Prep HPLC: [mobile phase (A): 0.1% ammonia in water; mobile phase (B): acetonitrile] to afford Example 31 (5- [(dimethylamino)methyl]-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-N-methyl-1,3- benzoxazol-2-amine) (18 mg, 35%) as a white solid. LCMS (ES) m/z = 354.3 [M+H]⁺. [0244] Examples 32-35 [0245] Synthesis of Examples 32-35. Examples 32-35 can be synthesized essentially according to procedures set forth in the preceding examples and Reaction Schemes 1 and 2. 4- 7- 5- benz [0246] Example 36 Synthesis of N-(5-((dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5- fluorobenzo[d]oxazol-2-amine [0247] Step 1: Synthesis of 5-fluorobenzo[d]oxazole-2-thiol [0248] To a stirred solution of 2-amino-4-fluorophenol (1 g, 7.87 mmol) in ethanol (20 mL) at room temperature potassium (ethoxymethanethioyl)sulfanide (3.15 g, 19.7 mmol) is added and stirred for 16 h at 80 °C. The process of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude. The crude is diluted with ice-cold water and acidified using 3N HCl (pH~4). Solid is precipitated out, filtered, and dried over vacuum to afford 5-fluoro-1,3-benzoxazole-2- thiol (1.2 g, 90%). [0249] Step 2: Synthesis of 2-chloro-5-fluorobenzo[d]oxazole [0250] To a stirred solution of 5-fluoro-1,3-benzoxazole-2-thiol (1 g, 5.91 mmol) in thionyl chloride (8 mL) at 0 °C is added dimethylformamide (1 mL, 12.9 mmol) and stirred for 2 h at room temperature. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is quenched with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers are separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford 2-chloro-5-fluoro-1,3-benzoxazole as a gummy liquid (530 mg, 52%). [0251] Step 3: Synthesis of methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H- benzo[d] imidazole-5-carboxylate [0252] To a stirred solution of 2-chloro-5-fluoro-1,3-benzoxazole (250 mg, 1.46 mmol) in dimethyl sulfoxide (10 mL) and dimethylformamide (1 mL) under an inert condition at 0 °C is added sodium hydride (60% dispersion in mineral oil) (67 mg, 2.91 mmol). The reaction mixture is stirred for 20 min at 0 °C. Then methyl 2-amino-1-methyl-1H-1,3-benzodiazole-5- carboxylate (359 mg, 1.75 mmol) is added to the reaction mixture, and the reaction mixture is stirred for 2 h at room temperature. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is diluted using cold water (20 mL) and extracted using ethyl acetate (2 x 20 mL). The combined organic layers are separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazole-5-carboxylate as a brown solid (358 mg, 72%). [0253] Step 4: Synthesis of (2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d] imidazol-5-yl)methanol [0254] To a stirred solution of methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3- benzodiazole-5-carboxylate (350 mg, 1.03 mmol) in tetrahydrofuran (10 mL, 123 mmol) at 0 °C is added lithium aluminum hydride solution 1.0 M in THF (5 mL, 2.06 mmol). The reaction mixture is stirred for 2 h at room temperature. The progress of the reaction is monitored by TLC and LCMS. The reaction mixture is quenched with saturated ammonium chloride (15 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford {2-[(5-fluoro- 1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-5-yl}methanol as a gummy solid (310 mg, 96%). [0255] Step 5: Synthesis of N-(5-(chloromethyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5- fluorobenzo[d]oxazol -2-amine [0256] To a stirred solution of {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3- benzodiazol-6-yl}methanol (0.3 g, 961 μmol) in thionyl chloride (6 mL) is added dimethylformamide (0.5 mL) at room temperature and stirred for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is cooled to 0 °C, neutralized using saturated sodium bicarbonate solution, and extracted using ethyl acetate (2 x 10 mL). The combined organic layers are separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford N-(5-(chloromethyl)-1- methyl-1H-benzo[d]imidazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine as an off-white solid (160 mg, 50%). [0257] Step 6: Synthesis of N-(5-((dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazol-2-yl)- 5-fluorobenzo[d]oxazol-2-amine [0258] To a stirred solution of N-[5-(chloromethyl)-1-methyl-1H-1,3-benzodiazol-2-yl]-5-fluoro- 1,3-benzoxazol-2-amine (155 mg, 469 μmol) in dimethylformamide (10 mL) are added dimethylamine hydrochloride (222 mg, 2.72 mmol) and potassium carbonate (188 mg, 1.36 mmol) and stirred for 16 h at 80 °C. The progress of the reaction is monitored by TLC. The reaction mixture is diluted with DM water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers are dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain a crude. The crude is purified using flash column chromatography and further purified using Prep HPLC [column: Inertsil ODS C18 (250x20)mm;5mic, flow:-19ml/min; mobile phase (A): 0.1% TFA in water; mobile phase (B): acetonitrile] to afford Example 36 (N-{5-[(dimethylamino)methyl]-1-methyl-1H-1,3- benzodiazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine) as a white solid (48 mg, 30%). LCMS (ES) m/z = 338.2 [M-H] -. [0259] Example 37 Synthesis of N-{6-[(dimethylamino)methyl]-1-methyl-1H-1,3-benzodiazol-2-yl}-5-fluoro-1,3- benzoxazol-2-amine [0260] Step 1: Synthesis of methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3- benzodiazole-6-carboxylate [0261] To a stirred solution of methyl 2-amino-1-methyl-1H-1,3-benzodiazole-6-carboxylate (0.4 g, 1.95 mmol) in 1,4-dioxane (15 mL) and dimethylformamide (3 mL) is added sodium hydride 60% w/w (156 mg, 3.9 mmol) at 0 °C and allowed to stir for 20 min. After 20 min, 5- fluoro-2-iodo-1,3-benzoxazole (513 mg, 1.95 mmol) is added at 0 °C. The reaction mixture is stirred at room temperature for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is quenched with saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3- benzodiazole-6-carboxylate (660 mg, 100%) as an off-white solid. [0262] Step 2: Synthesis of {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3- benzodiazol-6-yl}methanol [0263] Compound {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-6- yl}methanol is synthesized in an analogous manner to Step 6 of the synthesis of Example 1. [0264] Step 3: Synthesis of N-[6-(chloromethyl)-1-methyl-1H-1,3-benzodiazol-2-yl]-5-fluoro- 1,3-benzoxazol-2-amine [0265] Compound N-[6-(chloromethyl)-1-methyl-1H-1,3-benzodiazol-2-yl]-5-fluoro-1,3- benzoxazol-2-amine is synthesized in an analogous manner to Step 7 of the synthesis of Example 1. [0266] Step 4: Synthesis of N-{6-[(dimethylamino)methyl]-1-methyl-1H-1,3-benzodiazol-2-yl}- 5-fluoro-1,3-benzoxazol-2-amine [0267] Example 37 (N-{6-[(dimethylamino)methyl]-1-methyl-1H-1,3-benzodiazol-2-yl}-5- fluoro-1,3-benzoxazol-2-amine) is synthesized in an analogous manner to Step 8 of the synthesis of Example 1. LCMS (ES) m/z = 340.25 [M+H]⁺. [0268] Example 38 Synthesis of Synthesis of {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3- benzodiazol-6-yl}methanol [0269] Example 38 is synthesized in Step 2 of the synthesis of Example 37. LCMS (ES) m/z = 313.2 [M+H] ⁺. [0270] Example 39 Synthesis of 5-[(dimethylamino)methyl]-N-(1-ethyl-5-fluoro-1H-1,3-benzodiazol-2-yl)-1,3- benzoxazol-2-amine [0271] Example 39 is synthesized in an analogous manner to Example 1, except that ethylamine is used in Step 1. LCMS (ES) m/z = 354.2 [M+H]⁺. [0272] Example 40 Synthesis of 2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)-N-(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide [0273] Step 1 to Step -5 are conducted in an analogous manner to Step 1 to Step 5 of the synthesis of Example 1. [0274] Step 6: Synthesis of 2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d] oxazole-5-carboxylic acid [0275] To a stirred solution of methyl 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]- 1,3-benzoxazole-5-carboxylate (150 mg, 441 μmol) in methanol (6 mL), water (6 mL) and tetrahydrofuran (6 mL) at room temperature is added lithium hydroxide (92.5 mg, 2.2 mmol) and stirred for 4 h. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated under reduced pressure, diluted with DM water (15 mL), acidified using 1N HCl, and then extracted using ethyl acetate (2 x 20 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3- benzoxazole-5-carboxylic acid (110 mg, 76%) as an off-white solid. [0276] Step 7: Synthesis of 2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)-N-(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide [0277] To a stirred solution of 2-(2-aminoethoxy)ethan-1-ol (48.3 mg, 460 μmol) in dimethylformamide (5 mL) at room temperature are added {3- [cyano(ethyl)amino]propyl}dimethylazanium chloride (76.4 mg, 398 μmol), 1H-1,2,3- benzotriazol-1-ol hydrate (70.4 mg, 460 μmol) and ethylbis(propan-2-yl)amine (160 μL, 919 μmol) and stirred for 5 min. After 5 min, 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]- N-[2-(2-hydroxyethoxy)ethyl]-1,3-benzoxazole-5-carboxamide (46 mg, 111 μmol) is added and stirred for 16 h at 100 °C. The progress of the reaction is monitored by TLC. The reaction mixture is diluted with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude compound. The crude compound is purified by flash column chromatography using 1-10% methanol in dichloromethane as eluents to afford Example 40 (2-[(1,3-benzoxazol-2-yl)amino]-N-[2-(2-hydroxyethoxy)ethyl]-1-methyl-1H-1,3- benzodiazole-5-carboxamide) (29 mg, 36%) as an off-white solid. LCMS (ES) m/z = 414.3 [M+H]⁺. [0278] Example 41 Synthesis of 2-(((2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-6- yl)methyl)(methyl)amino)ethan-1-ol [0279] Example 41 is synthesized in an analogous manner to Example 1, except that 2- (methylamino)ethan-1-ol is used in Step 8. LCMS: (ES) m/z = 370.2 [M+H]. [0280] Example 42 Synthesis of 1-({2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5- yl}methyl)azetidin-3-ol [0281] Example 42 is synthesized in an analogous manner to Example 1, except that azetidin-3-ol is used in Step 8. LCMS (ES) m/z = 368.2 [M+H]⁺. [0282] Example 43 Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-[(3-methoxyazetidin-1- yl)methyl]-1,3-benzoxazol-2-amine [0283] Example 43 is synthesized in an analogous manner to Example 1, except that 3- methoxyazetidine is used in Step 8. LCMS (ES) m/z = 380.3 [M-H]^–. [0284] Example 44 Synthesis of 5-[(3-aminoazetidin-1-yl)methyl]-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- 1,3-benzoxazol-2-amine [0285] Step 1 to Step 8 are conducted in an analogous manner to the synthesis of Example 1. [0286] Step 9: Synthesis of 5-[(3-aminoazetidin-1-yl)methyl]-N-(5-fluoro-1-methyl-1H-1,3- benzodiazol-2-yl)-1,3-benzoxazol-2-amine [0287] To a stirred solution of tert-butyl N-[1-({2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2- yl)amino]-1,3-benzoxazol-5-yl}methyl)azetidin-3-yl]carbamate (150 mg, 322 μmol) in dichloromethane (3 mL) under an inert condition at 0°C is added 4N dioxane HCl (3.5 mL). The resulting reaction mixture is stirred at room temperature for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a solid. The solid is then purified by Prep- HPLC [column: Inertsil ODS C18 (250x20)mm;5mic; fFlow:-19ml/min; mobile phase (A): 0.1% ammonia in water; mobile phase (B): acetonitrile]. The collected spot is concentrated under reduced pressure to Example 44 (afford 5-[(3-aminoazetidin-1-yl)methyl]-N-(5-fluoro-1-methyl- 1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine) (20 mg, 17%) as a white solid. LCMS (ES) m/z = 367.3 [M+H]⁺. [0288] Example 45 Synthesis of 5-{[3-(dimethylamino)azetidin-1-yl]methyl}-N-(5-fluoro-1-methyl-1H-1,3- benzodiazol-2-yl)-1,3-benzoxazol-2-amine [0289] Example 45 is synthesized in an analogous manner to Example 1, except that N,N- dimethylazetidin-3-amine is used in Step 8. LCMS (ES) m/z = 395.3 [M+H]⁺. [0290] Example 46 Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-2-((1-methyl-1H-benzo[d]imidazol-2- yl)amino)benzo[d]oxazole-5-carboxamide [0291] Example 46 is synthesized in an analogous manner to Example 40. LCMS (ES) m/z = 396.4 [M+H]⁺. Biological Methods [0292] Cell Culture: The human monocytic THP-1 cell line is purchased from Invivogen (thp- null). The human monocytic THP-1 ASC-GFP reporter cell line is purchased from Invivogen (thp-ascgfp). The human monocytic THP-1 cell line overexpressing NLRC4 is purchased from Invivogen (thp1-nlrc4). The mouse macrophage cell line J774A.1 is purchased from ATCC (TIB-67). Cells are maintained according to the manufacturer’s suggested protocol. [0293] Human peripheral blood mononuclear cells are isolated from whole blood using Lymphoprep^TM density gradient according to the manufacturer’s instructions. PBMCs are used fresh. [0294] PMA differentiation of THP-1 cells: For ASC Spec assays, the human monocytic cell line THP-1 ASC-GFP cells are differentiated into a macrophage-like phenotype using Phorbol 12-myristate 13-acetate (PMA). THP-1 cells are suspended at a density of 1-2 x 10⁶ cells/mL and supplemented with 100 ng/mL PMA. One hundred thousand cells are seeded into each well of a 96 well plate and incubated for 72 hours. Adherent cells are washed three times with PMA free THP-1 media, then cells are rested for 24 hours in PMA free media. [0295] NLRP3 Inflammasome and pyroptosis assay in THP-1 Cells: THP-1 cells are primed with 300 ng/mL of ultra-pure LPS. One hour later, cells are treated as indicated in figure legend. Three hours post-LPS prime, the NLRP3 inflammasome is activated with 10 PM Nigericin. Two hours later, supernatants are collected and analyzed for IL-1E by ELISA. Pyroptotic cell death is assessed by Alamar blue assay as described below. [0296] Cytotoxicity Assay: THP-1 or PBMCs are treated with a dose titration of the indicated compound for 5 hours after which cell viability is assessed by Alamar blue assay, as described below. [0297] Alamar Blue Viability Assay: Alamar blue cell viability reagent is diluted 1:10 in cell culture media and filtered through a 40 μm filter the added to cell pellets at 100 ^L/well. After 2-24 hours, optical density is read according to manufacturer’s instructions. Viability is expressed as percent signal relative to wells containing untreated cells corrected for media control. [0298] Cell Free Inflammasome Assay: Cell free inflammasome activation and Caspase-1 cleavage is assessed as described previously. Briefly, lysates are prepared from THP-1 by hypotonic lysis to a final protein concentration > 7 mg/mL. Lysates are pretreated for 20 minutes with a final concentration of 1 mM of the indicated compound on ice. Inflammasome activation is induced by incubating samples for 60 minutes at 30 °C. Inflammasome activity is assessed through monitoring Caspase-1 cleavage by Western blot. [0299] NLRP3 Inflammasome activation in PBMCs: 2 x 10⁵ freshly isolated PBMCs are primed with 300 ng/mL LPS for 1 hour, then treated with a dose titration of the indicated compounds for an additional 2 hours. The NLRP3 inflammasome is then activated by treating cells with 10 ^M nigericin for 2 hours. Inflammasome activity is assessed by IL-1ȕ ELISA according to manufacturer’s instructions. [0300] AIM2 Inflammasome activation in PBMCs: 2 x 10⁵ freshly isolated PBMCs are transfected with poly dA:dT (100 ng/well) using Lipofectamine 2000 (1 ^L/well) according to the manufacturer’s instructions in order to activate the AIM2 inflammasome. One hour later, cells are treated with a dose titration of the indicated compounds for an additional 17 hours. Inflammasome activity is assessed by IL-1ȕ ELISA according to manufacturer’s instructions. [0301] NLRP1 Inflammasome activation in PBMCs: 2 x 10⁵ freshly isolated PBMCs are treated with 10 ^M Talabostat, a constitutive repressor of the NLRP1 inflammasome. One hour later, cells are treated with a dose titration of the indicated compounds for an additional 17 hours. Inflammasome activity is assessed by IL-1ȕ ELISA according to manufacturer’s instructions. [0302] NLRC4 Inflammasome activation PBMCs: 2 x 10⁵ freshly isolated PBMCs are primed with LPS (300 ng/mL) for 1 hour, then treated with 200 ng/mL NeedleTox [LFn Needle (Invivogen tlrl-ndl) + anthrax protective antigen (List Labs 171E)]. Compounds are added one hour after NeedleTox addition then incubated for an additional 4 hours after which inflammasome activity is assessed by IL-1ȕ ELISA according to the manufacturer’s directions. [0303] Assessment of HO-1 Induction: THP-1 cells (Invivogen cat# thp-null) are maintained at a density of 0.2-0.8 x 10⁶ cells/mL according to the manufacturer’s directions. For HO-1 assessment, 100,000 cells/well are seeded in 90 ^L of culture media into 96-well plates then treated with 10 ^L of compound prepared at 10X in culture media containing 5% DMSO, for a final DMSO concentration of 0.5% DMSO v/v. Cells are incubated for 5 hours at 37°C and 5% CO₂. Plates are centrifuged for 5 minutes at 500g at room temperature to pellet cells, then media is aspirated, and cells are washed in 100 ^L of PBS. Plates are again centrifuged for 5 minutes at 500g at room temperature to pellet cells, and PBS is aspirated. Cells are resuspended in 100 ^L of RIPA buffer containing protease inhibitors (Roche complete protease inhibitor cocktail). Samples are lysed by pipetting up and down15X with a multichannel pipette. Samples are diluted 1:2 in PBS containing 1% BSA, and cellular HO-1 levels are assessed by ELISA according to the manufacturer’s directions (R&D systems cat# DYC3776-5). Data is normalized to reference compound control (vTv/Anteris Bach1 inhibitor @ 10 ^M) present in triplicate on each plate and expressed as activity (% reference compound). [0304] NLRP1 Inflammasome Assay in Mouse Macrophages: J774A.1 cells (ATCC cat # TIB- 67) are maintained according to the manufacturer’s directions. For NLRP1 activation, cells are used < passage #12. 100,000 cells/well are seeded in 70 ^L of culture media into 96-well plates and allowed to adhere for 30 minutes at 37^oC and 5% CO₂. Cells are stimulated with 10 ^L of ultrapure LPS (Invivogen cat# tlrl-3pelps) at 3 ^g/mL for a final concentration of 300 ng/mL. Cells are incubated for 1 hour at 37°C and 5% CO₂. Compound prepared at 10X in culture media containing 5% DMSO, then 10 ^L are added to each well for a final DMSO concentration of 0.5% DMSO v/v. Cells are incubated for an additional 1 hour at 37°C and 5% CO₂. Anthrax lethal toxin (LT) is prepared 1 ug/mL by adding anthrax lethal factor (List Labs cat # 169L) and anthrax protective antigen (List Labs cat # 171E) to media for a final concentration of 1 ug/mL each. Each well is treated with 10^L of LT for a final concentration of 100 ng/mL. Cells are incubated for an additional 3 hours at 37°C and 5% CO₂. Plates are centrifuged for 5 minutes at 500g at room temperature to pellet cells, then supernatants are collected and diluted 1:10 in PBS containing 1% BSA, and IL-1ȕ is assessed by ELISA according to the manufacturer’s directions (R&D Systems cat# DY401). Alamar blue cell viability reagent (ThermoFisher cat# DAL1100) is diluted 1:10 in culture media, then 100 ^L is added to each cell pellet and incubated at 37°C and 5% CO₂ for 3 hours. Plates are read at 570 nm using a reference wavelength of 600 nm, and viability is expressed relative to untreated controls, using culture media for background correction. [0305] NLRC4 Inflammasome Assay in THP-1 Cells: NLRC4 overexpressing THP-1 cells (Invivogen cat # thp1-nlrc4) are maintained according to the manufacturer’s directions at a density of 0.2 – 0.8 x 10⁶ cells/mL. For NLRC4 activation, 100,000 cells/well are seeded in 70 ^L of culture media into 96-well plates and stimulated with 10 ^L of ultrapure LPS (Invivogen cat# tlrl-3pelps) at 3 ^g/mL in culture media for a final concentration of 300 ng/mL. Cells are incubated for 1 hour at 37°C and 5% CO₂. Compound prepared at 10X in culture media containing 5% DMSO, then 10 ^L are added to each well for a final DMSO concentration of 0.5% DMSO v/v. Cells are incubated for an additional 1 hour at 37°C and 5% CO₂. NeedleTox is prepared by mixing anthrax protective antigen (List Labs cat # 171E) to a final concentration of 1250 ng/mL and LFn-Needle (Invivogen cat# tlrl-ndl) to a final concentration of 250 ng/mL. Each well is treated with 10^L of NeedleTox for a final concentration of 150 ng/mL. Cells are incubated for an additional 3 hours at 37°C and 5% CO₂. Plates are centrifuged for 5 minutes at 500g at room temperature to pellet cells, then supernatants are collected and diluted 1:10 in PBS containing 1% BSA, and IL-1ȕ is assessed by ELISA according to the manufacturer’s directions (R&D Systems cat# DY201). Alamar blue cell viability reagent (ThermoFisher cat# DAL1100) is diluted 1:10 in culture media, then 100 ^L is added to each cell pellet and incubated at 37°C and 5% CO₂ for 3 hours. Plates are read at 570 nm using a reference wavelength of 600 nm, and viability is expressed relative to untreated controls, using culture media for background correction. Biological Example 1: Cellular Activity Assays [0306] The properties of each compound are assayed in a variety of cellular assays using THP- 1 human monocytic cells. Assessment of IL-1ȕ inhibition and protection from pyroptosis are assessed in an NLRP3 inflammasome assay. Results are provided in Table 2. Table 2 [0307] Comparative None compounds are tested and results provided in Table 3. Table 3 Biological Example 2: HO-1 Induction Assays [0308] The properties of each compound are assessed for Hemoxygenase-1 (HO-1) induction in assays using THP-1 human monocytic cells. Results are provided in Table 4. Table 4 Biological Example 3: Inhibition of ASC oligomerization [0309] ASC oligomerization is monitored using an ASC-GFP THP-1 reporter cell line. Upon inflammasome activation, ASC polymerizes and forms a single large ‘Spec’ per cell. By tagging ASC with GFP these ‘Specs’ are readily observable and the percentage of inflammasome containing cells can be assessed. THP-1 ASC-GFP cells are differentiated using PMA overnight, then rested in PMA-free media for one day. Cells are treated with a dose titration of the indicated drug 2 hours prior to NLRP3 inflammasome activation using nigericin. Forty-five minutes after nigericin treatment cells are fixed in 2% paraformaldehyde and imaged on a fluorescent microscope. The percentage of ASC-GFP Spec positive cells per field is quantified. Biological Example 4: Inhibition of Multiple Inflammasomes in human PBMCs [0310] The ability of a compound of interest to inhibit multiple inflammasomes is assessed in fresh primary human peripheral blood mononuclear cells (PBMCs). A dose titration of compound is added at the same time as the inflammasome stimuli as follows: a. NLRP3: LPS prime followed by 2-hour stimulation with nigericin. b. NLRP1: Overnight treatment with Talabostat (DPP8/9 inhibitor) c. NLRC4: Overnight transfection with bacterial flagellin protein d. AIM2: Overnight transfection with double stranded DNA [0311] Results provided in Figure 1 show that the compounds of the disclosure are potent pan- inflammasome inhibitors over the control compound MCC950 (sodium N-(1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide; CAS No. 256373-96-3). [0312] It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

What is claimed is: 1. A compound having the structural formula: , or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof, wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; R is H, C₁-C₆ alkyl, phenyl, -(C₁-C₃ alkyl)-phenyl, heteroaryl optionally substituted with methyl, C₃-C₈ cycloalkyl, or -(C₁-C₃ alkyl)-C₃-C₈ cycloalkyl; each R¹ is independently halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -OH, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, hydroxy(C₁-C₆ alkyl), hydroxy(C₁-C₆ alkoxy), alkoxy(C₁-C₆ alkyl), alkoxy(C₁-C₆ alkoxy), or amino(C₁-C₆ alkyl); R² is H or C₁-C₆ alkyl; each R³ is independently halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -OH, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -C₁-C₆ alkyl-NR⁴R⁵, -CN, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, -(C₁-C₆ alkyl)-aryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heteroaryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R₇, -(C₁-C₆ alkyl)-C₃-C₈ cycloalkyl optionally substituted with one or more R₇, -COH, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), or -CONR⁸R⁹ wherein R⁸ and R⁹ are independently H or C₁-C₆ alkyl wherein each alkyl within R⁸ and R⁹ is independently substituted with one, two or three halogen, cyano, hydroxy, C₁-C₃ alkoxy, amino or mono- or di(C₁-C₃ alkyl)amino, amino-C₁-C₃ alkoxy, mono- or di(C₁-C₃ alkyl)amino-C₁-C₃ alkoxy, hydroxy-C₁-C₃ alkoxy, or C₁-C₆ alkoxy-C₁-C₆ alkoxy, or two R³ together with the atoms to which they are attached, form a heterocycle, the heterocycle optionally substituted with one or more R₇, wherein R⁴ is H or C1-C6 alkyl; R⁵ is H, C₁-C₆ alkyl optionally substituted with one or more R₇, C₂-C₆ alkenyl, C₂- C₆ alkynyl, C₁-C₆ haloalkyl, –(C₁-C₆ alkyl)-O-C₁-C₆ alkyl, –(C₁-C₆ alkyl)-O-C₂- C₆ alkenyl, or –(C₁-C₆ alkyl)-O-C₂-C₆ alkynyl; each R⁶ is independently halogen, -NO₂, -CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -OH, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁-C₆ alkyl)₂; and each R⁷ is independently halogen, -NO₂, -CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -OH, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁-C₆ alkyl)₂, or two R⁷ groups, together with the carbon to which they are attached, form a =O; provided the compound is not 2-[(1-methyl-1H -benzimidazol-2-yl)amino]-5- benzoxazolecarboxylic acid. 2. The compound of claim 1, wherein R is H, C₁-C₃ alkyl, phenyl, benzyl, methylpyrazolyl, cyclopropyl, or cyclopropylmethyl. 3. The compound of claim 1 or claim 2, wherein R is H or methyl. 4. The compound of claim 1 or claim 2, wherein R is methyl, such as of formula: _. 5. The compound of any of claims 1 to 4, wherein m is 1 or 2. 6. The compound of any of claims 1 to 4, wherein m is 1. 7. The compound of claim 6, of formula: . The compound of claim 6, of formula: The compound of claim 6, of formula: . 10. The compound of claim 6, of formula: The compound of any of claims 1 to 10, wherein R¹ is independently halo, C1-C6 alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl. 12. The compound of any of claims 1 to 10, wherein R¹ is independently halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. 13. The compound of any of claims 1 to 10, wherein R¹ is independently halo, C₁-C₃ alkyl, or C₁-C₃ haloalkyl. 14. The compound of any of claims 1 to 10, wherein R¹ is independently halo. 15. The compound of any of claims 1 to 10, wherein at least one R¹ is halo.

16. The compound of any of claims 1 to 8, of formula: 17. The compound of any of claims 1 to 10, wherein R² is H or C₁-C₃ alkyl. 18. The compound of any of claims 1 to 10, wherein R² is H or methyl. 19. The compound of any of claims 1 to 10, wherein R² is H. 20. The compound of any . 21. The compound of any of claims 1 to 8, of formula: . 22. The compound of any of claims 1 to 21, wherein n is 1 or 2. 23. The compound of any of claims 1 to 21, wherein n is 1. 24. The compound of claim 23, of formula:

25. The compound of claim 23, of formula: 26. The compound of claim 23, of formula: . 27. The compound of claim 23, of formula: . 28. The compound of any of claims 1 to 27, wherein R³ is -C₁-C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, -(C₁-C₆ alkyl)-aryl optionally substituted with one or more R₆, -(C₁- C₆ alkyl)-heteroaryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R₇, -(C₁-C₆ alkyl)-C₃-C₈ cycloalkyl optionally substituted with one or more R₇, -COH, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁-C₆ alkyl)₂, or two R³ together with the atoms to which they are attached, form a heterocycle, the heterocycle optionally substituted with one or more R₇. 29. The compound of any of claims 1 to 27, wherein R³ is -C₁-C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, -(C₁-C₆ alkyl)-aryl optionally substituted with one or more R₆, -(C₁- C₆ alkyl)-heteroaryl optionally substituted with one or more R₆, -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R₇, -(C₁-C₆ alkyl)-C₃-C₈ cycloalkyl optionally substituted with one or more R₇, -COH, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁-C₆ alkyl)₂.

30. The compound of any of claims 1 to 27, wherein R³ is -C₁-C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R₇, -COH, -CO₂H, -CO₂(C₁-C₆ alkyl), -CO(C₁-C₆ alkyl), -CONH₂, -CONH(C₁-C₆ alkyl), or -CON(C₁-C₆ alkyl)₂; or two R³ together with the atoms to which they are attached, form a heterocycle, the heterocycle optionally substituted with one or more R₇. 31. The compound of any of claims 1 to 27, wherein R³ is -C₁-C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-CN, -C₁-C₆ alkyl-OR⁴, -(C₁-C₆ alkyl)-heterocyclyl optionally substituted with one or more R7, -COH, -CO2H, -CO2(C1-C6 alkyl), -CO(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl), or -CON(C₁-C₆ alkyl)₂. 32. The compound of any of claims 1 to 27, wherein R³ is -C₁-C₆ alkyl-NR⁴R⁵, -C₁-C₆ alkyl-OR⁴, or -(C1-C6 alkyl)-heterocyclyl optionally substituted with one or more R7. 33. The compound of any of claims 1 to 27, wherein R³ is -C₁-C₆ alkyl-NR⁴R⁵. 34. The compound of any of claims 1 to 33, wherein R⁴ is C₁-C₆ alkyl and R⁵ is C₁-C₆ alkyl optionally substituted with one or more R7, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, –(C₁-C₆ alkyl)-O-C₁-C₆ alkyl, –(C₁-C₆ alkyl)-O-C₂-C₆ alkenyl, or –(C₁-C₆ alkyl)-O-C₂-C₆ alkynyl. 35. The compound of any of claims 1 to 33, wherein R⁴ is C₁-C₆ alkyl and R⁵ is C₁-C₆ alkyl optionally substituted with one or more R₇. 36. The compound of any of claims 1 to 33, wherein R⁴ is C₁-C₃ alkyl and R⁵ is C₁-C₃ alkyl. 37. The compound of any of claims 1 to 33, wherein R⁴ is methyl and R⁵ is methyl optionally substituted with one or more R₇. 38. The compound of any of claims 1 to 27, wherein two R³ together with the atoms to which they are attached, form a heterocycle, the heterocycle optionally substituted with one or more R₇. 39. The compound of any of claims 1 to 27, wherein R³ is selected from: 40. The compound of any of claims 1 to 27, wherein R³ is , or . 41. The compound of any of claims 1 to 28, wherein R³ is . 42. The compound of claim 23 or 23, of formula: . 43. The compound of claim 42 or 42, wherein R¹ is independently halo, C₁-C₆ alkyl, or C₁- C₆ haloalkyl. 44. The compound of any of claims 1 to 27, wherein R³ is -CONR⁸R⁹ wherein R⁸ and R⁹ are independently H or C₁-C₆ alkyl wherein each alkyl within R⁸ and R⁹ is independently substituted with one, two or three halogen, cyano, hydroxy, C₁-C₃ alkoxy, amino, mono- or di(C₁-C₃ alkyl)amino, amino-C₁-C₃ alkoxy, mono- or di(C₁-C₃ alkyl)amino-C₁-C₃ alkoxy, hydroxy-C₁-C₃ alkoxy, or C₁-C₆ alkoxy-C₁-C₆ alkoxy. 45. The compound of any of claims 1 to 27, wherein R³ is -CONHR⁹ wherein R⁹ is C₁-C₆ alkyl substituted with one, two or three halogen, cyano, hydroxy, C₁-C₃ alkoxy, amino or mono- or di(C₁-C₃ alkyl)amino. 46. The compound of any of claims 1 to 27, wherein R³ is -CONHR⁹ wherein R⁹ is C₁-C₆ alkyl substituted with hydroxy-C1-C3 alkoxy or C1-C6 alkoxy-C1-C6 alkoxy. 47. The compound of any of claims 1 to 27, wherein R³ is -CONHR⁹ wherein R⁹ is C₁-C₆ alkyl substituted with hydroxy-C₁-C₃ alkoxy.

48. The compound of any of claims 1 to 27, wherein R³ is -CONHR⁹ wherein R⁹ is C₁-C₆ alkyl substituted with amino-C₁-C₃ alkoxy. 49. The compound of claim 1, which is: 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; 5-((ethyl(methyl)amino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; 5-((diethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; 5-((dimethylamino)methyl)-N-(5-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H- benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine; 5-(azetidin-1-ylmethyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; 5-((dimethylamino)methyl)-N-(1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol- 2-amine; 6-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5-(pyrrolidin-1- ylmethyl)benzo[d]oxazol-2-amine; 5-((dimethylamino)methyl)-N-(5-fluoro-1-phenyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5-((methyl(2-(prop-2-yn-1- yloxy)ethyl)amino)methyl)benzo[d]oxazol-2-amine; 5-((dimethylamino)methyl)-N-(6-fluoro-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol- 2-amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5- ((methyl(propyl)amino)methyl)benzo[d]oxazol-2-amine; (2-((5-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2- yl)amino)benzo[d]oxazol-5-yl)methanol; 5-((dimethylamino)methyl)-N-(5-fluoro-1-propyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5- (morpholinomethyl)benzo[d]oxazol-2-amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-7-methyl-7,8-dihydro-6H- oxazolo[4,5-e]isoindol-2-amine; (2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-5- yl)methanol; N-(1-cyclopropyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-5- ((dimethylamino)methyl)benzo[d]oxazol-2-amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5-((4-methylpiperazin-1- yl)methyl)benzo[d]oxazol-2-amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-6-methyl-6,7-dihydro-5H- oxazolo[4,5-f]isoindol-2-amine; N-(1-(cyclopropylmethyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-5- ((dimethylamino)methyl)benzo[d]oxazol-2-amine; 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2- amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5-(methoxymethyl)benzo[d]oxazol- 2-amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5-((methyl(prop-2-yn-1- yl)amino)methyl)benzo[d]oxazol-2-amine; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine; 2-(2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-5- yl)acetonitrile; (2-((1-cyclopropyl-5-fluoro-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-5- yl)methanol; 2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5- carbaldehyde; N-(1-benzyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-5- ((dimethylamino)methyl)benzo[d]oxazol-2-amine; 5-((dimethylamino)methyl)-N-(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-N- methylbenzo[d]oxazol-2-amine; 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-N- methylbenzo[d]oxazol-2-amine; 5-((dimethylamino)methyl)-N-(5-fluoro-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol- 2-amine; 4-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; 7-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-6- methoxybenzo[d]oxazol-2-amine; N-(5-((dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5- fluorobenzo[d]oxazol-2-amine; N-(6-((dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5- fluorobenzo[d]oxazol-2-amine; (2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazol-6- yl)methanol; 5-((dimethylamino)methyl)-N-(1-ethyl-5-fluoro-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; 2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)-N-(2-(2- hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide; 2-(((2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-5- yl)methyl)(methyl)amino)ethan-1-ol; 1-((2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-5- yl)methyl)azetidin-3-ol; N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5-((3-methoxyazetidin-1- yl)methyl)benzo[d]oxazol-2-amine; 5-((3-aminoazetidin-1-yl)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2- yl)benzo[d]oxazol-2-amine; 5-((3-(dimethylamino)azetidin-1-yl)methyl)-N-(5-fluoro-1-methyl-1H- benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine; N-(2-(2-hydroxyethoxy)ethyl)-2-((1-methyl-1H-benzo[d]imidazol-2- yl)amino)benzo[d]oxazole-5-carboxamide; or a pharmaceutically acceptable salt thereof. 50. A pharmaceutical composition comprising a compound according to any one of claims 1-44 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent. 51. A method of treating an inflammatory condition in a subject in need thereof, comprising providing to the subject a compound according to any one of claims 1-49 or a pharmaceutical composition according to claim 50. 52. The method of claim 51, wherein the inflammatory condition is an inflammatory bowel disease, Crohn’s and colitis, an arthritic disease, or a neurodegenerative disease.

53. The method of claim 51, wherein the inflammatory condition is an infectious disease, immune disease, blood disorder, cancer, ocular, pulmonary and systemic inflammatory conditions. 54. The method of claim 51, wherein the condition is metabolic, fibrotic, renal disorder, or neurological disease. 55. A compound as described in any of claims 1-49, wherein the compound binds to the transcriptional repressor Bach1, or is an HO-1 inducer. 56. A method of increasing the activity or the amount of HO-1 in a human subject, the method comprising: administering to a human subject an effective amount of the compound of any of claims 1-4949 or a pharmaceutical composition according to claim 50. 57. A method of activating transcription factor Nrf2 in human subjects comprising: administering to a human subject an effective amount of the compound of any of claims 1-49 or a pharmaceutical composition according to claim 50. 58. A method of reducing the amount of reactive oxygen species in human subjects comprising: administering to a human subject an effective amount of the compound of any of claims 1-49.