benzimidazole derivatives

Abstract

Benzimidazole derivatives, pharmaceutical compositions containing them, and methods of using them are disclosed.

Description

[Technical Field]

[0001] Background of the Disclosure FIELD OF THE DISCLOSURE The present disclosure relates generally to benzimidazole derivatives, pharmaceutical compositions containing them, and methods of using them. [Background technology]

[0002] Oxidative stress, characterized by elevated levels of intracellular reactive oxygen species (ROS), is mitigated by the cellular antioxidant response to maintain homeostasis. Unchecked, abnormal ROS production can result in damage to cellular components, including lipids and nucleic acids. Excessive and prolonged intracellular oxidative stress is associated with chronic diseases, including, but not limited to, autoimmune, pulmonary, neuroinflammatory, neurodegenerative, hematological, cardiovascular, renal, metabolic, and cancer. Therefore, therapeutic strategies that restore homeostatic oxidative status within cells are of considerable 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 for alleviating diseases driven by oxidative stress (e.g., the Nrf2-activating dimethyl fumarate is approved in the United States for use in the treatment of relapsing-remitting multiple sclerosis and psoriasis). Under homeostatic conditions, Bach1 occupies antioxidant response elements (AREs) in the promoters of diverse genes involved in the cellular antioxidant response, preventing their transcription. In response to oxidative stress, Bach1 dissociates from the ARE, allowing binding by the transcription factor Nrf2. This drives the expression of antioxidant response genes, including, but not limited to, heme oxygenase-1 (Hmox1). Bach1 / Nrf2 activation, and the resulting Hmox1 expression, have been 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 the inflammasome. These are large multiprotein complexes that play a key role in both sterile tissue injury and infection. However, due to the strongly pro-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, which result in a range of potentially life-threatening autoinflammatory diseases. Chronic and acute aberrant activation of the inflammasome pathway also contributes to the pathology of a wide range of arthritic, neurodegenerative, neurological, cardiovascular, hematological, cutaneous, fibrotic, metabolic, renal, ocular, pulmonary, and systemic inflammatory conditions.

[0005] Assembly of the inflammasome complex is controlled by a "two-hit" system, in which two independent signals are required for activation. Signal 1 stimulates the transcription of inflammasome-associated genes, leading to the upregulation of individual inflammasome components and the production of proforms of the inflammasome substrates interleukin-1β (IL-1β), interleukin-18 (IL-18), and gasdermin-D in the cytosol. Signal 2 is provided by a series of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) sensed by a family of cytoplasmic pattern-recognition receptors called nucleotide-binding oligomerization domain-like receptors (NLRs), as well as a small number of additional inflammasome formation sensors. Binding of DAMPs to their corresponding NLRs leads to a conformational change in the NLR, enabling the receptor to self-oligomerize. These NLR oligomers then recruit an adaptor protein, the apoptosis-associated speck-like protein (ASC), which contains a CARD. This NLR-ASC complex then nucleates the formation of ASC filaments mediated through the pyrin domain (PYD) of ASC. The ASC filaments then recruit caspase-1, leading to its autocatalytic cleavage and activation, creating a platform for 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-1β, pro-IL-18, and gasdermin D into their active forms, releasing 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 numerous NLRs (including pyrin, NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4, and NLRC5), the PYHIN family members IFI-16 and AIM2, and RIG-I. Previous approaches to inflammasome inhibition have targeted individual receptors, such as NLRP3, to inhibit subsets of inflammasomes. However, emerging evidence clearly demonstrates that activation of multiple distinct inflammasome-forming receptors is a common pathological feature of many diseases, including inflammatory bowel disease, arthritis, and neurodegenerative disorders, among others. Therefore, broader pharmaceutical approaches capable of simultaneously inhibiting multiple inflammasomes are needed to address pathological inflammasome-dependent inflammation.

[0007] One approach to achieving broader inflammasome inhibition is to target shared components of the inflammasome, such as caspase-1 or ASC filaments. Inflammasome assembly is induced by cytoplasmic sensors (e.g., NLRP3 or AIM2) that detect danger signals associated with infection or sterile injury. Upon sensing these signals, the sensors nucleate the formation of long filaments composed of repeating units of the inflammasome adaptor protein ASC. These filaments form a scaffold for caspase-1 recruitment, leading to autoproteolytic activation of the enzyme. However, the development of active site inhibitors for caspase-1 has been significantly hampered by the highly conserved active site shared by all caspases. This feature, combined with the diverse and essential biological roles of other caspase family members, leads to high cross-reactivity with off-target caspase proteins, resulting in unacceptable toxicity.

[0008] Although inflammasomes play 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. Therefore, developing compositions and methods to prevent inflammasome-driven inflammation is a significant challenge. Summary of the Invention

[0009] One aspect of the present disclosure is a compound of structural formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, solvate, 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; R 1 are independently halo, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, -NH, -NH(C-C alkyl), -N(C-C alkyl), -OH, C-C alkoxy, C-C haloalkoxy, hydroxy(C-C alkyl), hydroxy(C-C alkoxy), alkoxy(C-C alkyl), alkoxy(C-C alkoxy), or amino(C-C alkyl); R 2 is H or C1-C6 alkyl; Each R 3 are 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-NR 4 R 5 , -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 -CONR 8 R 9 (In the formula, R 8 and R 9 are independently H or C1-C6 alkyl, and R 8 and R 9 wherein each alkyl 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 The Two R's 3 together with the atoms to which they are attached form a heterocycle, the heterocycle being optionally substituted with one or more R7; R 4 is H or C1-C6 alkyl; R 5 is H, C-C alkyl optionally substituted with one or more R, C-C alkenyl, C-C alkynyl, C-C haloalkyl, —(C-C alkyl)-O—C-C alkyl, —(C-C alkyl)-O—C-C alkenyl, or —(C-C alkyl)-O—C-C alkynyl; Each R 6are 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; Each R 7 are 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 R 7 groups form =O together with the carbon to which they are attached).

[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 the compounds described herein (eg, compounds of Formula (I)).

[0012] In another aspect, the present disclosure provides compounds described herein that bind to the transcriptional repressor Bach1. For example, the present disclosure provides a method for inhibiting Bach1 activity, comprising administering to a human subject an effective amount of a compound described elsewhere herein.

[0013] Thus, in various embodiments described elsewhere herein, the compound is an HO-1 inducer. Thus, in another aspect, the disclosure provides a method of increasing the activity or amount of HO-1 in a human subject, comprising administering to the human subject an effective amount of a compound described elsewhere herein, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition thereof.

[0014] Nrf2 is a transcription factor that regulates HO-1 expression. In another aspect, the present disclosure provides a method for activating the transcription factor Nrf2 in a human subject, comprising administering to the human subject an effective amount of a compound as described elsewhere herein, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition thereof.

[0015] In another aspect, the present disclosure provides a method for reducing the amount of reactive oxygen species in a human subject, comprising administering to the human subject an effective amount of a compound described elsewhere herein, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition thereof. In various embodiments, the compounds described elsewhere herein are not inherently reducing. For example, the compounds may function to reduce the amount of reactive oxygen species through enhancing or suppressing biological targets involved in the natural oxidative stress response.

[0016] In another aspect, the present disclosure provides a method for treating an inflammatory condition or disorder in a subject, particularly a mammalian subject, and more particularly a human subject, the method comprising administering to the subject an effective amount of a compound described herein.

[0017] In another aspect, the present disclosure provides intermediates useful for preparing compounds of formula (I).

[0018] Other aspects and embodiments of the present disclosure will be apparent in view of the detailed description provided herein.

[0019] The accompanying drawings are included to provide a further understanding of the methods and compositions of the present disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiments of the present disclosure and, together with the description, serve to explain the principles and operation of the present disclosure. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 shows the inflammasome inhibitory activity of compounds of the present disclosure compared to a control compound, MCC950. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present disclosure provides compounds, pharmaceutical compositions, methods, and uses for treating various diseases associated with inhibiting inflammasome formation.

[0022] Thus, one aspect of the present disclosure is a compound of (I) above: [ka] to provide.

[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 certain embodiments, R is CH3.

[0025] In certain embodiments, each R2 is independently H or methyl. For example, in some embodiments, the present disclosure provides compounds of formula (I) described herein, such as the following formula: [ka]

[0026] One embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein m is 1 or 2. In one embodiment, m is 1. For example, such a compound may be of the following formula: [ka] .

[0027] In certain embodiments, the present disclosure provides compounds of the following formula: [ka] .

[0028] In certain embodiments, the present disclosure provides compounds of the following formula: [ka] .

[0029] Another embodiment of the present disclosure is a compound of formula (I) described herein, wherein R 1 is independently halo, C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C haloalkyl. 1 is independently halo, C-C alkyl, or C-C haloalkyl. 1 is independently halo, C-C alkyl, or C-C haloalkyl. 1 are independently halos.

[0030] In certain embodiments, the present disclosure provides compounds of formula (I) as described herein, wherein at least one R 1 is halo (e.g., fluoro).

[0031] In certain embodiments, the present disclosure provides compounds of the following formula: [ka] .

[0032] Another embodiment of the present disclosure is a compound of formula (I) described herein, wherein R 2 is H or C1-C3 alkyl. In certain embodiments, R 2 is H or methyl. In certain embodiments, R 2 is H.

[0033] In certain embodiments, the present disclosure provides compounds of the following formula: [ka] .

[0034] One embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein n is 1 or 2. In one embodiment, n is 1. For example, such a compound may be of the following formula: [ka] .

[0035] In certain embodiments, the present disclosure provides compounds of the following formula: [ka] .

[0036] In certain embodiments, the present disclosure provides compounds of the following formula: [ka] .

[0037] Another embodiment of the present disclosure is a compound of formula (I) described herein, wherein R 3-C1-C6 alkyl-NR 4 R 5 , -C1-C6 alkyl-CN, -C1-C6 alkyl-OR 4 , -(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 R 3 together with the atoms to which they are attached form a heterocycle, the heterocycle being optionally substituted with one or more R7).

[0038] In certain embodiments, R 3 is -C1-C6 alkyl-NR 4 R 5 , -C1-C6 alkyl-CN, -C1-C6 alkyl-OR 4 , -(C-C alkyl)-aryl optionally substituted with one or more R, -(C-C alkyl)-heteroaryl optionally substituted with one or more R, -(C-C alkyl)-heterocyclyl optionally substituted with one or more R, -(C-C alkyl)-C-C cycloalkyl optionally substituted with one or more R, -COH, -COH, -CO(C-C alkyl), -CO(C-C alkyl), -CONH, -CONH(C-C alkyl), or -CON(C-C alkyl).

[0039] In certain embodiments, R 3 is -C1-C6 alkyl-NR 4 R 5 , -C1-C6 alkyl-CN, -C1-C6 alkyl-OR 4, -(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 R 3 together with the atoms to which they are attached form a heterocycle, and the heterocycle is optionally substituted with one or more R. In certain embodiments, R 3 is -C1-C6 alkyl-NR 4 R 5 , -C1-C6 alkyl-CN, -C1-C6 alkyl-OR 4 , -(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) described herein, R 3 is --C1-C6 alkyl-NR 4 R 5 , -C1-C6 alkyl-OR 4 or -(C1-C6 alkyl)-heterocyclyl optionally substituted with one or more R7. In certain embodiments, R 3 is -C1-C6 alkyl-NR 4 R 5 is.

[0041] In certain embodiments of the compounds of Formula (I) described herein, R 3 -CONR 8 R 9 (In the formula, R 8 and R 9 are independently H or C1-C6 alkyl, and R 8 and R 9wherein each alkyl is independently substituted with 1, 2, or 3 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) described herein, R 3 -CONR 8 R 9 where R 8 and R 9 are independently H or C1-C6 alkyl, where R 8 and R 9 wherein each alkyl is independently substituted with 1, 2, or 3 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) described herein, R 3 -CONHR 9 (In the formula, R 9 is H or C1-C6 alkyl, wherein alkyl is substituted with 1, 2, or 3 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) described herein, R 3 -CONHR 9 (In the formula, R 9 is C1-C6 alkyl substituted with 1, 2, or 3 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) described herein, R 3 -CONHR 9 (In the formula, R 9 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) described herein, R 3 -CONHR 9 (In the formula, R 9 is C1-C6 alkyl substituted with hydroxy-C1-C3 alkoxy).

[0047] In certain embodiments of the compounds of Formula (I) described herein, R 3 -CONHR 9 (In the formula, R 9 is C1-C6 alkyl substituted with C1-C6 alkoxy-C1-C6 alkoxy).

[0048] In certain embodiments of the compounds of Formula (I) described herein, R 3 -CONHR 9 (In the formula, R 9 is C1-C6 alkyl substituted with amino-C1-C3 alkoxy).

[0049] In certain embodiments of the compounds of Formula (I) described herein, R 3 -CONHR 9 (In the formula, R 9 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) described herein, R 4 is C1-C6 alkyl, and R 5is C-C alkyl optionally substituted with one or more R, C-C alkenyl, C-C alkynyl, C-C haloalkyl, —(C-C alkyl)-O—C-C alkyl, —(C-C alkyl)-O—C-C alkenyl, or —(C-C alkyl)-O—C-C alkynyl. In certain embodiments, R 4 is C1-C6 alkyl, and R 5 is C1-C6 alkyl optionally substituted with one or more R7. In certain embodiments, R 4 is C1-C3 alkyl, and R 5 is C1-C3 alkyl. In certain embodiments, R 4 is methyl and R 5 is methyl optionally substituted with one or more R7.

[0051] In certain embodiments of the compounds of Formula (I) described herein, two R 3 together with the atoms to which they are attached form a heterocycle, the heterocycle being optionally substituted with one or more R7.

[0052] In certain embodiments of the compounds of Formula (I) described herein, R 3 teeth, H, -CH2Cl, -C(O)H, -OCH3, -CO2CH3, [ka] or two R 3 together with the atoms to which they are attached [ka] Form. In other embodiments, R 3 teeth, [ka] In other embodiments, R 3 teeth, [ka] is.

[0053] In certain embodiments, the compounds described herein have the formula: [ka] (In the formula, R is H or CH3, and R 1 is independently halo, C-C alkyl, or C-C haloalkyl; R 2 is H or C1-C3 alkyl).

[0054] In certain embodiments, the compounds described herein have the formula: [ka] (In the formula, R is H or CH3, and R 1 is independently halo, C-C alkyl, or C-C haloalkyl; R 2 is H or C1-C3 alkyl).

[0055] In other embodiments, the compound has the formula: [ka] (In the formula, R 1 is fluoro or hydrogen, R 4 and R 5 are independently hydrogen, methyl, ethyl, propyl, isopropyl, propargyloxyethyl, propargyloxymethyl, or propargyl; or R 4 and R 5 together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl group.

[0056] In certain embodiments of the compounds described elsewhere herein, the compounds are in the form of pharmaceutically acceptable salts of the compounds described herein. Those skilled in the art will understand that various pharmaceutically acceptable salts can be provided, as described in more detail below. In certain embodiments of the compounds described elsewhere herein, the compounds are in the form of solvates (e.g., hydrates) of the compounds or salts described herein. Those skilled in the art will understand that various solvates and / or hydrates can be formed. Those skilled in the art will understand 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 the above-mentioned base compounds or pharmaceutically acceptable salts. However, in certain embodiments described above, the compounds are not in the form of solvates or hydrates.

[0057] In certain embodiments, the compound of formula (I) is

[0058] [Table 1A] [Table 2B] [Table 2C] [Table 2D] [Table 2E] [Table 2F] [Table 2G] [Table 2H] or a pharmaceutically acceptable salt thereof.

[0059] therapeutic use The present disclosure also provides methods for treating various inflammatory conditions, i.e., inflammatory diseases and disorders, comprising administering to a subject in need of such treatment an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula (I)) or pharmaceutical compositions of the present disclosure described herein.

[0060] In certain embodiments, the present disclosure provides a method of treating an inflammatory condition in a subject, the method comprising providing to the subject a compound as described elsewhere herein. In certain embodiments as described elsewhere 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, an autoimmune disease, a cancer, a metabolic disorder, or a neurological disorder.

[0061] In other embodiments, the inflammatory condition is an autoinflammatory syndrome. In yet other embodiments, the inflammatory condition is an inflammasome-associated condition. Some conditions and / or diseases may be a combination of the above embodiments or may otherwise fall into multiple categories simultaneously.

[0062] In certain embodiments, diseases and disorders that may be treated according to the methods disclosed herein include adult-onset Still's disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), macrophage activation syndrome (MAS), autoinflammatory disease with infantile enteritis (AIFEC), bullous pemphigoid, pemphigus vulgaris, idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), systemic lupus erythematosus (SLE), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and the like. These include, but are not limited to, Alzheimer's disease, epilepsy, traumatic brain injury (TBI), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cryopyrin-associated periodic fever 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, pyridoxine hydrochloride, sickle cell disease, and autosomal dominant polycystic kidney disease (ADPKD).

[0063] In certain embodiments, the present disclosure provides methods for treating one or more diseases selected from the following categories: (i) fibrosis, e.g., associated with the lung (COPD, idiopathic pulmonary fibrosis, sarcoid disease), liver (alcoholic cirrhosis, steatosis, cholestasis, drug-induced fibrosis, viral infection), or skin (scleroderma, psoriasis); (ii) neurodegenerative diseases, e.g., Friedreich's ataxia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Charcot-Marie-Tooth syndrome; (iii) cardiovascular diseases, e.g., hypertension, heart failure, hypercholesterolemia, atherosclerosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease. , congestive heart failure, acute coronary syndrome, failure of arterial fistulas for dialysis and primary pulmonary hypertension, ischemia-reperfusion events; (iv) kidney diseases, e.g., diabetic nephropathy, glomerulonephritis, acute tubular necrosis, and autosomal dominant polycystic kidney disease; (v) liver diseases, e.g., drug-induced hepatotoxicity, nonalcoholic steatohepatitis, hepatitis C infection; (vi) eye diseases, e.g., glaucoma, uveitis, wound healing (post-operative), ocular trauma, corneal transplant, macular degeneration, cataract, photoretinopathy, retinopathy of prematurity; (vii) thyroid diseases, e.g., Graves' disease, follicular adenoma, and papillary and follicular carcinoma; (viii) viral infections, e.g., HIV, hepatitis B, hepatitis C, herpes viruses, coronaviruses (e.g., SARS-CoV) 2, SARS-CoV, or MERS), and (ix) diabetes, e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, hyperglycemia and metabolic syndrome, and pancreatic beta cell loss.

[0064] In certain embodiments, the present disclosure provides methods for treating an inflammatory condition in a human subject resulting from a viral, e.g., coronavirus (e.g., SARS-CoV 2, SARS-CoV, or MERS), bacterial, fungal, parasitic, or other type of infection, resulting in cell death or the release of pro-inflammatory cytokines or other inflammatory mediators.

[0065] The present invention also provides the use of the compounds 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, and antidotes (e.g., metformin). In one embodiment, the present invention provides a pharmaceutical composition comprising a compound described herein and at least one other medically effective ingredient selected from Nrf2 activators, antioxidants, antidotes, anti-inflammatory agents, and antidiabetic drugs (e.g., metformin). In another embodiment, the present invention provides the use of a compound described herein in combination with at least one other medically effective ingredient selected from Nrf2 activators, antioxidants, antidotes, anti-inflammatory agents, and antidiabetic drugs (e.g., metformin) for simultaneous, subsequent, or sequential administration.

[0066] Examples of Nrf2 activators include sulforaphane, avicin, 15dPGJ2, xanthofumolol, curcumin, carnosol, zerumbone, isothiocyanates, α-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).

[0067] Examples of antioxidants include vitamin C, vitamin E, carotenoids, retinoids, polyphenols, farvanoids, lignans, selenium, butylated hydroxyanisole, ethylenediaminetetra-acetate, calcium disodium, acetylcysteine, probucol, and tempo.

[0068] Examples of antidotes include dimethylcaprol, glutathione, acetylcysteine, methionine, sodium bicarbonate, deferoxamine mesylate, calcium disodium edetate, trientine hydrochloride, penicillamine, and medicinal charcoal.

[0069] Without wishing to be bound by theory, it is currently 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 a method for inhibiting caspase-1 in a subject, comprising administering a compound described elsewhere herein. Specifically, in some embodiments, inhibition may be through interaction with the CARD domain of caspase-1.

[0070] Pharmaceutical Compositions and Dosage Forms The compounds described herein can be effectively provided in the form of a pharmaceutical composition. Such a composition comprises a compound according to any one of the preceding aspects or embodiments described herein, together with a pharmaceutically acceptable excipient, diluent, or carrier.

[0071] The compounds can be formulated in pharmaceutical compositions per se or in the form of hydrates, solvates, or pharmaceutically acceptable salts as described above. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, although salts having lower solubility than the corresponding free acids and bases can also be formed.

[0072] The pharmaceutical composition may be in the form of, for example, a tablet, capsule, or parenteral formulation, although one of ordinary skill in the art will appreciate that the compounds may be provided in a wide variety of pharmaceutical compositions.

[0073] The compound of the present disclosure can be administered orally, topically, parenterally, or rectally, for example, by inhalation or spraying in a dosage unit formulation containing one or more pharmaceutically acceptable carriers, diluents, or excipients.As used herein, the term parenteral includes transdermal, subcutaneous, intravascular (for example, intravenous), intramuscular, or intrathecal injection or infusion techniques, etc.Medicines containing the compound of the present disclosure can be provided in any suitable formulation and dosage form as described herein.

[0074] Pharmaceutical compositions can be prepared using the compounds of the present disclosure.For example, in one embodiment, pharmaceutical compositions comprise a pharmaceutically acceptable carrier, diluent or excipient and the compound described above with reference to any one of the structural formulas.

[0075] In the pharmaceutical compositions disclosed herein, one or more compounds of the present 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 the compounds of the present disclosure may be in a form suitable for oral use, for example, as tablets, troches, drops, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0076] Compositions intended for oral use can be prepared according to any suitable method for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients 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 such as corn starch or alginic acid; binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. 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, thereby providing a sustained effect over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

[0077] Oral preparations can also be presented as hard gelatin capsules, with the active ingredient being mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, with the active ingredient being mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. Oral preparations can also be presented as drops.

[0078] Aqueous suspensions contain active material in admixture with excipients suitable for the manufacture of aqueous suspensions.Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing agents or wetting agents such as naturally occurring phosphatides, such as lecithin, or alkylene oxide condensation products with fatty acids, such as polyoxyethylene stearate, or ethylene oxide condensation products with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or ethylene oxide condensation products with fatty acid-derived partial esters and hexitols, such as polyoxyethylene sorbitol monooleate, or ethylene oxide condensation products with fatty acid-derived partial esters and hexitol anhydrides, such as polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, such as, 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.

[0079] Oily suspension can be prepared by suspending active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oil such as liquid paraffin.Oily suspension can contain thickening agent, such as beeswax, hard paraffin or cetyl alcohol.Sweetener and flavoring agent can be added to make the oral preparation palatable.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0080] Dispersible powders and granules suitable for preparing aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above.Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0081] The pharmaceutical composition can also be in the form of an oil-in-water emulsion.The oil phase can be vegetable oil or mineral oil or a mixture thereof.Suitable emulsifiers can be naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and the condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.Emulsions can also contain sweeteners and flavoring agents.

[0082] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not water. In other embodiments, water comprises less than 50% of the composition. In some embodiments, a composition containing less than 50% water has at least 1%, 2%, 3%, 4%, or 5% water. In other embodiments, the water content is present in the composition in trace amounts.

[0083] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not alcohol. In other embodiments, alcohol comprises less than 50% of the composition. In some embodiments, compositions containing 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 trace amounts.

[0084] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, glucose, or sucrose. Such formulations may also contain demulcents, preservatives, flavorings, and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be used as solvents or suspending media. For this purpose, any sterile fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, find use in the preparation of injectables.

[0085] The compound of the present disclosure can also be administered in the form of suppositories, for example, for rectal administration of drugs.These compositions can be prepared by mixing the compound with suitable non-irritating excipients, which are solid at normal temperature but liquid at rectal temperature, and therefore melt in rectum to release drug.Such materials include cocoa butter and polyethylene glycol.

[0086] The compound of the present disclosure can also be administered parenterally in sterile medium.Depending on the vehicle and concentration used, the drug can be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

[0087] The compositions can be formulated in unit dosage form of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as single dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0088] The compounds may be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered will typically be determined by a physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0089] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds described herein.When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be easily 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, for example, 0.1 to about 500 mg of the active ingredient of the compounds described herein.

[0090] Tablets or pills can be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope surrounding the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0091] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or therapy, the condition of the patient, the method of administration, etc. In therapeutic applications, the composition may 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. The effective dose will depend on the disease state being treated and factors such as the severity of the disease, the age, weight, and general condition of the patient, and the judgment of the attending physician.

[0092] The compositions administered to patients may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for immediate use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically 3-11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0093] The therapeutic dosage of a compound may vary according to, for example, the particular use for which the treatment is given, the method 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 may vary depending on numerous factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds described herein may 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 dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage will likely depend on variables such as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the formulation of the excipient, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0094] The compounds described herein may also be formulated in combination with, or administered sequentially with, one or more additional active ingredients, which may include any pharmaceutical agent, such as an antiviral agent, a vaccine, an antibody, an immune enhancer, an immunosuppressant, an anti-inflammatory agent, etc.

[0095] Those skilled in the art will formulate the compounds described herein into pharmaceutical preparations. For example, based on the physicochemical properties of the compound, those skilled in the art will know the pharmaceutically effective amount of the compound and the desired route of administration.

[0096] definition Terms used herein may be preceded and / or followed by a single dash, "-", or a double dash, "=" to indicate the attachment order of bonds between the named substituent and its parent moiety. A single dash indicates a single bond, and a double dash indicates a double bond, or, in the case of a spiro substituent, a pair of single bonds. 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. Furthermore, substituents are intended to be read "left to right" with reference to the referenced chemical structure, unless a dash dictates otherwise. For example, arylalkyl, arylalkyl-, and -alkylaryl indicate the same functional group.

[0097] For simplicity, chemical moieties are defined and referred to throughout primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under appropriate structural circumstances apparent to those of skill in the art. For example, an "alkyl" moiety can refer to a monovalent radical (e.g., CH3-CH2-), but in some situations, the divalent linking moiety can be "alkyl," in which case one of skill will understand that alkyl is a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term "alkylene." (Similarly, in situations where a divalent moiety is required and described as "aryl," one of skill will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal valence numbers 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 S). Nitrogen in the compounds of the present disclosure can be hypervalent, e.g., an N-oxide or tetrasubstituted ammonium salt. Sometimes the moiety is, for example, -B-(A) a where a is 0 or 1. In such case, when a is 0, the moiety is -B, and when a is 1, the moiety is -BA.

[0098] As used herein, the term "alkyl" includes saturated hydrocarbons having a designed number of carbon atoms, such as 1 to 10 carbons (i.e., 1 and 10 inclusive), 1 to 8 carbons, 1 to 6 carbons, 1 to 3 carbons, or 1, 2, 3, 4, 5, or 6. Alkyl groups can be straight or branched chain and, depending on the context, can be monovalent or divalent radicals (i.e., alkylene groups). For example, the moiety "-(C1C6 alkyl)-O-" represents the attachment of an oxygen through an alkylene bridge having 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.

[0099] 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.

[0100] As used herein, unless otherwise specified, the term "alkenyl" refers to an unsaturated hydrocarbon containing 2 to 10 carbons (i.e., inclusive), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5, or 6 carbons, and containing at least one carbon-carbon double bond. Alkenyl groups can be straight or branched chain and, depending on the context, can be monovalent or divalent radicals (i.e., alkenylene groups). For example, the moiety "-(C2-C6 alkenyl)-O-" refers to the attachment of an oxygen through an alkenylene bridge having 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.

[0101] As used herein, the term "alkynyl," unless otherwise specified, refers to an unsaturated hydrocarbon containing 2 to 10 carbons (i.e., inclusive), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5, or 6 carbons, and containing at least one carbon-carbon triple bond. Alkynyl groups can be straight-chained or branched and, depending on the context, can be monovalent or divalent radicals (i.e., alkynylene groups). For example, the moiety "-(C2-C6 alkynyl)-O-" refers to attachment of oxygen through an alkynylene bridge having 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.

[0102] The term "aryl" refers to an aromatic ring system having a single ring (e.g., phenyl) optionally fused to another aromatic hydrocarbon ring, or a non-aromatic hydrocarbon ring, or a heterocyclic ring. "Aryl" includes ring systems having multiple fused rings, at least one of which is carbocyclic and aromatic (e.g., 1,2,3,4 tetrahydronaphthyl, naphthyl). Examples of aryl groups include phenyl, 1 naphthyl, 2 naphthyl, 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 non-aromatic heterocyclic ring, such as 1H-2,3 dihydrobenzofuranyl and tetrahydroisoquinolinyl. The aryl groups herein are unsubstituted, or, when specified as "optionally substituted," can be substituted at one or more substitutable positions with various groups, as indicated, unless otherwise specified.

[0103] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine. In certain embodiments of any and all embodiments described elsewhere herein, the term "halogen" or "halo" refers to fluorine or chlorine. In certain embodiments of any and all embodiments described herein, the term "halogen" or "halo" refers to fluorine. The term "fluoroalkyl" refers to an alkyl group (i.e., as described elsewhere herein) that is substituted with at least one fluorine. "Fluoroalkyl" or "fluorinated alkyl" includes alkyl groups substituted with one or more 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.

[0104] The term "heteroaryl" refers to an aromatic ring system containing at least one aromatic heteroatom selected from nitrogen, oxygen, and sulfur in the aromatic ring. Most commonly, heteroaryl groups have 1, 2, 3, or 4 heteroatoms. Heteroaryls can be fused to one or more non-aromatic rings, such as cycloalkyl or heterocycloalkyl rings, as described herein. In one embodiment of the compound, the heteroaryl group is attached to the remainder of the structure through an atom in the aromatic ring of the heteroaryl group. In another embodiment, the heteroaryl group is attached 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, and the like. 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, chloro Mononyl, 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 Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, 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 be substituted in one or more substitutable positions with various groups as indicated, unless otherwise specified.

[0105] The term "heterocycloalkyl" refers to a non-aromatic ring or ring system containing at least one heteroatom, preferably selected from nitrogen, oxygen, and sulfur, wherein the heteroatom is in a non-aromatic ring. A heterocycloalkyl can have 1, 2, 3, or 4 heteroatoms. A heterocycloalkyl can be saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., heterocycloalkenyl). Heterocycloalkyl includes monocyclic groups of 3 to 8 ring atoms, as well as bicyclic and polycyclic ring systems (each ring containing 3 to 8 ring atoms), including bridged and fused systems. Heterocycloalkyl rings are optionally fused to other heterocycloalkyl rings and / or non-aromatic hydrocarbon rings. In certain embodiments, heterocycloalkyl groups have 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, 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 either 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, tetrahydropyran ... Examples include furanyl, tetrahydrothienyl, 3,4-dihydroisoquinolin-2(1H)-yl, isoindolinedionyl, 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.Particularly desirable heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl, tetrahydropyranyl, piperidinyl, azabicyclo[2.2.2]octyl, γ-butyrolactonyl (i.e., oxo-substituted tetrahydrofuranyl), γ-butriolactamyl (i.e., oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindionyl, and piperazinonyl. Heterocycloalkyl groups herein are unsubstituted or, when specified as "optionally substituted," can be substituted at one or more substitutable positions with various groups as indicated, unless otherwise specified.

[0106] The term "cycloalkyl" refers to a non-aromatic carbocyclic ring or ring system, which can be saturated (i.e., cycloalkyl) or partially unsaturated (i.e., cycloalkenyl). Cycloalkyl rings are optionally fused to or otherwise attached to other cycloalkyl rings (e.g., bridged systems). Certain examples of cycloalkyl groups present in the compounds of the present disclosure have 3 to 7 members in a single ring, such as 5 or 6 members in a single ring. In some embodiments, 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. Cycloalkyl groups herein can be unsubstituted or, when designated "optionally substituted," can be substituted in one or more substitutable positions with various groups as indicated.

[0107] The term "ring system" includes monocyclic rings as well as fused and / or bridged polycyclic rings.

[0108] The term "oxo" refers to a double-bonded oxygen, sometimes represented as =0, or may be used to indicate an oxo-substituted carbon, for example, in describing a carbonyl "C(O)".

[0109] The term "substituted," when used to modify a named group or radical, means, unless otherwise specified, that one or more hydrogen atoms of the named group or radical are each replaced, independently of one another, with the same or different substituents, as defined below.

[0110] As used herein, the phrase "pharmaceutically acceptable salts" refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include those derived from alkanoic acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, and acetic acids, and those derived from HOOC(CH2). n COOH, where n is 0 to 4. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, etc. One of ordinary skill in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

[0111] As used herein, "tautomers" refer to isomers of a compound that exist in equilibrium and differ from one another in the position of protons and / or electron distribution. Certain compounds disclosed herein may exist in tautomeric forms, and all tautomeric forms of such compounds are within the scope of the present disclosure.

[0112] Those skilled in the art of medicinal chemistry will also understand that the disclosed structures are intended to include isotopically enriched forms of the compounds. As used herein, "isotopes" include atoms with the same atomic number but different mass numbers. As known to those skilled 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 clear to those skilled in the art from considering the compounds, certain compounds may be enriched at a given position with a specific isotope of the atom at that position. For example, a compound having a fluorine atom may be enriched with a radioactive fluorine isotope. 18 The compounds can be synthesized in a form enriched in F. Similarly, the compounds can be enriched in heavy isotopes of hydrogen: deuterium and tritium, as well as 13 The compounds may be enriched in radioactive isotopes of carbon, such as C. Such isotopically variant compounds may be useful in studying different metabolic pathways, for example, the ubiquitination pathway and its role in disease. Of course, in certain embodiments, the compounds have substantially the same isotopic signature as the naturally occurring material.

[0113] Those skilled in the chemical arts will also understand that the disclosed structures are intended to encompass all possible stereoisomers of the claimed molecules, including mixtures of a particular or all stereoisomers, unless otherwise indicated. However, compounds drawn with a particular stereochemistry at one or more stereocenters are intended to have the stereochemistry shown. Compounds and stereocenters drawn with ambiguous stereochemistry are intended to convey any stereoisomer or mixture thereof, for example, a racemic mixture of the compound or a purified subset of stereoisomers.

[0114] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and refer to any animal, including mammals, preferably humans.

[0115] As used herein, the phrase "therapeutically effective amount" or "effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response desired in a tissue, system, animal, individual, or human by a researcher, veterinarian, physician, or other clinician.

[0116] In certain embodiments, the effective amount is: (i) inhibiting disease progression; (ii) prophylactic use, e.g., to prevent or limit the onset of a disease, condition, or disorder in individuals who may be predisposed to or otherwise at risk for the disease, condition, or disorder, but who have not yet experienced or exhibited the pathology or symptoms of the disease; (iii) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder; (iv) ameliorating the disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, e.g., reducing the severity of the disease, or (v) may be in an amount suitable to induce the biological effect referred to.

[0117] As used herein, the terms "treatment" and "treating" mean (i) improving the referenced pathology, condition, or disorder (or symptoms thereof), e.g., reducing the severity of the disease or its symptoms, or inhibiting the progression of the disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., reversing or alleviating the pathology and / or symptoms), or (ii) inducing the referenced biological effect (e.g., inhibiting inflammasome formation or function or inhibiting IL-1β).

[0118] Preparation method Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, 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).

[0119] The compounds described herein can be purified by any of the methods known in the art, including chromatographic methods such as HPLC, preparative thin-layer chromatography, flash column chromatography, and ion exchange chromatography.Any suitable stationary phase can be used, including normal phase and reverse phase and ionic resin.Most typically, the disclosed compounds are purified through silica gel and / or alumina chromatography.For example, see Introduction to Modern Liquid Chromatography, 2nd Edition, ed.L.Snyder and J.J.Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, ed.E.Stahl, Springer-Verlag, New York, 1969.

[0120] During any of the processes for the preparation of the compounds of interest, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is from JFW McOmie, “Protective Groups in Organic Chemistry,” Plenum Press, London and New York 1973, TW Greene and PGMWuts, “Protective Groups in Organic Synthesis,” Third edition, Wiley, New York 1999, “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York. York 1981, “Methoden der organischen Chemie,” Houben-Weyl, 4.sup.th edition, Vol. 15 / l, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Protein,” Verlag Chemie, Weinheim, Deerfield Beach, and Basel. 1982, and / or Jochen Lehmann, “Chemie der This can be achieved by conventional protecting groups as described in standard works such as "Kohlenhydrate: Monosaccharide and Derivate," Georg Thieme Verlag, Stuttgart 1974. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0121] As used herein, a "leaving group" (e.g., suitable as LG) refers to the portion of a reactant (e.g., an alkyl halide of the present disclosure) that is transferred from a first reactant in a chemical reaction. A comprehensive list of suitable leaving groups can be found in J. March, Advanced Organic Chemistry, John Wiley and Sons, NY (2013). Examples of suitable leaving groups include, but are not limited to, halogen groups (such as Cl or Br), acetoxy groups, and sulfonyloxy groups (such as methylsulfonyloxy, trifluoromethylsulfonyloxy ("triflate"), p-toluenesulfonyloxy ("tosylate"), etc.). [Example]

[0122] The compounds disclosed herein can be prepared using procedures and methods known to those skilled in the art, for example, the general reaction schemes and examples described herein.Those skilled in the art can adapt the reaction sequences of the schemes as provided herein to suit the desired target molecule.Of course, in certain circumstances, those skilled in the art will use different reagents to affect one or more of the individual steps, or use protected versions of certain substituents.In addition, those skilled in the art will recognize that the compounds of the present disclosure can be synthesized using completely different routes.For example, those skilled in the art can adapt the procedures described herein and / or other procedures well known to those skilled in the art to make the compounds described herein.

[0123] General reaction scheme 1: Preparation of benzimidazole derivatives [ka]

[0124] General reaction scheme 2: Preparation of benzimidazole-benzoxazole derivatives [ka]

[0125] The preparation of the compounds of the present disclosure is further illustrated by the following examples, which should not be construed as limiting the disclosure in scope or spirit to the specific procedures and compounds described therein.

[0126] Example 1 Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine [ka]

[0127] Step 1: Synthesis of 4-fluoro-N-methyl-2-nitroaniline To 1,4-difluoro-2-nitrobenzene (20 g, 126 mmol), aqueous methylamine (120 mL, 377 mmol) is added at room temperature and stirred in a sealed tube for 5 hours. The reaction progress is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is quenched with ice-cold water (100 mL) and stirred for 10 minutes. The solid precipitates, is filtered, and dried in vacuo to give 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 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, zinc dust (69.2 g, 1.06 mol) and ammonium chloride (84.9 g, 1.59 mol) are added. The resulting reaction mixture is stirred at room temperature for 3 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is filtered through a Celite bed and the Celite bed is washed with ethyl acetate (2 × 50 mL). The resulting filtrate is diluted with demineralized (DM) water (300 mL) and extracted with ethyl acetate (2 × 250 mL). The organic layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 4-fluoro-N1-methylbenzene-1,2-diamine (14 g, 94%) as a brown solid.

[0129] Step 3: Synthesis of 5-fluoro-1-methyl-1H-benzo[d]imidazol-2-amine 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, cyanogen bromide (18.9 g, 178 mmol) is added. The reaction mixture is stirred at room temperature for 16 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is concentrated to give the crude product, which is diluted with DM water (200 mL) and extracted with ethyl acetate (2 × 100 mL). The aqueous layer is basified to pH 12-14 using 1N sodium hydroxide solution (30 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers are separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-fluoro-1-methyl-1H-1,3-benzodiazol-2-amine (11.5 g, 97%) as a brown solid.

[0130] Step 4: Synthesis of methyl benzo[d]oxazole-5-carboxylate 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 in a sealed tube for 16 hours. The reaction progress is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to give the crude product. The crude product is purified by flash column chromatography using 0-30% ethyl acetate in n-heptane as the eluent to give methyl 1,3-benzoxazole-5-carboxylate (4 g, 75%) as a white solid.

[0131] Step 5: Synthesis of methyl 2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxylate To a stirred solution of methyl 1,3-benzoxazole-5-carboxylate (2.4 g, 13.5 mmol) in tetrahydrofuran (24 mL) was 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 was stirred for 10 minutes, and then 5-fluoro-1-methyl-1H-1,3-benzodiazol-2-amine (3.36 g, 20.3 mmol) was added, after which the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DM water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 0-60% ethyl acetate in n-heptane as eluent to give methyl 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazole-5-carboxylate (1.6 g, crude).

[0132] Step 6: Synthesis of (2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-5-yl)methanol 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 1 M lithium aluminum hydride in THF (7.05 mL, 7.05 mmol) at room temperature. The reaction mixture is stirred at room temperature for 2 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers are washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 0-10% methanol in dichloromethane as eluent to give {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.

[0133] Step 7: Synthesis of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine 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 at 0° C. for 2 hours. The progress of the reaction is monitored by TLC. After the reaction is complete, the reaction mixture is basified (pH ∼8) using saturated potassium carbonate solution and extracted with ethyl acetate (2 × 50 mL). The combined organic layers are washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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.

[0134] Step 8: Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine 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) is 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 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is diluted with DM water (60 mL) and extracted with ethyl acetate (2 × 40 mL). The combined organic layers are washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound is purified by reverse-phase preparative HPLC: [Column: ZORBAX Eclipse C18 (150 mm × 21.2 mm, 7 μm), flow rate: 19 mL / min, mobile phase (A) 0.1% ammonia in water, mobile phase (B) acetonitrile] to obtain 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] + .

[0135] 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 [ka] Example 2 is synthesized in a similar manner to Example 1, except that N-methylaminoethane is used in step 8. LCMS (ES) m / z=352.2 [M−H] - .

[0136] Example 3 Synthesis of 5-[(diethylamino)methyl]-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine [ka] Example 3 is synthesized in a similar manner to Example 1, except N,N-diethylamino is used in step 8. LCMS (ES) m / z=366.3 [M−H] - .

[0137] 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 [ka] Example 4 is synthesized in a similar 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] + .

[0138] Example 5 Synthesis of 5-(azetidin-1-ylmethyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine [ka] Example 5 is synthesized in a similar manner to Example 1, except azetidine is used in step 8. LCMS (ES) m / z=352.2 [M+H] + .

[0139] Example 6 Synthesis of 5-[(dimethylamino)methyl]-N-(1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine [ka] Example 6 is synthesized in a similar manner to Example 1, except that 1-fluoro-2-nitrobenzene is used in Step 1. LCMS (ES) m / z=322.3 [M+H] + .

[0140] Example 7 Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine [ka] Example 7 is synthesized in a similar manner to Example 1, except that methyl 4-amino-3-hydroxybenzoate is used in step 4. LCMS (ES) m / z=340.2 [M+H] + .

[0141] 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 [ka] Example 8 is synthesized in a similar manner to Example 1, except pyrrolidine is used in step 8. LCMS (ES) m / z=366.2 [M+H] + .

[0142] Example 9 Synthesis of 5-[(dimethylamino)methyl]-N-(5-fluoro-1-phenyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine [ka] Example 9 is synthesized in a similar manner to Example 1, except that phenylamine is used in Step 1. LCMS (ES) m / z=402.3 [M+H] + .

[0143] 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 [ka]

[0144] Step 1: Synthesis of tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate To a stirred solution of 2-(methylamino)ethan-1-ol (0.5 g, 6.66 mmol) in dichloromethane (5 mL) is 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 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to give the crude product. The crude product is diluted with DM water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layer is separated, washed with DM water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude material is purified by flash column chromatography using 30-40% ethyl acetate in n-heptane as eluent to give tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (0.8 g, 69%) as a colorless liquid.

[0145] Step 2: Synthesis of tert-butyl N-methyl-N-[2-(prop-2-yn-1-yloxy)ethyl]carbamate To a solution of sodium hydride (60% dispersion in mineral oil) (21.9 mg, 571 μmol) in dimethylformamide (3 mL) at 0° C., tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (0.8 g, 4.57 mmol) (diluted in 4 mL of dimethylformamide) is added dropwise to the reaction mixture. After 20 minutes, 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 hours. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is slowly quenched with saturated ammonium chloride solution (10 mL) at 0° C. and extracted with ethyl acetate (2×20 mL). The combined organic layers are separated, dried over sodium sulfate, and concentrated to give the crude compound. The crude compound is purified by flash column chromatography using 10-15% ethyl acetate in n-heptane as eluent to give tert-butyl N-methyl-N-[2-(prop-2-yn-1-yloxy)ethyl]carbamate (750 mg, 77%) as a yellow oil.

[0146] Step 3: Synthesis of methyl[2-(prop-2-yn-1-yloxy)ethyl]amine hydrochloride 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 stirred from 0° C. to room temperature for 2 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to obtain the crude compound. The crude compound is washed with n-pentane (5 mL), followed by diethyl ether (5 mL) and acetonitrile (5 mL) to obtain methyl[2-(prop-2-yn-1-yloxy)ethyl]amine hydrochloride (510 mg, 81%) as a white solid.

[0147] 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 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 of Step 7 of the synthesis of Example 1) (0.2 g, 605 μmol) in N,N-dimethylformamide (3 mL) in a sealed tube, potassium carbonate (167 mg, 1.21 mmol) and methyl[2-(prop-2-yn-1-yloxy)ethyl]amine hydrochloride (136 mg, 907 μmol) are added at room temperature. The resulting reaction mixture is stirred in a sealed tube at 80° C. for 2 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is quenched with DM water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 7-10% methanol in dichloromethane as eluent to give 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] + .

[0148] Example 11 Synthesis of 5-((dimethylamino)methyl)-N-(6-fluoro-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine [ka] Example 11 can be synthesized essentially following the procedures described in the preceding examples and in Reaction Schemes 1 and 2.

[0149] 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 [ka] Example 12 is synthesized in a similar manner to Example 1, except N-methylpropan-1-amino is used in step 8. LCMS (ES) m / z=368.3 [M+H] + .

[0150] Example 13 Synthesis of IMM-10749 (2-((5-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-5-yl)methanol [ka] Example 13 is synthesized in step 6 of the synthesis of Example 4. LCMS (ES) m / z = 379.2 [M+H] + .

[0151] Example 14 Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-propyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine [ka] Example 14 is synthesized in a similar manner to Example 1, except that 1-aminopropane is used in Step 1. LCMS (ES) m / z=367.2 [M−H] - .

[0152] 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 [ka] Example 15 is synthesized in a similar manner to Example 1, except morpholine is used in step 8. LCMS (ES) m / z=380.2 [M−H] - .

[0153] Examples 16 and 20 Synthesis of IMM-10759 and 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) [ka]

[0154] Step 1: Synthesis of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate 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) was added potassium acetate (6.58 g, 67.1 mmol) at room temperature. The reaction mixture was degassed under nitrogen for 10 minutes, and then tetrakis(triphenylphosphane)palladium (1.94 g, 1.68 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed, and the solvent was concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 0-20% ethyl acetate in n-heptane as eluent to give 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.

[0155] Step 2: Synthesis of tert-butyl 5-hydroxyisoindoline-2-carboxylate 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 hours. The reaction progress is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is quenched with saturated sodium thiosulfate 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 sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 0-30% ethyl acetate in n-heptane as eluent to afford tert-butyl 5-hydroxy-2,3-dihydro-1H-isoindole-2-carboxylate (3.4 g, 100%) as a white solid.

[0156] Step 3: Synthesis of a regioisomeric mixture of 4-nitro-2,3-dihydro-1H-isoindol-5-ol, trifluoroacetic acid, and 6-nitro-2,3-dihydro-1H-isoindol-5-ol, trifluoroacetic acid 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 nitrite (3.07 g, 36.1 mmol) in small portions at 0 °C. The reaction mixture is warmed to room temperature and stirred for 1 h. The reaction progress is monitored by LCMS. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to give a regioisomeric mixture 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.

[0157] Step 4: Synthesis of a mixture of regioisomeric 2-methyl-4-nitroisoindolin-5-ol and 2-methyl-6-nitroisoindolin-5-ol To a stirred solution of a regioisomeric mixture 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) was added water (2.02 mL, 27.2 mmol), sodium acetate (2.23 g, 27.2 mmol), and 37% formaldehyde in acetic acid (0.5 mL) at 0 °C. The reaction mixture was stirred for 15 minutes, and sodium cyanoborohydride (1.71 g, 27.2 mmol) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 2 hours. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was quenched with DM water (100 mL) and extracted with 5% methanol in dichloromethane (2 × 100 mL). The combined organic layers are washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound, which is purified by flash column chromatography using 0-10% methanol in dichloromethane as the eluent to give 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.

[0158] Step 5: Synthesis of a mixture of regioisomeric 6-amino-2-methyl-2,3-dihydro-1H-isoindol-5-ol and 4-amino-2-methyl-2,3-dihydro-1H-isoindol-5-ol To a stirred solution of the 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 (1.0 g, 5.15 mmol) in methanol (15 mL) under a nitrogen atmosphere, 10% palladium on carbon (0.4 g, 3.76 mmol) was added. The reaction mixture was degassed with an H atmosphere and stirred under an H atmosphere for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated under reduced pressure to give the regioisomeric mixture 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.

[0159] Step 6: Synthesis of the 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 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 at room temperature for 16 hours. 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 × 30 mL). The combined aqueous layers are basified with 1N sodium hydroxide solution (20 mL) and extracted with 5% methanol in dichloromethane (2 × 50 mL). The combined organic layers are washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate 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.

[0160] 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, trifluoroacetate, 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, trifluoroacetate 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) was added 2-chloro-5-fluoro-1-methyl-1H-benzo[d]imidazole (268 mg, 1.45 mmol) and cesium fluoride (602 mg, 3.96 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with DM water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by reverse-phase preparative HPLC [Column: Inertsil ODS C18 (250 × 20) mm, 5 mic, Flow rate: -19 ml / min, Mobile phase (A): 0.1% TFA in water, Mobile phase (B): acetonitrile, RT = 11.3 and 10.44] to give N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-7-methyl-7,8-dihydro-6H-oxazolo[4,5-e]isoindol-2-amine, trifluoroacetate salt (40 mg, 7%) as a light brown solid with 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, trifluoroacetate salt (45 mg, 7.5%) as an off-white solid with LCMS (ES) m / z = 338.2 [M+H] + (Example 20)

[0161] Example 17 Synthesis of IMM-10728 {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5-yl}methanol [ka] Example 17 is synthesized in step 6 of the synthesis of Example 1. LCMS (ES) m / z = 313.2 [M+H] + .

[0162] Example 18 Synthesis of N-(1-cyclopropyl-5-fluoro-1H-1,3-benzodiazol-2-yl)-5-[(dimethylamino)methyl]-1,3-benzoxazol-2-amine [ka] Example 18 is synthesized in a similar manner to Example 1, except that 1-aminocyclopropane is used in Step 1. LCMS (ES) m / z=366.29 [M+H] + .

[0163] 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 trifluoroacetic acid [ka] Example 19 is synthesized in a similar manner to Example 1, except 1-methylpiperazine is used in step 8. LCMS (ES) m / z=393.2 [M+H] + .

[0164] Example 21 Synthesis of N-[1-(cyclopropylmethyl)-5-fluoro-1H-1,3-benzodiazol-2-yl]-5-[(dimethylamino)methyl]-1,3-benzoxazol-2-amine [ka] Example 21 is synthesized in a similar manner to Example 1, except that 1-cyclopropylmethylamine is used in Step 1. LCMS (ES) m / z=380.2 [M+H] + .

[0165] Example 22 Synthesis of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine [ka] Example 22 is synthesized in step 7 of the synthesis of Example 1. LCMS (ES) m / z = 329.1 [M−H] - .

[0166] Example 23 Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(methoxymethyl)-1,3-benzoxazol-2-amine [ka] 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 of Step 7 of the synthesis of Example 1) (20 mg, 0.060 mmol) in tetrahydrofuran (2 mL) at room temperature, sodium methanolate (7.26 μL, 0.012 mmol) is added. The reaction mixture is stirred at room temperature for 16 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is diluted with DM water (10 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers are washed with DM water (2 × 10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 0-5% methanol in DCM as eluent to give 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] + .

[0167] 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 [ka]

[0168] Step 1: Synthesis of tert-butyl N-methyl-N-(prop-2-yn-1-yl)carbamate To a solution of sodium hydride (60% dispersion in mineral oil) (247 mg, 6.44 mmol) in tetrahydrofuran (3 mL) in a sealed tube at 0 °C, a solution of tert-butyl N-(prop-2-yn-1-yl)carbamate (0.5 g, 3.22 mmol) in tetrahydrofuran is added dropwise. After 20 minutes, iodomethane (401 μL, 6.44 mmol) is added dropwise to the reaction mixture at 0 °C. The resulting reaction mixture is allowed to stir at room temperature for 2 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is slowly quenched with saturated ammonium chloride solution (25 mL) at 0 °C and extracted with ethyl acetate (2 × 20 mL). The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 10-15% ethyl acetate in n-heptane as eluent to give tert-butyl N-methyl-N-(prop-2-yn-1-yl)carbamate as a yellow oil (450 mg, 83%).

[0169] Step 2: Synthesis of methyl(prop-2-yn-1-yl)amine hydrochloride 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 stirred from 0° C. to room temperature for 2 hours. The progress of the reaction is monitored by TLC. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to obtain the 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 obtain methyl(prop-2-yn-1-yl)amine hydrochloride as a white solid (240 mg, 85%).

[0170] 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 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 of step 7 of the synthesis of Example 1) (0.2 g, 605 μmol) in N,N-dimethylformamide (5 mL) in a sealed tube, potassium carbonate (167 mg, 1.21 mmol) and methyl(prop-2-yn-1-yl)amine hydrochloride (128 mg, 1.21 mmol) are added at room temperature. The resulting reaction mixture is stirred in a sealed tube at 75° C. for 2 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is quenched with DM water (25 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound is purified by reverse-phase preparative HPLC: [Column: Inertsil ODS C18 (250 × 20) mm, 5 microns, Flow rate: -19 ml / min, Mobile phase (A): 0.1% ammonia in water, Mobile phase (B): acetonitrile] to obtain 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] + .

[0171] Example 25 Synthesis of N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine [ka] To a stirred solution of 1,3-benzoxazole (0.1 g, 0.839 mmol) in tetrahydrofuran at room temperature (4 mL) is 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 minutes. After 10 minutes, 5-fluoro-1-methyl-1H-1,3-benzodiazol-2-amine (i.e., the intermediate product of step 3 of the synthesis of Example 1) (277 mg, 1.68 mmol) is added to the reaction mixture and stirred for an additional hour. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, 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 sulfate and concentrated under reduced pressure to give the crude compound. The crude compound is purified by preparative HPLC: [Column: Inertsil ODS-3 (250 mm × 20 mm × 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 give 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] + .

[0172] Example 26 Synthesis of 2-{2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5-yl}acetonitrile [ka] 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 of Step 7 of the synthesis of Example 1) (250 mg, 756 μmol) in tetrahydrofuran (25 mL) and acetonitrile (25 mL), tetrabutylammonium fluoride (0.1 mL, 756 μmol) and trimethylsilyl cyanide (0.3 mL, 756 μmol) are slowly added at room temperature under a nitrogen atmosphere. The resulting reaction mixture is stirred in a sealed tube at room temperature for 48 hours. The progress of the reaction is 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 (2×25 mL). The combined organic layer is separated, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 5-15% methanol in dichloromethane as eluent to give 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] + .

[0173] Example 27 Synthesis of {2-[(1-cyclopropyl-5-fluoro-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5-yl}methanol [ka] Example 27 is synthesized in step 6 of the synthesis of Example 18. LCMS (ES) m / z = 339.2 [M+H] + .

[0174] Example 28 Synthesis of 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazole-5-carbaldehyde [ka] 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 of Step 6 of the synthesis of Example 1) (80 mg, 0.256 mmol) in dichloromethane (5 mL) at 0° C. was added 1,1-bis(acetyloxy)-3-oxo-3H-1λ 5 ,2-Benziodaoxol-1-yl acetate (163 mg, 0.384 mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 2 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is diluted with DM water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound is purified using preparative HPLC [column: Inertsil ODS C18 (250 × 20) mm, 5 mic, flow rate: -19 ml / min, mobile phase (A): 0.1% ammonia in water, mobile phase (B): acetonitrile] to obtain 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] + .

[0175] Example 29 Synthesis of N-(1-benzyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-5-((dimethylamino)methyl)benzo[d]oxazol-2-amine [ka] Example 29 is synthesized in a similar manner to Example 1, except benzylamine is used in Step 1. LCMS (ES) m / z=416.3 [M+H] + .

[0176] Example 30 Synthesis of 5-((dimethylamino)methyl)-N-(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-N-methylbenzo[d]oxazol-2-amine [ka] Example 30 can be synthesized essentially following the procedures described in the preceding examples and in Reaction Schemes 1 and 2.

[0177] 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 [ka]

[0178] Step 1: Synthesis of 5-fluoro-2-iodo-1-methyl-1H-1,3-benzodiazole 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) is added diiodomethane (1.02 mL, 12.1 mmol) and 3-methylbutyl nitrite (1.24 mL, 9.08 mmol) at 0 °C. The reaction mixture is stirred at 60 °C for 4 h. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is diluted with DM water (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 0-50% ethyl acetate in n-heptane as the eluent to give 5-fluoro-2-iodo-1-methyl-1H-1,3-benzodiazole (250 mg, 30%) as an off-white solid.

[0179] Step 2: Synthesis of methyl 1,3-benzoxazole-5-carboxylate 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 (515 mg, 2.99 mmol) at room temperature. The reaction mixture is stirred in a sealed tube at 120 °C for 16 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to give 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 sulfate and concentrated under reduced pressure to give methyl 1,3-benzoxazole-5-carboxylate (3.3 g, crude) as a pale yellow solid.

[0180] Step 3: Synthesis of methyl 2-iodo-1,3-benzoxazole-5-carboxylate To a stirred solution of methyl 1,3-benzoxazole-5-carboxylate (1 g, 5.64 mmol) in tetrahydrofuran (10 mL), lithium(1+) bis(trimethylsilyl)azanide (2.83 g, 16.9 mmol) is added dropwise under inert conditions at −78° C. and stirred for 1 hour. After 1 hour, 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 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is diluted with DM water (40 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 0-40% ethyl acetate in n-heptane as eluent to give methyl 2-iodo-1,3-benzoxazole-5-carboxylate (0.6 g, 35%) as a pale yellow solid.

[0181] Step 4: Synthesis of methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate A stirred solution of methyl 2-iodo-1,3-benzoxazole-5-carboxylate (0.6 g, 2.97 mmol) in 30% methylamine in ethanol (366 μL, 8.91 mmol) is stirred at room temperature for 30 minutes. The reaction progress is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 0-10% methanol in DCM as the eluent to give methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate (0.550 g, 98%) as a white solid.

[0182] Step 5: Synthesis of [2-(methylamino)-1,3-benzoxazol-5-yl]methanol To a stirred solution of methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate (550 mg, 2.67 mmol) in tetrahydrofuran (20 mL) is added 1 M lithium aluminum hydride in THF (152 mg, 4 mmol) at 0 °C. The reaction mixture is stirred at room temperature for 2 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 × 40 mL). The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give [2-(methylamino)-1,3-benzoxazol-5-yl]methanol (350 mg, crude) as a brown solid.

[0183] Step 6: Synthesis of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methyl-1,3-benzoxazol-2-amine To a stirred solution of [2-(methylamino)-1,3-benzoxazol-5-yl]methanol (0.350 g, 1.68 mmol) in dimethylformamide (2 mL) is added 1H-imidazole (172 mg, 2.53 mmol) and tert-butyl(chloro)dimethylsilane (381 mg, 2.53 mmol) at 0 °C. The reaction mixture is stirred at room temperature for 1.5 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is diluted with DM water (25 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 0-20% ethyl acetate in n-heptane as eluent to afford 5-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methyl-1,3-benzoxazol-2-amine (450 mg, 91%) as a brown oil.

[0184] 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 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) was added cesium carbonate (223 mg, 684 μmol) at room temperature. The reaction mixture was degassed under nitrogen for 5 min. After 5 minutes, 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 hours. The reaction progress 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 × 40 mL). The combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give §s (120 mg, 80%) as an off-white solid.

[0185] Step 8: Synthesis of {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)methyl)amino]-1,3-benzoxazol-5-yl}methanol 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) at 0° C. The reaction mixture is stirred at room temperature for 2 hours. The reaction progress is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is diluted with DM water (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give {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.

[0186] Step 9: Synthesis of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-N-methyl-1,3-benzoxazol-2-amine 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 hour. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to give a solid. The solid is washed with ether (15 mL) and dried under reduced pressure to give 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.

[0187] 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 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) is added potassium carbonate (60.1 mg, 435 μmol) and dimethylamine hydrochloride (17.7 mg, 218 μmol). The reaction mixture is stirred at 80° C. for 2 hours. The reaction progress is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is diluted with DM water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound is purified by preparative HPLC: [Mobile phase (A): 0.1% ammonia in water, Mobile phase (B): acetonitrile] to give 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] + .

[0188] Examples 32 to 35 Synthesis of Examples 32-35. Examples 32-35 can be synthesized essentially according to the procedures described in the preceding examples and in Reaction Schemes 1 and 2.

[0189] [Table 2]

[0190] Example 36 Synthesis of N-(5-((dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine [ka]

[0191] Step 1: Synthesis of 5-fluorobenzo[d]oxazole-2-thiol 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 at 80 °C for 16 hours. The reaction process is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to obtain the crude product. The crude product is diluted with ice-cold water and acidified using 3N HCl (pH about 4). The solid is precipitated, filtered, and dried in vacuo to obtain 5-fluoro-1,3-benzoxazole-2-thiol (1.2 g, 90%).

[0192] Step 2: Synthesis of 2-chloro-5-fluorobenzo[d]oxazole 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., dimethylformamide (1 mL, 12.9 mmol) is added and stirred at room temperature for 2 hours. The reaction progress is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is quenched with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (2×40 mL). The combined organic layers are separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-chloro-5-fluoro-1,3-benzoxazole as a gummy liquid (530 mg, 52%).

[0193] Step 3: Synthesis of methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate 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 inert conditions at 0° C., sodium hydride (60% dispersion in mineral oil) (67 mg, 2.91 mmol) is added. The reaction mixture is stirred at 0° C. for 20 minutes. Then, 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 at room temperature for 2 hours. The progress of the reaction is monitored by TLC. After the reaction is complete, the reaction mixture is diluted with cold water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers are separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazole-5-carboxylate (358 mg, 72%) as a brown solid.

[0194] Step 4: Synthesis of (2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazol-5-yl)methanol To a stirred solution of methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-5-carboxylate (350 mg, 1.03 mmol) in tetrahydrofuran (10 mL, 123 mmol) at 0° C., a 1.0 M solution of lithium aluminum hydride in THF (5 mL, 2.06 mmol) is added. The reaction mixture is stirred at room temperature for 2 hours. 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 (2×25 mL). The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give {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%).

[0195] Step 5: Synthesis of N-(5-(chloromethyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine 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) was added dimethylformamide (0.5 mL) at room temperature and stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to 0° C., neutralized using saturated sodium bicarbonate solution, and extracted with ethyl acetate (2×10 mL). The combined organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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%).

[0196] Step 6: Synthesis of N-(5-((dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine 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), dimethylamine hydrochloride (222 mg, 2.72 mmol) and potassium carbonate (188 mg, 1.36 mmol) are added and stirred at 80° C. for 16 hours. The reaction progress is monitored by TLC. The reaction mixture is diluted with DM water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product is purified using flash column chromatography and further purified using preparative HPLC [Column: Inertsil ODS C18 (250 × 20) mm, 5 microns, Flow rate: -19 ml / min, Mobile phase (A): 0.1% TFA in water, Mobile phase (B): acetonitrile] to give 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] - .

[0197] Example 37 Synthesis of N-{6-[(dimethylamino)methyl]-1-methyl-1H-1,3-benzodiazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine [ka]

[0198] Step 1: Synthesis of methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazole-6-carboxylate 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), sodium hydride 60% w / w (156 mg, 3.9 mmol) is added at 0° C. and allowed to stir for 20 minutes. After 20 minutes, 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 hours. 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 (2×80 mL). The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 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.

[0199] Step 2: Synthesis of {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-6-yl}methanol The compound {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-6-yl}methanol is synthesized in a manner similar to step 6 of the synthesis of Example 1.

[0200] Step 3: Synthesis of N-[6-(chloromethyl)-1-methyl-1H-1,3-benzodiazol-2-yl]-5-fluoro-1,3-benzoxazol-2-amine The compound N-[6-(chloromethyl)-1-methyl-1H-1,3-benzodiazol-2-yl]-5-fluoro-1,3-benzoxazol-2-amine is synthesized in a manner similar to step 7 of the synthesis of Example 1.

[0201] Step 4: Synthesis of N-{6-[(dimethylamino)methyl]-1-methyl-1H-1,3-benzodiazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine Example 37 (N-{6-[(dimethylamino)methyl]-1-methyl-1H-1,3-benzodiazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine) is synthesized in a manner similar to step 8 of the synthesis of Example 1. LCMS (ES) m / z=340.25 [M+H] + .

[0202] Example 38 Synthesis of IMM-10769 {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-6-yl}methanol [ka] Example 38 is synthesized in step 2 of the synthesis of Example 37. LCMS (ES) m / z = 313.2 [M+H] + .

[0203] Example 39 Synthesis of 5-[(dimethylamino)methyl]-N-(1-ethyl-5-fluoro-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine [ka] Example 39 is synthesized in a similar manner to Example 1, except ethylamine is used in Step 1. LCMS (ES) m / z=354.2 [M+H] + .

[0204] 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 [ka]

[0205] Steps 1 to 5 are carried out in a manner similar to steps 1 to 5 of the synthesis of Example 1.

[0206] Step 6: Synthesis of 2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxylic acid 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, lithium hydroxide (92.5 mg, 2.2 mmol) is added and stirred for 4 hours. The reaction progress is monitored by TLC. After the reaction is complete, the reaction mixture is concentrated under reduced pressure, diluted with DM water (15 mL), acidified using 1N HCl, and then extracted with ethyl acetate (2×20 mL). The combined organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 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.

[0207] 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 To a stirred solution of 2-(2-aminoethoxy)ethan-1-ol (48.3 mg, 460 μmol) in dimethylformamide (5 mL), {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) were added and stirred for 5 minutes. After 5 minutes, 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) was added and stirred at 100° C. for 16 hours. The reaction progress was 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 sulfate and concentrated under reduced pressure to give the crude compound. The crude compound is purified by flash column chromatography using 1-10% methanol in dichloromethane as the eluent to give 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] + .

[0208] 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 [ka] Example 41 is synthesized in a similar manner to Example 1, except 2-(methylamino)ethan-1-ol is used in step 8. LCMS: (ES) m / z=370.2 [M+H].

[0209] 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 [ka] Example 42 is synthesized in a similar manner to Example 1, except azetidin-3-ol is used in step 8. LCMS (ES) m / z=368.2 [M+H] + .

[0210] 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 [ka] Example 43 is synthesized in a similar manner to Example 1, except 3-methoxyazetidine is used in step 8. LCMS (ES) m / z=380.3 [M−H] - .

[0211] 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 [ka]

[0212] Steps 1 to 8 are carried out in a manner similar to the synthesis of Example 1.

[0213] 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 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 inert conditions at 0° C., 4N dioxane HCl (3.5 mL) is added. The resulting reaction mixture is stirred at room temperature for 2 hours. The progress of the reaction is monitored by TLC and LCMS. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to obtain a solid. The solid is then purified by preparative HPLC [column: Inertsil ODS C18 (250 × 20) mm, 5 microns, flow rate: −19 ml / min, mobile phase (A): 0.1% ammonia in water, mobile phase (B): acetonitrile]. The collected spot is concentrated under reduced pressure to give Example 44 (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] + .

[0214] 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 [ka] Example 45 is synthesized in a similar manner to Example 1, except N,N-dimethylazetidin-3-amine is used in step 8. LCMS (ES) m / z=395.3 [M+H] + .

[0215] Example 46 Synthesis of N-(2-(2-hydroxyethoxy)ethyl)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxamide [ka] Example 46 is synthesized in a similar manner to Example 40. LCMS (ES) m / z=396.4 [M+H] + .

[0216] biological methods Cell culture: Human monocyte THP-1 cell line is purchased from Invivogen (thp-null). Human monocyte THP-1 ASC-GFP reporter cell line is purchased from Invivogen (thp-ascgfp). Human monocyte THP-1 cell line overexpressing NLRC4 is purchased from Invivogen (thp1-nlrc4). Mouse macrophage cell line J774A.1 is purchased from ATCC (TIB-67). Cells are maintained according to the manufacturer's recommended protocol.

[0217] Human peripheral blood mononuclear cells are isolated from whole blood using a Lymphoprep™ density gradient according to the manufacturer's instructions. PBMCs are used fresh.

[0218] PMA differentiation of THP-1 cells: For the ASC Spec assay, human monocytic cell line THP-1 ASC-GFP cells are differentiated to a macrophage-like phenotype using phorbol 12-myristate 13-acetate (PMA). THP-1 cells are cultured at 1–2 × 10 6 The cells are suspended at a density of 100,000 cells / mL and supplemented with 100 ng / mL PMA. 100,000 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 medium, and then the cells are left in PMA-free medium for 24 hours.

[0219] NLRP3 inflammasome and pyroptosis assay in THP-1 cells: THP-1 cells are primed with 300 ng / mL ultrapure LPS. After 1 hour, cells are treated as indicated in the figure captions. Three hours after LPS priming, the NLRP3 inflammasome is activated with 10 μM nigericin. After 2 hours, supernatants are collected and analyzed for IL-1β by ELISA. Pyroptotic cell death is assessed by Alamar Blue assay as described below.

[0220] Cytotoxicity Assay: THP-1 or PBMC are treated with dose titrations of the indicated compounds for 5 hours, after which cell viability is assessed by Alamar Blue assay as described below.

[0221] AlamarBlue viability assay: AlamarBlue cell viability reagent is diluted 1:10 in cell culture medium, filtered through a 40 µm filter, and added to the cell pellet at 100 µL / well. After 2-24 h, optical density is read according to the manufacturer's instructions. Viability is expressed as the percent signal relative to wells containing untreated cells, corrected for the medium control.

[0222] Cell-free inflammasome assay: Cell-free inflammasome activation and caspase-1 cleavage are evaluated as described above. Briefly, lysate is prepared from THP-1 by hypotonic lysis to a final protein concentration of more than 7 mg / mL. The lysate is pretreated with the indicated compound at a final concentration of 1 mM on ice for 20 minutes. Inflammasome activation is induced by incubating the sample at 30°C for 60 minutes. Inflammasome activity is evaluated by monitoring caspase-1 cleavage by Western blot.

[0223] NLRP3 inflammasome activation in PBMCs: 2 × 10 5Freshly isolated PBMCs are primed with 300 ng / mL LPS for 1 hour and then treated with titrated doses of the indicated compounds for an additional 2 hours. NLRP3 inflammasomes are then activated by treating the cells with 10 μM nigericin for 2 hours. Inflammasome activity is assessed by IL-1β ELISA according to the manufacturer's instructions.

[0224] AIM2 inflammasome activation in PBMCs: To activate the AIM2 inflammasome, 2 x 10 cells were cultured according to the manufacturer's instructions. 5 Freshly isolated PBMCs are transfected with poly dA:dT (100 ng / well) using Lipofectamine 2000 (1 µL / well). After 1 h, cells are treated with a dose titration of the indicated compounds for an additional 17 h. Inflammasome activity is assessed by IL-1β ELISA according to the manufacturer's instructions.

[0225] NLRP1 inflammasome activation in PBMCs: 2 × 10 5 Freshly isolated PBMCs are treated with 10 µM talabostat, a constitutive repressor of the NLRP1 inflammasome. After 1 h, cells are treated with a dose titration of the indicated compound for an additional 17 h. Inflammasome activity is assessed by IL-1β ELISA according to the manufacturer's instructions.

[0226] NLRC4 inflammasome-activated PBMC: 2 x 10 5 Freshly isolated PBMCs were primed with LPS (300 ng / mL) for 1 hour and then treated with 200 ng / mL NeedleTox [LFn Needle (Invivogen tlrl-ndl) + anthrax protective antigen (List Labs 171E)]. Compounds were added 1 hour after NeedleTox addition and then incubated for an additional 4 hours, after which inflammasome activity was assessed by IL-1β ELISA according to the manufacturer's instructions.

[0227] Assessment of HO-1 induction: THP-1 cells (Invivogen catalog number thp-null) were cultured at 0.2–0.8 × 10 cells per the manufacturer's instructions. 6 Cells are maintained at a density of 100,000 cells / mL. For HO-1 evaluation, 100,000 cells / well are seeded in 90 μL of culture medium into a 96-well plate and then treated with 10 μL of compound prepared 10x in culture medium containing 5% DMSO, for a final DMSO concentration of 0.5% DMSO v / v. Cells are incubated at 37°C and 5% CO2 for 5 hours. The plate is centrifuged at 500g for 5 minutes at room temperature to pellet the cells, then the medium is aspirated and the cells are washed in 100 μL of PBS. The plate is centrifuged again at 500g for 5 minutes at room temperature to pellet the cells, then the PBS is aspirated. Cells are resuspended in 100 μL of RIPA buffer (Roche Complete Protease Inhibitor Cocktail) containing protease inhibitors. Samples are lysed by pipetting up and down (15x) using 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 instructions (R&D systems catalog number DYC3776-5). Data are normalized to a reference compound control (10 μM vTv / Anteris Bach1 inhibitor) present in triplicate on each plate and expressed as activity (% reference compound).

[0228] NLRP1 inflammasome assay in mouse macrophages: J774A.1 cells (ATCC catalog number TIB-67) were maintained according to the manufacturer's instructions. For NLRP1 activation, cells over passage 12 were used. 100,000 cells / well were seeded into a 96-well plate in 70 μL of culture medium and allowed to adhere for 30 minutes at 37°C and 5% CO2. Cells were stimulated with 10 μL of ultra-pure LPS (Invivogen catalog number tlrl-3pelps) at 3 μg / mL for a final concentration of 300 ng / mL. Cells were incubated for 1 hour at 37°C and 5% CO2. Compounds were prepared 10x in culture medium containing 5% DMSO, and 10 μL was then added to each well for a final DMSO concentration of 0.5% DMSO v / v. Cells were incubated for an additional hour at 37°C and 5% CO2. Anthrax lethal toxin (LT) is prepared at 1 μg / mL by adding anthrax lethal factor (List Labs Catalog No. 169L) and anthrax protective antigen (List Labs Catalog No. 171E) to the medium to a final concentration of 1 μg / mL each. Each well is treated with 10 μL of LT to a final concentration of 100 ng / mL. Cells are incubated for an additional 3 hours at 37°C and 5% CO2. The plate is centrifuged at 500g for 5 minutes at room temperature to pellet the cells, and the supernatant is then collected and diluted 1:10 in PBS containing 1% BSA. IL-1β is assessed by ELISA according to the manufacturer's instructions (R&D Systems Catalog No. DY401). Alamar Blue cell viability reagent (ThermoFisher catalog number DAL1100) is diluted 1:10 in culture medium, then 100 μL is added to each cell pellet and incubated for 3 hours at 37° C. and 5% CO. Plates are read at 570 nm with a reference wavelength of 600 nm and represent viability relative to untreated controls, using culture medium for background correction.

[0229] NLRC4 inflammasome assay in THP-1 cells: Inoculate THP-1 cells overexpressing NLRC4 (Invivogen catalog number thp1-nlrc4) at 0.2–0.8 × 10 dilutions according to the manufacturer's instructions. 6 Cells are maintained at a density of 100,000 cells / mL. For NLRC4 activation, 100,000 cells / well are seeded in 70 μL of culture medium into a 96-well plate and stimulated with 10 μL of ultra-pure LPS (Invivogen catalog number tlrl-3pelps) at 3 μg / mL in culture medium for a final concentration of 300 ng / mL. Cells are incubated at 37°C and 5% CO2 for 1 hour. Compounds are prepared 10x in culture medium containing 5% DMSO, and then 10 μL is added to each well for a final DMSO concentration of 0.5% DMSO v / v. Cells are incubated for an additional hour at 37°C and 5% CO2. NeedleTox is prepared by mixing anthrax protective antigen (List Labs catalog number 171E) to a final concentration of 1250 ng / mL and LFn-Needle (Invivogen catalog number tlrl-ndl) to a final concentration of 250 ng / mL. Each well is treated with 10 μL of NeedleTox to a final concentration of 150 ng / mL. Cells are incubated for an additional 3 hours at 37°C and 5% CO2. The plate is centrifuged at 500g for 5 minutes at room temperature to pellet the cells, and the supernatant is then collected and diluted 1:10 in PBS containing 1% BSA, and IL-1β is assessed by ELISA according to the manufacturer's instructions (R&D Systems catalog number DY201). Alamar Blue cell viability reagent (ThermoFisher catalog number DAL1100) is diluted 1:10 in culture medium, then 100 μL is added to each cell pellet and incubated for 3 hours at 37° C. and 5% CO. Plates are read at 570 nm with a reference wavelength of 600 nm and represent viability relative to untreated controls, using culture medium for background correction.

[0230] Biological Example 1: Cellular Activity Assay The properties of each compound were assayed in various cellular assays using THP-1 human monocytic cells. IL-1β inhibition and protection from pyroptosis were assessed in the NLRP3 inflammasome assay. The results are presented in Table 2.

[0231] [Table 3]

[0232] Comparative non-compounds were tested and the results are provided in Table 3.

[0233] [Table 4A] [Table 4B]

[0234] Biological Example 2: HO-1 Induction Assay The properties of each compound are evaluated for hemoxygenase-1 (HO-1) induction in an assay using THP-1 human monocytic cells. The results are provided in Table 4.

[0235] [Table 5]

[0236] Biological Example 3: Inhibition of ASC Oligomerization ASC oligomerization is monitored using the ASC-GFP THP-1 reporter cell line. Upon inflammasome activation, ASC polymerizes, forming a single, large "speck" per cell. By tagging ASC with GFP, these "specks" are easily observable, allowing the percentage of inflammasome-containing cells to be assessed. THP-1 ASC-GFP cells are differentiated overnight using PMA and then left in PMA-free medium for 1 day. Cells are treated with dose titrations of the indicated drugs 2 hours before NLRP3 inflammasome activation using nigericin. After 45 minutes of nigericin treatment, cells are fixed in 2% paraformaldehyde and imaged under a fluorescent microscope. The percentage of ASC-GFP speck-positive cells per field is quantified.

[0237] Biological Example 4: Inhibition of Multiple Inflammasomes in Human PBMCs The ability of compounds of interest to inhibit multiple inflammasomes is assessed in fresh primary human peripheral blood mononuclear cells (PBMCs). Dose titrations of compounds are added simultaneously with inflammasome stimulation as follows: a, NLRP3: LPS prime followed by stimulation with nigericin for 2 h. 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

[0238] The results provided in Figure 1 demonstrate that the compounds of the present disclosure are more potent pan-inflammasome inhibitors than 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 number 256373-96-3).

[0239] It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the 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 invention may be utilized in accordance with the teachings herein. Accordingly, the invention is not limited to that precisely as shown and described.

Claims

1. Structural formula: 【Chemistry 1】 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, C １ -C ６ Alkyl, phenyl, -(C １ -C ３ alkyl)-phenyl, heteroaryl optionally substituted with methyl, C ３ -C ８ cycloalkyl, or -(C １ -C ３ alkyl)-C ３ -C ８ is cycloalkyl, Each R １ became independent, Halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, —NH ２ , —NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, hydroxy (C １ -C ６ alkyl), hydroxy (C １ -C ６ alkoxy), alkoxy(C １ -C ６ alkyl), alkoxy (C １ -C ６ alkoxy), or amino (C １ -C ６ alkyl), R ２ is H or C １ -C ６ is alkyl, Each R ３ became independent, Halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, —NH ２ , —NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, —C １ -C ６ Alkyl-NR ４ R ５ , -CN, -C １ -C ６ Alkyl-CN, -C １ -C ６ Alkyl-OR ４ , one or more R ６ -(C １ -C ６ alkyl)-aryl, one or more R ６ -(C １ -C ６ alkyl)-heteroaryl, one or more R ７ -(C １ -C ６ alkyl)-heterocyclyl, one or more R ７ -(C １ -C ６ alkyl)-C ３ -C ８ Cycloalkyl, —COH, —CO ２ H, -CO ２ (C １ -C ６ alkyl), -CO(C １ -C ６ alkyl), or -CONR ８ R ９ (In the formula, R ８ and R ９ are independently H or C １ -C ６ alkyl, and R ８ and R ９ each alkyl independently selected from 1, 2, or 3 halogen, cyano, hydroxy, C １ -C ３ Alkoxy, amino, or mono- or di(C １ -C ３ alkyl)amino, amino-C １ -C ３ Alkoxy, mono- or di(C １ -C ３ alkyl)amino-C １ -C ３ Alkoxy, hydroxy-C １ -C ３ Alkoxy, or C １ -C ６ Alkoxy-C １ -C ６ substituted with alkoxy) or Two R's ３ together with the atoms to which they are attached form a heterocycle, and said heterocycle is ７ is optionally replaced by R ４ is H or C １ -C ６ is alkyl, R ５ is H, one or more R ７ C optionally substituted with １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, -(C １ -C ６ alkyl)-O-C １ -C ６ Alkyl, -(C １ -C ６ alkyl)-O-C ２ -C ６ alkenyl, or -(C １ -C ６ alkyl)-O-C ２ -C ６ is alkynyl, Each R ６ are independently halogen, -NO ２ , -CN,C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, —NH ２ , —NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, —CO ２ H, -CO ２ (C １ -C ６ alkyl), -CO(C １ -C ６ alkyl), -CONH ２ , -CONH(C １ -C ６ alkyl), or -CON(C １ -C ６ alkyl) ２ and Each R ７ are independently halogen, -NO ２ , -CN,C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, —NH ２ , —NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, —CO ２ H, -CO ２ (C １ -C ６ alkyl), -CO(C １ -C ６ alkyl), -CONH ２ , -CONH(C １ -C ６ alkyl), or -CON(C １ -C ６ alkyl) ２ or two R ７ groups together with the carbon to which they are attached form =O, provided that the compound is not 2-[(1-methyl-1H-benzimidazol-2-yl)amino]-5-benzoxazolecarboxylic acid).

2. 2. The compound of claim 1, wherein m is 1 or 2.

3. 3. A compound according to claim 1 or 2 of the following formula: 【Chemistry 2】

4. A compound according to any one of claims 1 to 3, of the following formula: 【Transformation 3】

5. R １ became independent, Halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, or C １ -C ６ The compound of any one of claims 1 to 4, which is haloalkyl.

6. R ２ is H or C １ -C ３ The compound of any one of claims 1 to 5, which is alkyl.

7. The compound according to any one of claims 1 to 6, wherein n is 1 or 2.

8. R ３ But, -C １ -C ６ Alkyl-NR ４ R ５ , -C １ -C ６ Alkyl-OR ４ , or one or more R ７ -(C １ -C ６ The compound of any one of claims 1 to 7, wherein the heterocyclyl is aryl, ...

9. R ４ But C １ -C ６ alkyl, and R ５ However, one or more R ７ C optionally substituted with １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, -(C １ -C ６ alkyl)-O-C １ -C ６ Alkyl, -(C １ -C ６ alkyl)-O-C ２ -C ６ alkenyl, or -(C １ -C ６ alkyl)-O-C ２ -C ６ The compound of any one of claims 1 to 8, which is alkynyl.

10. R ３ but, H、-E ２ Cl、-C(O)H、-OH ３ ,--C ２ CH ３ 、 【Chemistry 4】 or two R ３ together with the atoms to which they are attached 【Transformation 5】 The compound according to any one of claims 1 to 9, which forms

11. R ３ But, -CONHR ９ (In the formula, R ９ is 1, 2 or 3 halogen, cyano, hydroxy, C １ -C ３ Alkoxy, amino, or mono- or di(C １ -C ３ C substituted with alkyl)amino １ -C ６ alkyl), or R ９ But hydroxy-C １ -C ３ Alkoxy or C １ -C ６ Alkoxy-C １ -C ６ Alkoxy-substituted C １ -C ６ alkyl or R ９ However, amino-C １ -C ３ Alkoxy-substituted C １ -C ６ The compound of any one of claims 1 to 10, which is alkyl.

12. 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 10. The compound of claim 1, a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier, solvent, adjuvant, or diluent.

14. 14. A method of treating an inflammatory condition in a subject in need thereof, comprising providing to said subject a compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13.

15. 15. The method of claim 14, wherein the condition is a metabolic, fibrotic, renal disorder, or neurological disease.

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