Benzimidazole derivatives

Abstract

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

Description

Background of the Invention Technical Field

[0002] The present disclosure generally relates to benzimidazole derivatives, pharmaceutical compositions comprising them, and methods of using them. Background Art

[0003] Oxidative stress, characterized by elevated intracellular reactive oxygen species (ROS) levels, is counteracted by the cellular antioxidant response to maintain homeostasis. If left uncontrolled, abnormal ROS production can lead to 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 diseases, lung diseases, neuroinflammatory diseases, neurodegenerative diseases, blood diseases, cardiovascular diseases, kidney diseases, metabolic diseases, and cancer. Thus, therapeutic strategies that restore the homeostatic oxidative state of cells have important therapeutic implications.

[0004] The Bach1 (BTB and CNC homology 1) / Nrf2 (nuclear factor erythroid 2-related factor 2) axis is a major regulator of the cellular antioxidant response and is a proven therapeutic target for diseases driven by oxidative stress (e.g., the Nrf2 activator dimethyl fumarate has been approved in the United States for the treatment of relapsing-remitting multiple sclerosis and psoriasis). Under homeostatic conditions, Bach1 occupies the antioxidant response element (ARE) in the promoters of multiple genes involved in the cellular antioxidant response, thereby 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). Activation of Bach1 / Nrf2 and the consequent Hmox1 expression have been associated with positive outcomes in many epidemiological association studies, genetic models, and animal disease models.

[0005] One pathway regulated by the Bach1 / Nrf2 pathway is the inflammasome. They are large multi-protein complexes that play important roles in sterile tissue injury and infection. However, due to the highly inflammatory nature of inflammasome-derived mediators, complex regulatory mechanisms have evolved to inhibit inflammasome activation in the absence of injury or infection. Mutations in the inflammasome activation pathway can lead to a range of potentially life-threatening autoinflammatory diseases, highlighting the importance of such mechanisms. Chronic and acute abnormal activation of the inflammasome pathway also contributes to the pathology of a variety of arthritic, neurodegenerative, neurological, cardiovascular, hematological, dermatological, fibrotic, metabolic, renal, ocular, pulmonary, and systemic inflammatory conditions.

[0006] The assembly of the inflammasome complex is under the control of a "two-hit" system and thus requires two independent signals for activation. Signal 1 stimulates the transcription of inflammasome-related genes, leading to the upregulation of the various components of the inflammasome and the production of precursor (pro) forms of the inflammasome substrates interleukin-1β (IL-1β), interleukin-18 (IL-18), and Gasdermin-D in the cytosol. Signal 2 is provided by a range of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which are sensed by the family of cytosolic pattern recognition receptors known as nucleotide-binding oligomerization domain-like receptors (NLRs) and some additional inflammasome-forming sensors. The binding of a DAMP to its corresponding NLR results in a conformational change in the NLR, allowing self-oligomerization of the receptor. These NLR oligomers then recruit the adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC). The NLR-ASC complex then acts as a core to promote the formation of ASC filaments mediated by the pyrin domain (PYD) of ASC. The ASC filaments in turn create a platform for the recruitment of caspase-1, leading to autocatalytic cleavage and activation, and act as a core to promote subsequent caspase-1 filament formation mediated by 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, releases inflammatory mediators from the cell, and induces Gasdermin-D-mediated pyroptotic cell death.

[0007] The formation of inflammasomes can be initiated by at least 11 different sensors, including pyrin, multiple NLRs (including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4, and NLRC5), members of the PYHIN family IFI-16 and AIM2, and RIG-I. Traditional methods of inflammasome inhibition target individual receptors, such as NLRP3, to inhibit a subset of inflammasomes. However, emerging evidence clearly shows that the activation of multiple different inflammasome-forming receptors is a common pathological feature of many diseases, including inflammatory bowel disease, arthritis diseases, and neurodegenerative diseases. Therefore, more broad-based pharmaceutical approaches that can simultaneously inhibit multiple inflammasomes are needed to address pathologically inflammasome-dependent inflammation.

[0008] One way to achieve broader inflammasome inhibition is to target common components of the inflammasome, such as caspase-1 or ASC filaments. The assembly of the inflammasome is induced by cytosolic sensors (e.g., NLRP3 or AIM2), which detect danger signals associated with infection or sterile injury. After sensing these signals, the sensor acts as a core to promote the formation of filaments composed of repeating units of the inflammasome adaptor protein ASC. These filaments form a scaffold for recruiting caspase-1, leading to autoproteolytic activation of the enzyme. However, the development of active site inhibitors for caspase-1 has been severely hampered by the highly conserved active site shared by all caspases. This feature, combined with the diverse and important biological roles of other caspase family members, results in a high degree of cross-reactivity with off-target caspase proteins, leading to unacceptable toxicity.

[0009] Although the inflammasome plays a protective role against infection and injury, abnormal activation of this complex in the absence of infection or injury can lead to a variety of inflammatory conditions. Therefore, the development of compositions and methods for preventing inflammasome-driven inflammation is an important challenge. Summary of the Invention

[0010] One aspect of the present disclosure provides a compound having the structural formula (I):

[0011]

[0012] and pharmaceutically acceptable salts, tautomers, solvates, and hydrates thereof, wherein

[0013] m is 0, 1, 2, or 3;

[0014] n is 0, 1, 2, or 3;

[0015] 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;

[0016] R 1 independently is halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), or amino(C1-C6 alkyl);

[0017] R 2 is H or C1-C6 alkyl;

[0018] Each R 3 is independently halogen, 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-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)-heterocyclic group optionally substituted with one or more R7, -(C1-C6 alkyl)-C3-C8 cycloalkyl optionally substituted with one or more R7, -COH,

[0019] -CO2H, -CO2(C1-C6 alkyl), -CO(C1-C6 alkyl) or -CONR 8 R 9 , where R 8 and R 9 are independently H or C1-C6 alkyl, where each alkyl within R 8 and R 9 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

[0020] -C1-C6 alkoxy, or

[0021] two Rs 3 together with the atom to which they are attached form a heterocycle, which is optionally substituted with one or more R7,

[0022] where

[0023] R 4 is H or C1-C6 alkyl;

[0024] R 5 is H, C1-C6 alkyl optionally substituted with one or more R7, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(C1-C6 alkyl)-O-C1-C6 alkyl,

[0025] -(C1-C6 alkyl)-O-C2-C6 alkenyl or -(C1-C6 alkyl)-O-C2-C6 alkynyl;

[0026] Each R 6 independently is 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),

[0027] -CO(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl) or

[0028] -CON(C1-C6 alkyl)2; and

[0029] Each R 7 independently is 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),

[0030] -CO(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl) or

[0031] -CON(C1-C6 alkyl)2, or two R 7 groups together with the carbon to which they are attached form ═O.

[0032] In certain embodiments, the compound of formula (I) is not 2-[(1-methyl-1H-benzoimidazol-2-yl)amino]-5-benzoxazolecarboxylic acid.

[0033] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as described herein (e.g., a compound of formula (I)).

[0034] In another aspect, the present disclosure provides that the compounds described herein bind to the transcriptional repressor Bach1. For example, the present disclosure provides a method of inhibiting Bach1 activity, the method comprising administering to a human subject an effective amount of a compound as further described herein.

[0035] Thus, in various embodiments further described herein, the compound is an HO-1 inducer. Thus, in another aspect, the present disclosure provides a method of increasing the activity or amount of HO-1 in a human subject, which comprises: administering to a human subject an effective amount of a compound as further described herein or a pharmaceutically acceptable salt thereof or an effective amount of a pharmaceutical composition thereof.

[0036] Nrf2 is a transcription factor that regulates the expression of HO-1. In another aspect, the present disclosure provides a method of activating the transcription factor Nrf2 in a human subject, comprising: administering to the human subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as further described herein or an effective amount of a pharmaceutical composition thereof.

[0037] In another aspect, the present disclosure provides a method of reducing the amount of reactive oxygen species in a human subject, comprising: administering to the human subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as further described herein or an effective amount of a pharmaceutical composition thereof. In various embodiments, the compound as further described herein is not reductive in nature. For example, the compound can reduce the amount of reactive oxygen species by enhancing or inhibiting a biological target associated with the natural oxidative stress response.

[0038] In another aspect, the present disclosure provides a method of treating an inflammatory condition or disorder in a subject, particularly a mammalian subject, more particularly a human subject. The method comprises administering to the subject an effective amount of a compound as described herein.

[0039] In another aspect, the present disclosure provides intermediates useful for preparing the compounds of formula (I).

[0040] Other aspects and embodiments of the present disclosure are apparent in view of the detailed description provided herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The presence of the drawings is to provide a further understanding of the methods and compositions of the present disclosure and is incorporated into and constitutes a part of this specification. The drawings illustrate one or more embodiments of the present disclosure and, together with the description, are used to explain the principles and operations of the present disclosure.

[0042] Figure 1 The inflammasome inhibitory activity of the compounds of the present disclosure compared to the control compound MCC950 is shown. DETAILED DESCRIPTION

[0043] The present disclosure provides compounds, pharmaceutical compositions, methods, and uses for treating a variety of diseases associated with the inhibition of inflammasome formation.

[0044] Thus, one aspect of the present disclosure provides a compound of formula (I) as described above:

[0045]

[0046] In certain embodiments, the compound of formula (I) is not: 2-[(1-methyl-1H-benzoimidazol-2-yl)amino]-5-benzoxazolecarboxylic acid.

[0047] 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 a particular embodiment, R is CH3.

[0048] In certain embodiments, each R 2 is independently H or methyl. For example, in some embodiments, the present disclosure provides a compound of formula (I) as described herein, a compound of the following formula:

[0049]

[0050] 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 can be a compound of the following formula:

[0051]

[0052] In certain embodiments, the present disclosure provides a compound of the following formula:

[0053]

[0054] In certain embodiments, the present disclosure provides a compound of the following formula:

[0055]

[0056] Another embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein R 1 is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl. In certain embodiments, R 1 is independently halogen, C1-C6 alkyl or C1-C6 haloalkyl. In certain embodiments, R 1 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl. In certain embodiments, R 1 is independently halogen.

[0057] In certain embodiments, the present disclosure provides a compound of formula (I) as described herein, wherein at least one R 1 is halogen (such as fluorine).

[0058] In certain embodiments, the present disclosure provides a compound of the following formula:

[0059]

[0060] Another embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein R2 is H or a C1-C3 alkyl group. In certain embodiments, R 2 is H or methyl. In certain embodiments, R 2 is H.

[0061] In certain embodiments, the present disclosure provides a compound of the following formula:

[0062]

[0063] 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 can be a compound of the following formula:

[0064]

[0065] In certain embodiments, the present disclosure provides a compound of the following formula:

[0066]

[0067] In certain embodiments, the present disclosure provides a compound of the following formula:

[0068]

[0069] Another embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein R 3 is -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)-heterocyclic group 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, which heterocycle is optionally substituted with one or more R7.

[0070] 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)-aryl optionally substituted by one or more R6, -(C1-C6 alkyl)-heteroaryl optionally substituted by one or more R6, -(C1-C6 alkyl)-heterocycloalkyl optionally substituted by one or more R7, -(C1-C6 alkyl)-C3-C8 cycloalkyl optionally substituted by 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.

[0071] 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)-heterocycloalkyl optionally substituted by 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 atom to which they are attached form a heterocycle, which heterocycle is optionally substituted by one or more R7. 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)-heterocycloalkyl optionally substituted by 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.

[0072] In certain embodiments of the compounds of formula (I) as described herein, R 3 is -C1-C6 alkyl-NR 4 R 5 、-C1-C6 alkyl-OR 4 or -(C1-C6 alkyl)-heterocycloalkyl optionally substituted by one or more R7. In certain embodiments, R 3 is -C1-C6 alkyl-NR 4 R 5 .

[0073] In certain embodiments of the compounds of formula (I) as described herein, R 3 is -CONR 8 R 9 , wherein R8 and R 9 are independently H or C1-C6 alkyl, wherein each alkyl within R 8 and R 9 is independently substituted with one, two or three halogens, 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.

[0074] In certain embodiments of the compounds of formula (I) as described herein, R 3 is -CONR 8 R 9 wherein R 8 and R 9 are independently H or C1-C6 alkyl, wherein each alkyl within R 8 and R 9 is independently substituted with one, two or three halogens, cyano, hydroxy, C1-C3 alkoxy, amino, mono- or di(C1-C3 alkyl)amino, hydroxy-C1-C3 alkoxy or C1-C6 alkoxy-C1-C6 alkoxy.

[0075] In certain embodiments of the compounds of formula (I) as described herein, R 3 is -CONHR 9 wherein R 9 is H or C1-C6 alkyl, wherein the alkyl is substituted with one, two or three halogens, cyano, hydroxy, C1-C3 alkoxy, amino, mono- or di(C1-C3 alkyl)amino, hydroxy-C1-C3 alkoxy or C1-C6 alkoxy-C1-C6 alkoxy.

[0076] In certain embodiments of the compounds of formula (I) as described herein, R 3 is -CONHR 9 wherein R 9 is C1-C6 alkyl substituted with one, two or three halogens, cyano, hydroxy, C1-C3 alkoxy, amino or mono- or di(C1-C3 alkyl)amino.

[0077] In certain embodiments of the compounds of formula (I) as described herein, R 3 is -CONHR 9 wherein R 9 is C1-C6 alkyl substituted with hydroxy-C1-C3 alkoxy or C1-C6 alkoxy-C1-C6 alkoxy.

[0078] In certain embodiments of the compounds of formula (I) as described herein, R3 is -CONHR 9 , where R 9 is a C1-C6 alkyl group substituted by a hydroxy-C1-C3 alkoxy group.

[0079] In certain embodiments of the compounds of formula (I) as described herein, R 3 is -CONHR 9 , where R 9 is a C1-C6 alkyl group substituted by a C1-C6 alkoxy-C1-C6 alkoxy group.

[0080] In certain embodiments of the compounds of formula (I) as described herein, R 3 is -CONHR 9 , where R 9 is a C1-C6 alkyl group substituted by an amino-C1-C3 alkoxy group.

[0081] In certain embodiments of the compounds of formula (I) as described herein, R 3 is -CONHR 9 , where R 9 is a C1-C6 alkyl group substituted by a mono- or di(C1-C3 alkyl)amino-C1-C3 alkoxy group.

[0082] In certain embodiments of the compounds of formula (I) as described herein, R 4 is a C1-C6 alkyl group and R 5 is a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, –(C1-C6 alkyl)-O-C1-C6 alkyl group, –(C1-C6 alkyl)-O-C2-C6 alkenyl group or –(C1-C6 alkyl)-O-C2-C6 alkynyl group optionally substituted by one or more R7. In certain embodiments, R 4 is a C1-C6 alkyl group and R 5 is a C1-C6 alkyl group optionally substituted by one or more R7. In certain embodiments, R 4 is a C1-C3 alkyl group and R 5 is a C1-C3 alkyl group. In certain embodiments, R 4 is methyl and R 5 is methyl optionally substituted by one or more R7.

[0083] In certain embodiments of the compounds of formula (I) as described herein, two R 3 together with the atoms to which they are attached form a heterocyclic ring which is optionally substituted by one or more R7.

[0084] In a particular embodiment of the compounds of formula (I) as described herein, R3 Selected from: H, -CH2Cl, -C(O)H, -OCH3, -CO2CH3,

[0085] or two Rs 3 together with the atom to which they are attached form In other embodiments, R 3 is In other embodiments, R 3 is

[0086] In certain embodiments, the compounds described herein are compounds of the formula:

[0087]

[0088] wherein

[0089] R is H or CH3; R 1 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl; and R 2 is H or C1-C3 alkyl.

[0090] In certain embodiments, the compounds described herein are compounds of the formula:

[0091]

[0092] wherein

[0093] R is H or CH3; R 1 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl; and R 2 is H or C1-C3 alkyl.

[0094] In other embodiments, the compound has the formula:

[0095]

[0096] wherein

[0097] R 1 is fluorine or hydrogen; and

[0098] R 4 and R 5 are independently hydrogen, methyl, ethyl, propyl, isopropyl, propargyloxyethyl, propargyloxymethyl, or propargyl; or

[0099] R 4 and R 5 together with the nitrogen to which they are attached form a 3-7 membered heteroalkyl ring.

[0100] In certain embodiments of the compounds as further described herein, the compound is in the form of a pharmaceutically acceptable salt of the compound as described herein. One of ordinary skill in the art will understand that, as described in more detail below, a variety of pharmaceutically acceptable salts can be provided. In certain embodiments of the compounds as further described herein, the compound is in the form of a solvate (e.g., hydrate) of the compound or salt as described herein. One of ordinary skill in the art will understand that a variety of solvates and / or hydrates can be formed. One of ordinary skill in the art will understand that the phrase "optionally in the form of its pharmaceutically acceptable salt and / or its solvate or hydrate" includes compounds that are in the form of solvates and hydrates of the base compound or pharmaceutically acceptable salt as described above. However, in certain embodiments as described above, the compound is not in the form of a solvate or hydrate.

[0101] In certain embodiments, the compound of formula (I) is:

[0102] Table 1

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] or a pharmaceutically acceptable salt thereof.

[0113] Therapeutic Use

[0114] The present disclosure also provides methods for treating a variety of inflammatory conditions, i.e., inflammatory diseases and disorders. These methods include administering to a subject in need of such treatment an effective amount of one or more of the compounds of the present disclosure as described herein (e.g., a compound of formula (I)) or a pharmaceutical composition of the present disclosure as described herein.

[0115] In certain embodiments, the present disclosure provides methods of treating an inflammatory condition in a subject, the method comprising providing to the subject a compound as further described herein. In certain embodiments as further described herein, the inflammatory condition is inflammatory bowel disease, an arthritis disease, or a neurodegenerative disease. In certain embodiments, the inflammatory condition is an infectious disease, an autoimmune disease, cancer, a metabolic disorder, or a neurological disease.

[0116] In other embodiments, the inflammatory condition is an autoinflammatory syndrome. In yet other embodiments, the inflammatory condition is an inflammasome-related condition. Some conditions and / or diseases may be a combination of the above embodiments, or fall into multiple categories simultaneously.

[0117] In certain embodiments, diseases and disorders that can be treated according to the methods disclosed herein include, but are not limited to, adult-onset Still's disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), macrophage activation syndrome (MAS), autoinflammatory infantile enterocolitis (AIFEC), bullous pemphigoid, pemphigus vulgaris, idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), systemic lupus erythematosus (SLE), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, epilepsy, traumatic brain injury (TBI), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cryopyrin-associated periodic syndromes (CAPS), vitiligo, multiple self-healing squamous epithelioma (MSPC), autoimmune Addison's disease, familial Mediterranean fever (FMF), autoimmune thyroiditis, stroke, type 2 diabetes (T2D), osteoarthritis, gout, atherosclerosis, hidradenitis suppurativa, psoriasis, a cryopyrinopathy, sickle cell disease, and autosomal dominant polycystic kidney disease (ADPKD).

[0118] In certain embodiments, the present disclosure provides methods of treating one or more diseases selected from the categories of: (i) fibrotic diseases, such as fibrotic diseases associated with the lung (COPD, idiopathic pulmonary fibrosis, sarcoidosis), liver (alcoholic cirrhosis, steatosis, cholestasis, drug-induced fibrosis, viral infection), or skin (scleroderma, psoriasis); (ii) neurodegenerative diseases, such as Friedreich's ataxia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Charcot-Marie-Tooth syndrome; (iii) cardiovascular diseases, such as hypertension, heart failure, hypercholesterolemia, atherosclerosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease, congestive heart failure, acute coronary syndrome, dialysis arteriovenous fistula failure, and primary pulmonary hypertension, ischemic reperfusion events; (iv) kidney diseases, such as diabetic nephropathy, glomerulonephritis, acute tubular necrosis, and autosomal dominant polycystic kidney disease; (v) liver diseases, such as drug-induced hepatotoxicity, non-alcoholic steatohepatitis, hepatitis C infection; (vi) eye diseases, such as glaucoma, uveitis, wound healing (post-surgery), ocular trauma, corneal transplantation, macular degeneration, cataract, photoretinopathy, retinopathy of prematurity; (vii) thyroid diseases, such as Graves' disease, follicular adenoma, papillary carcinoma, and follicular carcinoma; (viii) viral infections, such as HIV, hepatitis B, hepatitis C, herpesvirus, coronavirus (e.g., SARS-CoV 2, SARS-CoV, or MERS); and (ix) diabetic conditions, such as type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, hyperglycemia, and metabolic syndrome, and pancreatic β-cell loss.

[0119] In certain embodiments, the present disclosure provides methods of treating an inflammatory condition in a human subject, the inflammatory condition being caused by viral (e.g., coronavirus (e.g., SARS-CoV 2, SARS-CoV, or MERS)) infection, bacterial infection, fungal infection, parasitic infection, or other type of infection, and thus resulting in cell death or the release of pro-inflammatory cytokines or other inflammatory mediators.

[0120] The present invention also provides the use of a compound as described herein in combination with one or more pharmaceutically effective active compounds for simultaneous, subsequent or sequential administration. Examples of such pharmaceutically effective ingredients include, but are not limited to, Nrf2 activators, antioxidants, antidotes (e.g., metformin). In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as described herein and at least one other pharmaceutically effective ingredient selected from Nrf2 activators, antioxidants, antidotes, anti-inflammatory agents and anti-diabetic agents (e.g., metformin). In another embodiment, the present invention provides the use of a compound as described herein in combination with at least one other pharmaceutically effective ingredient selected from Nrf2 activators, antioxidants, antidotes, anti-inflammatory agents and anti-diabetic agents (e.g., metformin) for simultaneous, subsequent or sequential administration.

[0121] Examples of Nrf2 activators include sulforaphane, avicin, 15dPGJ2, xanthohumol, curcumin, salvigenin, zingiberenone, isothiocyanates, alpha-lipoic acid, olipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiol-3-thione), 1,2-dithiol-3-thione, 2,3-butyl-4-hydroxyanisole, monomethyl fumarate and dimethyl fumarate (Tefidera).

[0122] Examples of antioxidants include vitamin C, vitamin E, carotenoids, retinoids, polyphenols, flavonoids, lignans, selenium, butylated hydroxyanisole, calcium disodium edetate, acetylcysteine, probucol and tempo.

[0123] Examples of antidotes include dimercaprol, glutathione, acetylcysteine, methionine, sodium bicarbonate, deferoxamine mesylate, calcium disodium edetate, trientine hydrochloride, penicillamine and medicinal charcoal.

[0124] Without wishing to be bound by theory, it is currently believed that certain compounds of the present disclosure may help treat inflammatory conditions by inhibiting caspase-1. Accordingly, in certain embodiments, the present disclosure provides a method of inhibiting caspase-1 in a subject, the method comprising administering a compound as further described herein. In particular, in some embodiments, the inhibition can be achieved by interacting with the CARD domain of caspase-1.

[0125] Pharmaceutical Compositions and Dosage Forms

[0126] The compounds described herein can be usefully provided in the form of pharmaceutical compositions. Such compositions comprise a compound according to any one of the foregoing aspects or embodiments described herein, and a pharmaceutically acceptable excipient, diluent or carrier.

[0127] The compounds can be formulated into pharmaceutical compositions per se, or in the form of hydrates, solvates or pharmaceutically acceptable salts as described above. Generally, such salts have higher solubility in aqueous solutions than the corresponding free acids and bases, but salts with lower solubility than the corresponding free acids and bases may also be formed.

[0128] The pharmaceutical compositions can be, for example, in the form of tablets, capsules or parenteral preparations, but those of ordinary skill in the art will understand that the compounds can be provided in a variety of pharmaceutical compositions.

[0129] For example, the compounds of the present disclosure can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing one or more pharmaceutically acceptable carriers, diluents or excipients. As used herein, the term "parenteral" includes transdermal, subcutaneous, intravascular (e.g., intravenous), intramuscular or intrathecal injection or infusion techniques, etc. The drugs containing the compounds of the present disclosure can be provided in any suitable formulations and dosage forms described herein.

[0130] The pharmaceutical compositions can be prepared using the currently disclosed compounds. For example, in one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent or excipient, and a compound described with reference to any of the foregoing structural formulas.

[0131] In the pharmaceutical compositions disclosed herein, one or more of the compounds of the present disclosure can 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 can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs.

[0132] Compositions intended for oral use can be prepared according to any suitable method for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preservatives in order to provide a pharmaceutically elegant and palatable product. Tablets contain the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets. These excipients may 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; binding agents such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques. In some cases, such coatings may be prepared by appropriate techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be employed.

[0133] Preparations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. Preparations for oral use may also be presented as lozenges.

[0134] Aqueous suspensions contain the active substance admixed with excipients suitable for the preparation of aqueous suspensions. Such excipients may be suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and acacia; dispersing or wetting agents such as naturally occurring phosphatides, for example lecithin, or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyvinyl sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

[0135] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0136] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Examples of suitable dispersants or wetting agents or suspending agents are those already mentioned above. Additional excipients may also be present, such as sweeteners, flavoring agents, and coloring agents.

[0137] The pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifying agents can be naturally occurring gums, such as gum arabic or tragacanth, naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners and flavoring agents.

[0138] 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 comprising less than 50% water has at least 1%, 2%, 3%, 4%, or 5% water. In other embodiments, the water content in the composition is present in trace amounts.

[0139] 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, a composition comprising less than 50% alcohol has at least 1%, 2%, 3%, 4%, or 5% alcohol. In other embodiments, the alcohol content in the composition is present in trace amounts.

[0140] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, glucose, or sucrose. Such formulations can also contain demulcents, preservatives, flavoring agents, and coloring agents. The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension. The suspension can be formulated according to known techniques using the suitable dispersants or wetting agents and suspending agents already mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, a sterile non-volatile oil can be used as a solvent or suspending medium. For this purpose, any mild non-volatile oil can be used, including synthetic mono- or di-glycerides of fatty acids. Additionally, fatty acids such as oleic acid can be used in the preparation of injectables.

[0141] The compounds 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 a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0142] The compounds of the present disclosure can also be administered parenterally in a 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.

[0143] The compositions can be formulated as unit dosage forms of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as a single dosage for human subjects and other mammals, each unit containing a predetermined quantity of the active substance combined with a suitable pharmaceutical excipient, the quantity being calculated to produce the desired therapeutic effect.

[0144] The compounds may be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, it should be understood that the amount of the compound actually administered will generally be determined by the physician in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0145] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound described herein. When these preformulation compositions are said to be homogeneous, the active ingredient is generally uniformly dispersed throughout the composition so that the composition can be readily subdivided into equivalent unit dosage forms such as tablets, pills, and capsules. The solid preformulation is then subdivided into unit dosage forms of the above types, which contain, for example, from 0.1 to about 500 mg of the active ingredient of the compound described herein.

[0146] Tablets or pills can be coated or otherwise compounded to provide dosage forms having the advantage of extended action. For example, a tablet or pill can contain an inner dose and an outer dose component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that is resistant to disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be released retarded. A variety of materials can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0147] The amount of the compound or composition administered to a patient will vary depending on the substance being administered, the purpose of administration such as prophylaxis or treatment, the condition of the patient, the mode of administration, etc. In therapeutic applications, the composition may be administered to a patient already suffering from the 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 condition being treated and the judgment of the attending physician based on factors such as the severity of the disease, the age, weight and general condition of the patient.

[0148] The composition administered to the patient 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 use as is or lyophilized, and the lyophilized product is combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is generally from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It should be understood that the use of certain excipients, carriers or stabilizers as described above may result in the formation of pharmaceutical salts.

[0149] The therapeutic dose of the compound may vary depending on, for example, the specific use for which the treatment is being carried out, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds described herein in the pharmaceutical composition may vary depending on a variety of factors including the dose, chemical properties (such as hydrophobicity) and route of administration. For example, the compounds described herein may be provided in an aqueous physiological buffer solution containing from about 0.1% to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dose range is from about 0.01 mg / kg to about 100 mg / kg body weight per day. The dose may depend on variables such as the type and progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipients and its route of administration. The effective dose can be inferred from dose-response curves obtained from in vitro or animal model test systems.

[0150] The compounds described herein may also be formulated in combination with one or more additional active ingredients or administered sequentially, and the additional active ingredients may include any pharmaceutical agents such as antiviral agents, vaccines, antibodies, immunostimulants, immunosuppressants, anti-inflammatory agents, etc.

[0151] One of ordinary skill in the art will formulate the compounds into the pharmaceutical formulations described herein. For example, based on the physicochemical properties of the compound, one of ordinary skill in the art will recognize the pharmaceutically effective amount of the compound and the required route of administration.

[0152] Definitions

[0153] The terms used herein may be preceded and / or followed by a single dash "-" or a double dash "=" to indicate the order of the bond between a specified substituent and its parent moiety; in the case of a spiro substituent, a single dash represents a single bond, while a double dash represents a double bond or a pair of single bonds. In the absence of a single dash or a double dash, it should be understood that a single bond is formed between the substituent and its parent moiety; in addition, substituents should be read "from left to right" with reference to the chemical structure mentioned, unless otherwise indicated by a dash. For example, arylalkyl, arylalkyl- and -alkylaryl represent the same functional group.

[0154] For simplicity, chemical moieties are mainly defined and referred to throughout as monovalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, in appropriate structures that are clear to those skilled in the art, such terms are also used to express the corresponding polyvalent moieties. For example, while an "alkyl" moiety may refer to a monovalent group (e.g., CH3-CH2-), in some cases, a divalent linking moiety may be "alkyl", in which case those skilled in the art will understand alkyl as a divalent group (e.g., -CH2-CH2-), which is equivalent to the term "alkylene". (Similarly, in cases where a divalent moiety is required and expressed as "aryl", those skilled in the art will understand the term "aryl" to refer to the corresponding divalent moiety - arylene). All atoms are understood to have their normal bonding valences (i.e., carbon has 4, N has 3, O has 2, and S has 2, 4, or 6, depending on the oxidation state of S). Nitrogen in the currently disclosed compounds may be hypervalent, e.g., N-oxides or tetra-substituted ammonium salts. Sometimes, a moiety may be defined as, for example, -B-(A) a , where a is 0 or 1. In such a case, when a is 0, the moiety is -B, and when a is 1, the moiety is -B-A.

[0155] As used herein, the term "alkyl" includes saturated hydrocarbons having a specified number of carbon atoms, such as 1 to 10 carbons (i.e., including 1 and 10), 1 to 8 carbons, 1 to 6 carbons, 1 to 3 carbons, or 1, 2, 3, 4, 5, or 6 carbons. Alkyl can be straight-chain or branched-chain, and depending on the context, can be a monovalent group or a divalent group (i.e., alkylene). For example, the "-(C1C6 alkyl)-O-" moiety represents that oxygen is connected 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 isobutyl, sec-butyl, and tert-butyl), pentyl, and hexyl.

[0156] The term "alkoxy" represents an alkyl having a specified number of carbon atoms connected to the parent molecular moiety through an oxygen bridge. Examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, and isopropoxy.

[0157] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon which, unless otherwise specified, contains from 2 to 10 carbons (i.e., including 2 and 10), from 2 to 8 carbons, from 2 to 6 carbons, or 2, 3, 4, 5, or 6 carbons and contains at least one carbon-carbon double bond. The alkenyl can be straight-chain or branched-chain and, depending on the context, can be a monovalent group or a divalent group (i.e., alkenylene). For example, the moiety "-(C2-C6 alkenyl)-O-" indicates that oxygen is linked through an alkenylene bridge having 2 to 6 carbons. Representative examples of alkenyl include, but are not limited to, vinyl, 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.

[0158] As used herein, the term "alkynyl" refers to an unsaturated hydrocarbon which, unless otherwise specified, contains from 2 to 10 carbons (i.e., including 2 and 10), from 2 to 8 carbons, from 2 to 6 carbons, or 2, 3, 4, 5, or 6 carbons and contains at least one carbon-carbon triple bond. The alkynyl can be straight-chain or branched-chain and, depending on the context, can be a monovalent group or a divalent group (i.e., alkynylene). For example, the moiety "-(C2-C6 alkynyl)-O-" indicates that oxygen is linked through an alkynylene bridge having 2 to 6 carbons. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0159] The term "aryl" denotes an aromatic ring system having a single ring (e.g., phenyl), which single ring is optionally fused to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings or heterocycles. "Aryl" includes ring systems having multiple fused rings, wherein at least one ring is a carbocyclic and aromatic ring (e.g., 1,2,3,4-tetrahydronaphthalenyl, naphthalenyl). Examples of aryl include phenyl, 1-naphthalenyl, 2-naphthalenyl, indanyl, indenyl, dihydronaphthalenyl, fluorenyl, tetrahydronaphthalenyl, 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 heterocycle, e.g., 1H-2,3-dihydrobenzofuranyl and tetrahydroisoquinolinyl. The aryl herein is unsubstituted or, when designated as "optionally substituted", can be substituted at one or more substitutable positions with the various groups shown, unless otherwise indicated.

[0160] The term "halogen" or "halo" means fluorine, chlorine, bromine, and iodine. In certain embodiments of each and every embodiment described herein, the term "halogen" or "halo" means fluorine or chlorine. In certain embodiments of each and every embodiment described herein, the term "halogen" or "halo" means fluorine. The term "fluoroalkyl" means an alkyl group substituted with at least one fluorine (i.e., as otherwise described herein). "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-hexafluoropropan-2-yl, and 2,2,3,3,3-pentafluoropropan-1-yl.

[0161] The term "heteroaryl" refers to an aromatic ring system containing at least one aromatic heteroatom selected from nitrogen, oxygen, and sulfur in an aromatic ring. Most commonly, heteroaryl has 1, 2, 3, or 4 heteroatoms. The heteroaryl can be fused to one or more non-aromatic rings such as cycloalkyl or heterocycloalkyl rings, where the cycloalkyl and heterocycloalkyl rings are as described herein. In one embodiment of the compounds of the invention, the heteroaryl is bonded to the remainder of the structure through an atom in the heteroaryl aromatic ring. In another embodiment, the heteroaryl is bonded to the remainder of the structure through a non-aromatic ring atom. Examples of heteroaryl include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indazolyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, isoindolinyl, isobenzothienyl, benzoxazolyl, pyridinopyridyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, benzoisoxazinyl, benzoxazinyl, benzopyranyl, benzothiopyranyl, chromone, chromanone, pyridyl-N-oxide, isoindolinone, benzodioxanyl, benzoxazolinone, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolinyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indazolyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. Preferred heteroaryls include pyridyl, pyrimidinyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, and imidazolyl, pyrazolyl, indazolyl, thiazolyl, and benzothiazolyl.In certain embodiments, each heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, pyridyl-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 heteroaryls include pyridyl, pyrimidinyl, quinolinyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl, and benzothiazolyl. The heteroaryls herein are unsubstituted or, when designated as "optionally substituted", may be substituted at one or more substitutable positions with the various groups shown, unless otherwise specified.

[0162] 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 the non-aromatic ring. Heterocycloalkyl can have 1, 2, 3, or 4 heteroatoms. Heterocycloalkyl can be saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., heterocycloalkenyl). Heterocycloalkyl includes monocyclic groups having three to eight ring atoms and bicyclic and polycyclic ring systems, including bridged and fused ring systems, wherein each ring includes three to eight ring atoms. The heterocycloalkyl ring is optionally fused to other heterocycloalkyl rings and / or non-aromatic hydrocarbon rings. In certain embodiments, heterocycloalkyl has 3 to 7 members in a monocyclic ring. In other embodiments, heterocycloalkyl has 5 or 6 members in a monocyclic ring. In some embodiments, heterocycloalkyl has 3, 4, 5, 6, or 7 members in a monocyclic ring. Examples of heterocycloalkyl include, for example, azabicyclo[2.2.2]octyl (also referred to as "quinuclidinyl" or quinuclidine derivative in each case), azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, 2-oxazolidinonyl, piperazinyl, homopiperazinyl, piperazinone, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, 3,4-dihydroisoquinolin-2(1H)-yl, isoindoline dione, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, imidazolidinone, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide. Particularly desirable heterocycloalkyl includes morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl, tetrahydropyranyl, piperidinyl, azabicyclo[2.2.2]octyl, γ-butyrolactonyl (i.e., oxo-substituted tetrahydrofuranyl), γ-butyrolactamyl (i.e., oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, 2-oxazolidinonyl, imidazolidinone, isoindoline dione, piperazinone. The heterocycloalkyl herein is unsubstituted or, when designated as "optionally substituted", can be substituted at one or more substitutable positions with the various groups shown, unless otherwise indicated.

[0163] 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). The cycloalkyl ring is optionally fused to or otherwise attached to other cycloalkyl rings (e.g., a bridging system). Some examples of cycloalkyl present in the disclosed compounds have 3 to 7 members in a monocyclic ring, such as 5 or 6 members in a monocyclic ring. In some embodiments, the cycloalkyl has 3, 4, 5, 6, or 7 members in a monocyclic ring. Examples of cycloalkyl include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl, and bicyclo[2.2.1]heptane. The cycloalkyl herein is unsubstituted or, when designated as "optionally substituted", can be substituted at one or more substitutable positions with the various groups shown.

[0164] The term "ring system" encompasses monocyclic rings as well as fused and / or bridged polycyclic rings.

[0165] The term "oxo" represents a double bond oxygen, sometimes represented as =O, or, for example, when describing a carbonyl group, "C(O)" can be used to represent an oxo-substituted carbon.

[0166] When used to modify a specified group, the term "substituted" means that one or more hydrogen atoms of the specified group are each independently replaced by the same or different substituents as defined below, unless otherwise specified.

[0167] As used herein, the phrase "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of acids, such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acids such as acetic acid, HOOC(CH2) n COOH (where n is 0-4), etc. Non-toxic medicinal base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, etc. Those skilled in the art will recognize numerous non-toxic pharmaceutically acceptable addition salts.

[0168] As used herein, "tautomer" refers to compound isomers that exist in equilibrium and have different positions of protons and / or electron distributions from each other. Certain compounds disclosed herein can exist in tautomeric forms, and all tautomeric forms of such compounds are within the scope of this disclosure.

[0169] One of ordinary skill in the art of medicinal chemistry will also understand that the disclosed structures are intended to include isotopically enriched forms of the compounds of the invention. As used herein, "isotope" includes those atoms having the same atomic number but different mass numbers. As is known to those skilled in the art, certain atoms such as hydrogen exist in different isotopic forms. For example, hydrogen includes three isotopic forms: protium, deuterium, and tritium. It will be apparent to those skilled in the art upon consideration of the compounds of the invention that certain compounds can be enriched in a particular isotope of an atom at a given position. For example, a compound having a fluorine atom can be synthesized in a form enriched in the radioactive fluorine isotope 18 F. Similarly, a compound can be enriched in the heavy isotopes of hydrogen: deuterium and tritium; similarly, it can also be enriched in radioactive isotopes of carbon, such as 13 C. Such isotopically variant compounds undergo different metabolic pathways and can be used, for example, to study the ubiquitination pathway and its role in diseases. Of course, in certain embodiments, the compounds have substantially the same isotopic characteristics as naturally occurring materials.

[0170] One of ordinary skill in the art of chemistry should also understand that, unless otherwise indicated, the disclosed structures are intended to include all possible stereoisomers of the claimed molecules, including mixtures of some or all of the stereoisomers. However, a compound drawn with a specific stereochemistry at one or more stereocenters is intended to have the indicated stereochemistry. A compound and a stereocenter drawn with ambiguous stereochemistry are intended to represent any stereoisomer or a mixture thereof, e.g., a racemic mixture of the compound or a purified subset of stereoisomers.

[0171] As used herein, the terms "individual", "patient", or "subject" are used interchangeably and refer to any animal, including mammals, preferably humans.

[0172] As used herein, the phrase "therapeutically effective amount" or "effective amount" refers to the amount of an active compound or agent that elicits the biological or medical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human.

[0173] In certain embodiments, the effective amount can be an amount suitable for the following purposes:

[0174] (i) inhibiting disease progression;

[0175] (ii) prophylactic use, e.g., preventing or limiting the development of a disease, condition, or disorder in an individual who may be predisposed to or at risk of developing the disease, condition, or disorder but has not yet experienced or manifested the pathology or symptoms of the disease;

[0176] (iii) Suppressing a disease; for example, suppressing a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder;

[0177] (iv) Improving the mentioned disease state; for example, improving a disease, condition or disorder (i.e., reversing or improving the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder, such as reducing the severity of the disease; or

[0178] (v) Eliciting the mentioned biological effect.

[0179] As used herein, the terms "treatment" and "treating" refer to (i) improving the mentioned disease state, condition or disorder (or its symptoms), for example, improving a disease, condition or disorder (i.e., reversing or improving the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder, such as reducing the severity of the disease or its symptoms, or suppressing the progression of the disease; or (ii) eliciting the mentioned biological effect (e.g., suppressing the formation or function of an inflammasome, or suppressing IL-1β).

[0180] Preparation method

[0181] There are many available general references that provide well-known chemical synthesis schemes and conditions that can be used to synthesize the disclosed compounds (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, 4th Edition, New York: Longman, 1978).

[0182] The compounds described herein can be purified by any means known in the art, including chromatographic means such as HPLC, preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal phase, reverse phase, and ionic resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, edited by L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, edited by E. Stahl, Springer-Verlag, New York, 1969.

[0183] In any process for preparing the subject compounds, it may be necessary and / or desirable to protect sensitive or reactive groups on any relevant molecules. This can be accomplished by means of conventional protecting groups described in standard works such as J.F.W. McOmie, "Protective Groups in Organic Chemistry,” Plenum Press, London and New York 1973, T.W. Greene and P.G.M. Wuts, "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 1981, "Methoden der organischen Chemie,” Houben-Weyl, 4th Edition, Volume 15 / l, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine,” Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and / or Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate,” Georg Thieme Verlag, Stuttgart 1974. The protecting groups can be removed by methods known in the art at a convenient subsequent stage.

[0184] As used herein, a "leaving group" (e.g., represented as LG when appropriate) refers to a moiety of a reactant (e.g., an alkyl halide of the present disclosure) that is transferred from the first reactant during a chemical reaction. A complete list of suitable leaving groups can be found in J. March, Advanced Organic Chemistry, John Wiley and Sons, N.Y. (2013). Examples of suitable leaving groups include, but are not limited to, halogens (such as Cl or Br), acetoxy, and sulfonyloxy (such as methanesulfonyloxy, trifluoromethanesulfonyloxy ("triflate"), p-toluenesulfonyloxy ("tosylate")).

[0185] Examples

[0186] The compounds disclosed herein can be prepared using procedures and methods known to those of ordinary skill in the art and, for example, the general reaction schemes and examples described herein. Those skilled in the art can adjust the reaction sequence of the schemes provided herein to accommodate the desired target molecule. Of course, in some cases, those skilled in the art will use different reagents to effect one or more individual steps or use protected forms of certain substituents. Additionally, those skilled in the art will recognize that the compounds of the present disclosure can be synthesized using an entirely different route. For example, those of ordinary skill in the art can modify the procedures described herein and / or other procedures familiar to those of ordinary skill in the art to prepare the compounds described herein.

[0187] General Reaction Scheme 1: Preparation of Benzimidazole Derivatives

[0188]

[0189] General Reaction Scheme 2: Preparation of Benzimidazole-Benzoxazole Derivatives

[0190]

[0191] The preparation of the compounds of the present disclosure is further illustrated by the following examples, which should not be construed as limiting the present disclosure in scope or spirit to the specific procedures and compounds described herein.

[0192] Example 1

[0193] Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine

[0194]

[0195] Step 1: Synthesis of 4-Fluoro-N-methyl-2-nitroaniline

[0196] At room temperature, aqueous methylamine solution (120 mL, 377 mmol) was added to 1,4-difluoro-2-nitrobenzene (20 g, 126 mmol) and the mixture was stirred in a sealed tube for 5 h. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was quenched with ice-cold water (100 mL) and stirred for 10 min. The solid was precipitated, filtered and dried under vacuum to obtain crude 4-fluoro-N-methyl-2-nitroaniline as an orange solid (18 g, 84%).

[0197] Step 2: Synthesis of 4-fluoro-N1-methylbenzene-1,2-diamine

[0198] Zinc powder (69.2 g, 1.06 mol) and ammonium chloride (84.9 g, 1.59 mol) were added to a solution of 4-fluoro-N-methyl-2-nitroaniline (18 g, 106 mmol) in ethyl acetate (90 mL) and demineralized (DM) water (90 mL) stirred at room temperature. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was filtered through a celite bed and the celite bed was washed with ethyl acetate (2 x 50 mL). The resulting filtrate was diluted in demineralized (DM) water (300 mL) and extracted with ethyl acetate (2 x 250 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 4-fluoro-N1-methylbenzene-1,2-diamine as a brown solid (14 g, 94%).

[0199] Step 3: Synthesis of 5-fluoro-1-methyl-1H-benzo[d]imidazol-2-amine

[0200] Cyanogen bromide (18.9 g, 178 mmol) was added to a solution of 4-fluoro-N1-methylbenzene-1,2-diamine (10 g, 71.3 mmol) in acetonitrile (30 mL) and water (10 mL) stirred at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was concentrated to obtain the crude product, which was diluted with DM water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The aqueous layer was alkalized to pH ~12 - 14 using 1N sodium hydroxide solution (30 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5-fluoro-1-methyl-1H-1,3-benzodiazol-2-amine as a brown solid (11.5 g, 97%).

[0201] Step 4: Synthesis of methyl benzo[d]oxazole-5-carboxylate

[0202] At room temperature, p-toluenesulfonic acid (0.5 g, 2.9 mmol) was added to a stirred solution of methyl 3-amino-4-hydroxybenzoate (5 g, 29.9 mmol) in triethyl orthoformate (50 mL). The reaction mixture was heated to 100 °C in a sealed tube for 16 h. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was 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.

[0203] Step 5: Synthesis of methyl 2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxylate

[0204] At room temperature, lithium 2-methylpropan-2-olate (1+)(3.25 g, 40.6 mmol) and iodine (2.58 g, 20.3 mmol) were added to a stirred solution of methyl 1,3-benzoxazole-5-carboxylate (2.4 g, 13.5 mmol) in tetrahydrofuran (24 mL). The reaction mixture was stirred for 10 min, then 5-fluoro-1-methyl-1H-1,3-benzodiazol-2-amine (3.36 g, 20.3 mmol) was added, and then the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, 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 obtain the crude compound. The crude compound was purified by flash column chromatography using 0 - 60% ethyl acetate in n-heptane as the 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).

[0205] Step 6: Synthesis of (2-((5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-5-yl)methanol

[0206] At room temperature, 1M lithium aluminum hydride in THF (7.05 mL, 7.05 mmol) was added 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). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using 0 - 10% methanol in dichloromethane as the 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.

[0207] Step 7: Synthesis of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine

[0208] At 0 °C, thionyl chloride (307 μL, 4.23 mmol) was added 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), and the reaction mixture was stirred at 0 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was basified with saturated potassium carbonate solution (pH ~ 8) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were 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.

[0209] Step 8: Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine

[0210] At room temperature, dimethylamine hydrochloride (351 mg, 4.31 mmol) and potassium carbonate (1.19 g, 8.62 mmol) were added 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). The reaction mixture was stirred at 60 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was diluted with DM water (60 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by reverse-phase preparative HPLC: [column: ZORBAX Eclipse C18 (150 mm x 21.2 mm; 7 μm); flow rate: 19 mL / min; mobile phase (A) 0.1% ammonia water; mobile phase (B) acetonitrile], to give Example 1 (5-[(dimethylamino)methyl]-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine) as an off-white solid (380 mg, 38%). LCMS (ES) m / z = 340.3 [M+H] + 。

[0211] Example 2

[0212] Synthesis of 5-{[ethyl(methyl)amino]methyl}-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine

[0213]

[0214] Example 2 was synthesized in a similar manner to Example 1, except that N-methylethylamine was used in Step 8. LCMS (ES) m / z = 352.2 [M-H] – 。

[0215] Example 3

[0216] Synthesis of 5-[(diethylamino)methyl]-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine

[0217]

[0218] Example 3 was synthesized in a similar manner to Example 1, except that N,N-diethylamine was used in Step 8. LCMS (ES) m / z = 366.3 [M-H]– .

[0219] Example 4

[0220] 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

[0221]

[0222] Example 4 was synthesized in a similar manner to Example 1, except that 1-methyl-1H-pyrazol-4-amine was used in Step 1. LCMS(ES) m / z = 406.3 [M+H] + .

[0223] Example 5

[0224] Synthesis of 5-(azetidin-1-ylmethyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine

[0225]

[0226] Example 5 was synthesized in a similar manner to Example 1, except that azetidine was used in Step 8. LCMS(ES) m / z = 352.2 [M+H] + .

[0227] Example 6

[0228] Synthesis of 5-[(dimethylamino)methyl]-N-(1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine

[0229]

[0230] Example 6 was synthesized in a similar manner to Example 1, except that 1-fluoro-2-nitrobenzene was used in Step 1. LCMS(ES) m / z = 322.3 [M+H] + .

[0231] Example 7

[0232] Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine

[0233]

[0234] Example 7 was synthesized in a similar manner to Example 1, except that methyl 4-amino-3-hydroxybenzoate was used in Step 4. LCMS(ES) m / z = 340.2 [M+H] + .

[0235] Example 8

[0236] Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-[(pyrrolidin-1-yl)methyl]-1,3-benzoxazol-2-amine

[0237]

[0238] Example 8 was synthesized in a similar manner to Example 1, except that pyrrolidine was used in Step 8. LCMS(ES) m / z = 366.2 [M+H] + .

[0239] Example 9

[0240] Synthesis of 5-[(dimethylamino)methyl]-N-(5-fluoro-1-phenyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine

[0241]

[0242] Example 9 was synthesized in a similar manner to Example 1, except that aniline was used in Step 1. LCMS(ES) m / z = 402.3 [M+H] + .

[0243] Example 10

[0244] 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

[0245]

[0246] Step 1: Synthesis of tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate

[0247] At 0 °C, triethylamine (1.86 mL, 13.3 mmol) and di-tert-butyl dicarbonate (1.45 g, 6.66 mmol) were added to a stirred solution of 2-(methylamino)ethan-1-ol (0.5 g, 6.66 mmol) in dichloromethane (5 mL). The resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with DM water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were separated, washed with DM water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using 30 - 40% ethyl acetate in n-heptane as the eluent to give tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (0.8 g, 69%) as a colorless liquid.

[0248] Step 2: Synthesis of tert-butyl N-methyl-N-[2-(prop-2-yn-1-yloxy)ethyl]carbamate

[0249] To a 0 °C solution of sodium hydride (60% dispersion in mineral oil) (21.9 mg, 571 μmol) in dimethylformamide (3 mL) was added dropwise N-(2-hydroxyethyl)-N-methylcarbamate (0.8 g, 4.57 mmol) (diluted in 4 mL of dimethylformamide) to the reaction mixture. After 20 min, 3-bromoprop-1-yne (815 mg, 6.85 mmol) was added dropwise to the reaction mixture at 0 °C. The resulting reaction mixture was stirred from 0 °C to room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was slowly quenched with saturated ammonium chloride solution (10 mL) at 0 °C and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were separated, dried over sodium sulfate, and concentrated to give the crude compound. The crude compound was purified by flash column chromatography using 10 - 15% ethyl acetate in n-heptane as the eluent to give tert-butyl N-methyl-N-[2-(prop-2-yn-1-yloxy)ethyl]carbamate (750 mg, 77%) as a yellow oil.

[0250] Step 3: Synthesis of methyl[2-(prop-2-yn-1-yloxy)ethyl]amine hydrochloride

[0251] At 0 °C, 4.0 M hydrogen chloride in 1,4-dioxane (615 mg, 16.9 mmol) was added 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). The resulting reaction mixture was stirred from 0 °C to room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude compound. The crude compound was washed with n-pentane (5 mL), followed by diethyl ether (5 mL) and acetonitrile (5 mL), to give methyl [2-(prop-2-yn-1-yloxy)ethyl]amine hydrochloride as a white solid (510 mg, 81%).

[0252] 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

[0253] At room temperature, 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) were added 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 in Step 7 of the synthesis of Example 1) (0.2 g, 605 μmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixture was stirred in the sealed tube at 80 °C for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with DM water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using 7-10% methanol in dichloromethane as the 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] + 。

[0254] Example 11

[0255] Synthesis of 5-((dimethylamino)methyl)-N-(6-fluoro-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine

[0256]

[0257] Example 11 can be synthesized substantially according to the procedures described in the foregoing examples and Reaction Schemes 1 and 2.

[0258] Example 12

[0259] Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-{[methyl(propyl)amino]methyl}-1,3-benzoxazol-2-amine

[0260]

[0261] Example 12 was synthesized in a similar manner to Example 1, except that N-methylpropan-1-amine was used in Step 8. LCMS(ES) m / z = 368.3 [M+H] + 。

[0262] Example 13

[0263] Synthesis of (2-((5-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazol-5-yl)methanol

[0264]

[0265] Example 13 was synthesized in Step 6 of the synthesis of Example 4. LCMS(ES) m / z = 379.2 [M+H] + 。

[0266] Example 14

[0267] Synthesis of 5-((dimethylamino)methyl)-N-(5-fluoro-1-propyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine

[0268]

[0269] Example 14 was synthesized in a similar manner to Example 1, except that 1-aminopropane was used in Step 1. LCMS(ES) m / z = 367.2 [M-H] – 。

[0270] Example 15

[0271] Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-[(morpholin-4-yl)methyl]-1,3-benzoxazol-2-amine

[0272]

[0273] Example 15 was synthesized in a similar manner to Example 1, except that morpholine was used in Step 8. LCMS(ES) m / z = 380.2 [M-H] - 。

[0274] Examples 16 and 20

[0275] Synthesis of N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-7-methyl-7,8-dihydro-6H-oxazolo[4,5-e]isoindol-2-amine (Example 16) and N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-6-methyl-6,7-dihydro-5H-oxazolo[4,5-f]isoindol-2-amine (Example 20)

[0276]

[0277] Step 1: Synthesis of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate

[0278] At room temperature, potassium acetate (6.58 g, 67.1 mmol) was added 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). The reaction mixture was degassed with a nitrogen atmosphere for 10 min, and then tetrakis(triphenylphosphine)palladium (1.94 g, 1.68 mmol) was added. The reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a celite bed, and the solvent was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using 0 - 20% ethyl acetate in n-heptane as the 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.

[0279] Step 2: Synthesis of tert-butyl 5-hydroxyisoindoline-2-carboxylate

[0280] At room temperature, hydrogen peroxide (5.66 mL, 72.4 mmol) was added 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), and the mixture was stirred for 2 h. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was quenched with saturated sodium thiosulfate solution (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using 0 - 30% ethyl acetate in n-heptane as the eluent to give tert-butyl 5-hydroxy-2,3-dihydro-1H-isoindole-2-carboxylate as a white solid (3.4 g, 100%).

[0281] 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

[0282] At 0 °C, sodium nitrate (3.07 g, 36.1 mmol) was added portionwise 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). The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 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 as a brown liquid (4.0 g, crude). The crude material was used in the next step without purification.

[0283] Step 4: Synthesis of a regioisomeric mixture of 2-methyl-4-nitroisoindolin-5-ol and 2-methyl-6-nitroisoindolin-5-ol

[0284] At 0 °C, 37% aqueous formaldehyde solution (2.02 mL, 27.2 mmol), sodium acetate (2.23 g, 27.2 mmol) and acetic acid (0.5 mL) were added to a stirred solution of the 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). The reaction mixture was stirred for 15 min and sodium cyanoborohydride (1.71 g, 27.2 mmol) was added to the reaction mixture. Then the reaction mixture was stirred at room temperature for 2 h. 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 x 100 mL). The combined organic layers were washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound. The crude compound was 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 as a brown solid (2.0 g, 76%).

[0285] Step 5: Synthesis of the regioisomeric mixture of 6-amino-2-methyl-2,3-dihydro-1H-isoindol-5-ol and 4-amino-2-methyl-2,3-dihydro-1H-isoindol-5-ol

[0286] Under a nitrogen atmosphere, 10% palladium on carbon (0.4 g, 3.76 mmol) was added to a stirred solution of the regioisomeric mixture of 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). The reaction mixture was degassed with H2 atmosphere and stirred under H2 atmosphere for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure to give a regioisomeric mixture of 6-amino-2-methyl-2,3-dihydro-1H-isoindol-5-ol and 4-amino-2-methyl-2,3-dihydro-1H-isoindol-5-ol as a brown solid (0.8 g, 95%).

[0287] Step 6: Synthesis of the regioisomeric mixture of 6-methyl-5H,6H,7H-[1,3]oxazolo[4,5-f]isoindol-2-amine and 7-methyl-6H,6H,8H-[1,3]oxazolo[4,5-e]isoindol-2-amine

[0288] At 0 °C, cyanogen bromide (1.03 g, 9.74 mmol) was added 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). The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with DM water (20 mL), and extracted with ethyl acetate (2 x 30 mL). The combined aqueous layers were basified with 1N sodium hydroxide solution (20 mL) and extracted with 5% methanol in dichloromethane (2 x 50 mL). The combined organic layers were washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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 as an off-white solid (0.5 g, 54%).

[0289] 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

[0290] At room temperature, 2-chloro-5-fluoro-1-methyl-1H-benzo[d]imidazole (268 mg, 1.45 mmol) and cesium fluoride (602 mg, 3.96 mmol) were added to a stirred solution of the 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). The reaction mixture was stirred at 100 °C for 16 h. 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 x 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 obtain the crude compound. The crude compound was purified by reverse-phase preparative HPLC [column: Inertsil ODS C18 (250x20) mm; 5 mic; flow rate: -19 ml / min; mobile phase (A): 0.1% aqueous TFA; 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 (40 mg, 7%), 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 (45 mg, 7.5%), LCMS (ES) m / z = 338.2 [M+H] as an off-white solid + (Example 20).

[0291] Example 17

[0292] Synthesis of {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5-yl}methanol

[0293]

[0294] Example 17 was synthesized in Step 6 of Example 1. LCMS (ES) m / z = 313.2 [M+H] + .

[0295] Example 18

[0296] Synthesis of N-(1-cyclopropyl-5-fluoro-1H-1,3-benzodiazol-2-yl)-5-[(dimethylamino)methyl]-1,3-benzoxazol-2-amine

[0297]

[0298] Example 18 was synthesized in a similar manner to Example 1, except that 1-aminocyclopropane was used in Step 1. LCMS(ES) m / z = 366.29 [M+H] + .

[0299] Example 19

[0300] Synthesis of N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-5-((4-methylpiperazin-1-yl)methyl)benzo[d]oxazol-2-amine trifluoroacetate

[0301]

[0302] Example 19 was synthesized in a similar manner to Example 1, except that 1-methylpiperazine was used in Step 8. LCMS(ES) m / z = 393.2 [M+H] + 。

[0303] Example 21

[0304] Synthesis of N-[1-(cyclopropylmethyl)-5-fluoro-1H-1,3-benzodiazol-2-yl]-5-[(dimethylamino)methyl]-1,3-benzoxazol-2-amine

[0305]

[0306] Example 21 was synthesized in a similar manner to Example 1, except that 1-cyclopropylmethylamine was used in Step 1. LCMS(ES) m / z = 380.2 [M+H] + 。

[0307] Example 22

[0308] Synthesis of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine

[0309]

[0310] Example 22 was synthesized in Step 7 of the synthesis of Example 1. LCMS(ES) m / z = 329.1 [M-H] – 。

[0311] Example 23

[0312] Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(methoxymethyl)-1,3-benzoxazol-2-amine

[0313]

[0314] To a solution of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine (i.e., the intermediate in step 7 of the synthesis of Example 1) (20 mg, 0.060 mmol) in tetrahydrofuran (2 mL) stirred at room temperature was added sodium methoxide (7.26 μL, 0.012 mmol). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DM water (10 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with DM water (2 x 10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography using 0 - 5% methanol in DCM as the eluent to give Example 23 (N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(methoxymethyl)-1,3-benzoxazol-2-amine) as an off-white solid (5 mg, 25%). LCMS (ES) m / z = 327.2 [M + H] + 。

[0315] Example 24

[0316] 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

[0317]

[0318] Step 1: Synthesis of tert-butyl N-methyl-N-(prop-2-yn-1-yl)carbamate

[0319] To a 0 °C solution of sodium hydride (60% dispersion in mineral oil) (247 mg, 6.44 mmol) in tetrahydrofuran (3 mL) in a sealed tube was added dropwise a solution of tert-butyl N-(prop-2-yn-1-yl)carbamate (0.5 g, 3.22 mmol) in tetrahydrofuran. After 20 min, methyl iodide (401 μL, 6.44 mmol) was added dropwise to the reaction mixture at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched slowly with saturated ammonium chloride solution (25 mL) at 0 °C and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by flash column chromatography using 10 - 15% ethyl acetate in n-heptane as the eluent to give tert-butyl N-methyl-N-(prop-2-yn-1-yl)carbamate (450 mg, 83%) as a yellow oil.

[0320] Step 2: Synthesis of methyl(prop-2-yn-1-yl)amine hydrochloride

[0321] At 0 °C, 4.0 M hydrogen chloride in dioxane (388 mg, 10.6 mmol) was added 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). The resulting reaction mixture was stirred from 0 °C to room temperature over 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the crude compound. The crude compound was washed with n-pentane (5 mL), diethyl ether (5 mL) and acetonitrile (5 mL), and then dried under reduced pressure to give methyl(prop-2-yn-1-yl)amine hydrochloride (240 mg, 85%) as a white solid.

[0322] 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

[0323] At room temperature, 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) were added 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 in step 7 of the synthesis of Example 1) (0.2 g, 605 μmol) in N,N-dimethylformamide (5 mL). The resulting reaction mixture was stirred in a sealed tube at 75 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with DM water (25 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were 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 x 20) mm; 5 mic; flow rate: -19 ml / min; mobile phase (A): 0.1% ammonia water; mobile phase (B): acetonitrile], to give 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] + .

[0324] Example 25

[0325] Synthesis of N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine

[0326]

[0327] To a solution of 1,3-benzoxazole (0.1 g, 0.839 mmol) in tetrahydrofuran (4 mL) stirred at room temperature was added lithium tert-butoxide (202 mg, 2.52 mmol) and iodine (160 mg, 1.26 mmol). The reaction mixture was stirred for 10 min. After 10 min, 5-fluoro-1-methyl-1H-1,3-benzodiazol-2-amine (i.e., the intermediate in Step 3 of the synthesis of Example 1) (277 mg, 1.68 mmol) was added to the reaction mixture and stirred for an additional 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DM water (50 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC: [Column: Inertsil ODS-3 (250 mm x 20 mm x 5 μm); Mobile phase (A): 0.1% aqueous ammonia; 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 were concentrated to give Example 25 (N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzoxazol-2-amine) as an off-white solid (38 mg, 13%). LCMS (ES) m / z = 283.2 [M+H] + 。

[0328] Example 26

[0329] Synthesis of 2-{2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5-yl}acetonitrile

[0330]

[0331] At room temperature and under a nitrogen atmosphere, tetrabutylammonium fluoride (0.1 mL, 756 μmol) and trimethylsilyl cyanide (0.3 mL, 756 μmol) were slowly added 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 in Step 7 of the synthesis of Example 1) (250 mg, 756 μmol) in tetrahydrofuran (25 mL) and acetonitrile (25 mL). The resulting reaction mixture was stirred in a sealed tube at room temperature for 48 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was quenched with DM water (30 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by flash column chromatography using 5-15% methanol in dichloromethane as the eluent to obtain 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] + 。

[0332] Example 27

[0333] Synthesis of {2-[(1-cyclopropyl-5-fluoro-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5-yl}methanol

[0334]

[0335] Example 27 was synthesized in Step 6 of the synthesis of Example 18. LCMS (ES) m / z = 339.2 [M+H] + 。

[0336] Example 28

[0337] Synthesis of 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazole-5-carbaldehyde

[0338]

[0339] To a solution of {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5-yl}methanol (i.e., the intermediate in Step 6 of the synthesis of Example 1) (80 mg, 0.256 mmol) in dichloromethane (5 mL) stirred at 0 °C was added 1,1-bis(acetyloxy)-3-oxo-3H-1λ5 ,2-Benziodoxol-1-yl acetate (163 mg, 0.384 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was diluted with DM water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified using preparative HPLC [column: Inertsil ODS C18 (250 x 20) mm; 5 mic; flow rate: -19 ml / min; mobile phase (A): 0.1% ammonia water; mobile phase (B): acetonitrile] to give Example 28 (2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazole-5-carbaldehyde) as an off-white solid (22 mg, 28%). LCMS (ES) m / z: 311.2 [M+H] + .

[0340] Example 29

[0341] Synthesis of N-(1-benzyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-5-((dimethylamino)methyl)benzo[d]oxazol-2-amine

[0342]

[0343] Example 29 was synthesized in a similar manner to Example 1, except that benzylamine was used in Step 1. LCMS (ES) m / z = 416.3 [M+H] + .

[0344] Example 30

[0345] Synthesis of 5-((dimethylamino)methyl)-N-(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-N-methylbenzo[d]oxazol-2-amine

[0346]

[0347] Example 30 can be synthesized substantially according to the procedures described in the foregoing examples and Reaction Schemes 1 and 2.

[0348] Example 31

[0349] Synthesis of 5-[(dimethylamino)methyl]-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-N-methyl-1,3-benzoxazol-2-amine

[0350]

[0351] Step 1: Synthesis of 5-Fluoro-2-iodo-1-methyl-1H-1,3-benzodiazole

[0352] At 0 °C, diiodomethane (1.02 mL, 12.1 mmol) and 3-methylbutyl nitrite (1.24 mL, 9.08 mmol) were added 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). The reaction mixture was stirred at 60 °C for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DM water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound. The crude compound was 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 as an off-white solid (250 mg, 30%).

[0353] Step 2: Synthesis of methyl 1,3-benzoxazole-5-carboxylate

[0354] At room temperature, 4-methylbenzenesulfonic acid (515 mg, 2.99 mmol) was added to a stirred solution of methyl 3-amino-4-hydroxybenzoate (5 g, 29.9 mmol) in triethyl orthoformate (50 mL). The reaction mixture was stirred in a sealed tube at 120 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude residue. The crude residue was diluted with DM water (100 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 1,3-benzoxazole-5-carboxylate as a pale yellow solid (3.3 g, crude).

[0355] Step 3: Synthesis of methyl 2-iodo-1,3-benzoxazole-5-carboxylate

[0356] Under inert conditions and at -78 °C, lithium bis(trimethylsilyl)amide (1+) (2.83 g, 16.9 mmol) was added dropwise to a stirred solution of methyl 1,3-benzoxazole-5-carboxylate (1 g, 5.64 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred for 1 h. After 1 h, iodine (1.07 g, 8.47 mmol) in tetrahydrofuran (5 mL) was added dropwise at -78 °C. The reaction mixture was stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DM water (40 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using 0 - 40% ethyl acetate in n-heptane as the eluent to give methyl 2-iodo-1,3-benzoxazole-5-carboxylate as a pale yellow solid (0.6 g, 35%).

[0357] Step 4: Synthesis of methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate

[0358] A stirred solution of methyl 2-iodo-1,3-benzoxazole-5-carboxylate (0.6 g, 2.97 mmol) in 30% methylamine ethanol solution (366 μL, 8.91 mmol) was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using 0 - 10% methanol in DCM as the eluent to give methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate as a white solid (0.550 g, 98%).

[0359] Step 5: Synthesis of [2-(methylamino)-1,3-benzoxazole-5-yl]methanol

[0360] At 0 °C, 1 M lithium aluminum hydride in THF (152 mg, 4 mmol) was added to a stirred solution of methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate (550 mg, 2.67 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give [2-(methylamino)-1,3-benzoxazole-5-yl]methanol as a brown solid (350 mg, crude).

[0361] Step 6: Synthesis of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methyl-1,3-benzoxazol-2-amine

[0362] At 0 °C, 1H-imidazole (172 mg, 2.53 mmol) and tert-butyl(chloro)dimethylsilane (381 mg, 2.53 mmol) were added to a stirred solution of [2-(methylamino)-1,3-benzoxazol-5-yl]methanol (0.350 g, 1.68 mmol) in dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 1.5 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DM water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography using 0 - 20% ethyl acetate in n-heptane as the eluent to give 5-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methyl-1,3-benzoxazol-2-amine as a brown oil (450 mg, 91%).

[0363] 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

[0364] At room temperature, cesium carbonate (223 mg, 684 μmol) was added 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). The reaction mixture was degassed with a nitrogen atmosphere for 5 min. After 5 min, tris(1,5-diphenylpent-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) were added to the reaction mixture. The reaction mixture was stirred at 120 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DM water (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give §s as an off-white solid (120 mg, 80%).

[0365] Step 8: Synthesis of {2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)(methyl)amino]-1,3-benzoxazol-5-yl}methanol

[0366] At 0 °C, tetrabutylammonium fluoride (125 mg, 477 μmol) was added 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). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DM water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were 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.

[0367] Step 9: Synthesis of 5-(chloromethyl)-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-N-methyl-1,3-benzoxazol-2-amine

[0368] At 0 °C, sulfuryl chloride (43.7 mg, 368 μmol) was added 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). The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a solid. The solid was washed with diethyl 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.

[0369] 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

[0370] 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) was added potassium carbonate (60.1 mg, 435 μmol) and dimethylamine hydrochloride (17.7 mg, 218 μmol). The reaction mixture was stirred at 80 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DM water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by preparative HPLC: [mobile phase (A): 0.1% aqueous ammonia; 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) as a white solid (18 mg, 35%). LCMS (ES) m / z = 354.3 [M+H] + 。

[0371] Examples 32 - 35

[0372] Synthesis of Examples 32 - 35

[0373] Examples 32 - 35 can be synthesized substantially according to the procedures described in the foregoing examples and Reaction Schemes 1 and 2

[0374]

[0375]

[0376] Example 36

[0377] Synthesis of N-(5-((dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine

[0378]

[0379] Step 1: Synthesis of 5-fluorobenzo[d]oxazole-2-thiol

[0380] To a solution of 2-amino-4-fluorophenol (1 g, 7.87 mmol) in ethanol (20 mL) stirred at room temperature was added potassium (ethoxymethanethioyl)sulfide (3.15 g, 19.7 mmol), and the mixture was stirred at 80 °C for 16 h. The reaction process was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with ice-cold water and acidified with 3N HCl (pH ~ 4). The solid was precipitated, filtered, and dried in vacuo to give 5-fluoro-1,3-benzoxazole-2-thiol (1.2 g, 90%).

[0381] Step 2: Synthesis of 2-chloro-5-fluorobenzo[d]oxazole

[0382] To a solution of 5-fluoro-1,3-benzoxazole-2-thiol (1 g, 5.91 mmol) in thionyl chloride (8 mL) stirred at 0 °C was added dimethylformamide (1 mL, 12.9 mmol), and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was quenched with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were 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%).

[0383] Step 3: Synthesis of methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazole-5-carboxylate

[0384] To a solution of 2-chloro-5-fluoro-1,3-benzoxazole (250 mg, 1.46 mmol) in dimethyl sulfoxide (10 mL) and dimethylformamide (1 mL) stirred at 0 °C under inert conditions was added sodium hydride (60% dispersion in mineral oil) (67 mg, 2.91 mmol). The reaction mixture was stirred at 0 °C for 20 min. Then, methyl 2-amino-1-methyl-1H-1,3-benzodiazole-5-carboxylate (359 mg, 1.75 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were 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 as a brown solid (358 mg, 72%).

[0385] Step 4: Synthesis of (2-((5-Fluorobenzo[d]oxazol-2-yl)amino)-1-methyl-1H-benzo[d]imidazol-5-yl)methanol

[0386] To a solution of methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazole-5-carboxylate (350 mg, 1.03 mmol) in tetrahydrofuran (10 mL, 123 mmol) stirred at 0 °C was added a 1.0 M solution of lithium aluminum hydride in THF (5 mL, 2.06 mmol). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with saturated ammonium chloride (15 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-5-yl}methanol (310 mg, 96%) as a gummy solid.

[0387] Step 5: Synthesis of N-(5-(Chloromethyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine

[0388] At room temperature, dimethylformamide (0.5 mL) was added 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) and the mixture was stirred for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to 0 °C, neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford N-(5-(chloromethyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine (160 mg, 50%) as an off-white solid.

[0389] Step 6: Synthesis of N-(5-((Dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine

[0390] 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) were added dimethylamine hydrochloride (222 mg, 2.72 mmol) and potassium carbonate (188 mg, 1.36 mmol), and the mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with DM water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography and further purified by preparative HPLC [column: Inertsil ODS C18 (250 x 20) mm; 5 mic, flow rate: -19 ml / min; mobile phase (A): 0.1% aqueous TFA; 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] - 。

[0391] Example 37

[0392] Synthesis of N-{6-[(dimethylamino)methyl]-1-methyl-1H-1,3-benzodiazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine

[0393]

[0394] Step 1: Synthesis of methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazole-6-carboxylate

[0395] At 0 °C, sodium hydride 60% w / w (156 mg, 3.9 mmol) was added 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), and the mixture was stirred for 20 min. After 20 min, 5-fluoro-2-iodo-1,3-benzoxazole (513 mg, 1.95 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were 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.

[0396] Step 2: Synthesis of {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-6-yl}methanol

[0397] Compound {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-6-yl}methanol was synthesized in a similar manner to Step 6 of the synthesis of Example 1.

[0398] Step 3: Synthesis of N-[6-(chloromethyl)-1-methyl-1H-1,3-benzodiazol-2-yl]-5-fluoro-1,3-benzoxazol-2-amine

[0399] Compound N-[6-(chloromethyl)-1-methyl-1H-1,3-benzodiazol-2-yl]-5-fluoro-1,3-benzoxazol-2-amine was synthesized in a similar manner to Step 7 of the synthesis of Example 1.

[0400] Step 4: Synthesis of N-{6-[(dimethylamino)methyl]-1-methyl-1H-1,3-benzodiazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine

[0401] Example 37 (N-{6-[(dimethylamino)methyl]-1-methyl-1H-1,3-benzodiazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine) was synthesized in a similar manner to Step 8 of the synthesis of Example 1. LCMS (ES) m / z = 340.25 [M+H] + 。

[0402] Example 38

[0403] Synthesis of {2-[(5-Fluoro-1,3-benzoxazol-2-yl)amino]-1-methyl-1H-1,3-benzodiazol-6-yl}methanol

[0404]

[0405] Example 38 was synthesized in Synthesis Step 2 of Example 37. LCMS(ES) m / z = 313.2 [M+H] + 。

[0406] Example 39

[0407] Synthesis of 5-[(Dimethylamino)methyl]-N-(1-ethyl-5-fluoro-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine

[0408]

[0409] Example 39 was synthesized in a similar manner to Example 1, except that ethylamine was used in Step 1. LCMS(ES) m / z = 354.2 [M+H] + 。

[0410] Example 40

[0411] Synthesis of 2-((5-Fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazole-5-carboxamide

[0412]

[0413] Steps 1 to 5 were carried out in a similar manner to Synthesis Steps 1 to 5 of Example 1.

[0414] Step 6: Synthesis of 2-((5-Fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxylic acid

[0415] To a 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) stirred at room temperature was added lithium hydroxide (92.5 mg, 2.2 mmol) and the mixture was stirred for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with DM water (15 mL), acidified with 1N HCl, and then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were 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 as an off-white solid (110 mg, 76%).

[0416] 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

[0417] To a solution of 2-(2-aminoethoxy)ethanol (48.3 mg, 460 μmol) in dimethylformamide (5 mL) stirred at room temperature was added {3-[cyano(ethyl)amino]propyl}dimethylammonium chloride (76.4 mg, 398 μmol), 1H-1,2,3-benzotriazol-1-ol hydrate (70.4 mg, 460 μmol) and ethyldi(propan-2-yl)amine (160 μL, 919 μmol) and the mixture was stirred for 5 min. After 5 min, 2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-N-[2-(2-hydroxyethoxy)ethyl]-1,3-benzoxazole-5-carboxamide (46 mg, 111 μmol) was added and the mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound. The crude compound was 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) as an off-white solid (29 mg, 36%). LCMS (ES) m / z = 414.3 [M+H] + 。

[0418] Example 41

[0419] 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

[0420]

[0421]

[0422] Example 41 was synthesized in a similar manner to Example 1, except that 2-(methylamino)ethan-1-ol was used in Step 8. LCMS: (ES) m / z = 370.2 [M+H].

[0423] Example 42

[0424] Synthesis of 1-({2-[(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)amino]-1,3-benzoxazol-5-yl}methyl)azetidin-3-ol

[0425]

[0426] Example 42 was synthesized in a similar manner to Example 1, except that azetidin-3-ol was used in Step 8. LCMS (ES) m / z = 368.2 [M+H] + .

[0427] Example 43

[0428] Synthesis of N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-[(3-methoxyazetidin-1-yl)methyl]-1,3-benzoxazol-2-amine

[0429]

[0430] Example 43 was synthesized in a similar manner to Example 1, except that 3-methoxyazetidine was used in Step 8. LCMS (ES) m / z = 380.3 [M-H] – .

[0431] Example 44

[0432] Synthesis of 5-[(3-aminoazetidin-1-yl)methyl]-N-(5-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-1,3-benzoxazol-2-amine

[0433]

[0434] ​Steps 1 to 8 were carried out in a manner similar to the synthesis of Example 1.

[0435] 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

[0436] To a 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) stirred at 0 °C under inert conditions was added 4N dioxane HCl (3.5 mL). The resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a solid. The solid was then purified by preparative HPLC [column: Inertsil ODS C18 (250x20) mm; 5 mic; flow rate: -19 ml / min; mobile phase (A): 0.1% aqueous ammonia; mobile phase (B): acetonitrile]. The collected fractions were concentrated under reduced pressure to give Example 44 as a white solid, 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%). LCMS (ES) m / z = 367.3 [M+H] + 。

[0437] Example 45

[0438] 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

[0439]

[0440] Example 45 was synthesized in a manner similar to Example 1, except that N,N-dimethylazetidin-3-amine was used in Step 8. LCMS (ES) m / z = 395.3

[0441] [M+H] + 。

[0442] Example 46

[0443] Synthesis of N-(2-(2-Hydroxyethoxy)ethyl)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxamide

[0444]

[0445] Example 46 was synthesized in a similar manner to Example 40. LCMS(ES) m / z = 396.4 [M+H] + 。

[0446] Biological methods

[0447] Cell culture: The human monocytic THP-1 cell line was purchased from Invivogen (thp-null). The human monocytic THP-1 ASC-GFP reporter cell line was purchased from Invivogen (thp-ascgfp). The human monocytic THP-1 cell line overexpressing NLRC4 was purchased from Invivogen (thp1-nlrc4). The murine macrophage cell line J774A.1 was purchased from ATCC (TIB-67). Cells were maintained according to the protocols recommended by the manufacturer.

[0448] Human peripheral blood mononuclear cells were isolated from whole blood using Lymphoprep TM by density gradient according to the manufacturer's instructions. Fresh PBMCs were used.

[0449] PMA differentiation of THP-1 cells: For ASC Spec analysis, the human monocytic cell line THP-1 ASC-GFP cells were differentiated into a macrophage-like phenotype using phorbol 12-myristate 13-acetate (PMA). THP-1 cells were suspended at a density of 1 - 2x10 6 cells / mL and supplemented with 100 ng / mL PMA. 100,000 cells were seeded into each well of a 96-well plate and incubated for 72 hours. The adherent cells were washed three times with THP-1 medium without PMA and then allowed to rest in medium without PMA for 24 hours.

[0450] Measurement of NLRP3 inflammasome and pyroptosis in THP-1 cells: THP-1 cells were primed with 300 ng / mL ultrapure LPS. After 1 hour, the cells were treated as indicated in the legend. Three hours after LPS priming, the NLRP3 inflammasome was activated with 10 μM nigericin. Two hours later, the supernatant was collected and IL-1β was analyzed by ELISA. Pyroptotic cell death was evaluated by Alamar blue assay as described below.

[0451] Cytotoxicity assay:The indicated compounds at dose titration were used to treat THP-1 or PBMCs for 5 hours, and then the cell viability was evaluated by Alamar Blue assay as described below.

[0452] AlamarBlue viability assay: The Alamar Blue cell viability reagent was diluted in cell culture medium at a ratio of 1:10, filtered through a 40 μm filter, and then added to the cell pellet at 100 μL / well. After 2 - 24 hours, the optical density was read according to the manufacturer's instructions. The viability was expressed as a percentage of the signal relative to the wells containing untreated cells, which was corrected for the medium control.

[0453] Cell-free inflammasome assay: Cell-free inflammasome activation and caspase-1 cleavage were evaluated as previously described. Briefly, lysates were prepared from THP-1 by hypotonic lysis to a final protein concentration > 7 mg / mL. The lysates were pre-treated with the indicated compounds at a final concentration of 1 mM on ice for 20 minutes. Inflammasome activation was induced by incubating the samples at 30 °C for 60 minutes. Inflammasome activity was evaluated by monitoring caspase-1 cleavage by Western blotting.

[0454] Activation of NLRP3 inflammasome in PBMC: 2 x 10 5 freshly isolated PBMCs were primed with 300 ng / mL LPS for 1 hour and then re-treated with the indicated compounds at dose titration for 2 hours. Then, the NLRP3 inflammasome was activated by treating the cells with 10 μM nigericin for 2 hours. Inflammasome activity was evaluated by IL-1β ELISA according to the manufacturer's instructions.

[0455] Activation of AIM2 inflammasome in PBMC: 2 x 10 5 freshly isolated PBMCs were transfected with poly dA:dT (100 ng / well) using Lipofectamine 2000 (1 μL / well) to activate the AIM2 inflammasome. One hour later, the cells were re-treated with the indicated compounds at dose titration for 17 hours. Inflammasome activity was evaluated by IL-1β ELISA according to the manufacturer's instructions.

[0456] Activation of NLRP1 inflammasome in PBMC: 2 x 10 5 freshly isolated PBMCs were treated with 10 μM Talabostat - a constitutive inhibitor of the NLRP1 inflammasome. One hour later, the cells were re-treated with the indicated compounds at dose titration for 17 hours. Inflammasome activity was evaluated by IL-1β ELISA according to the manufacturer's instructions.

[0457] Activation of NLRC4 inflammasome in PBMC: 2 x 10 5Freshly 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)]. The compound was added 1 hour after the addition of NeedleTox and then incubated for an additional 4 hours, after which inflammasome activity was evaluated by IL-1β ELISA according to the manufacturer's instructions.

[0458] Evaluation of HO-1 induction: THP-1 cells (Invivogen catalog number thp-null) were maintained at a density of 0.2 - 0.8 x 10 6 cells / mL according to the manufacturer's instructions. For HO-1 evaluation, 100,000 cells / well were seeded into 96-well plates in 90 μL of medium and then treated with 10 μL of the compound prepared at 10X in medium containing 5% DMSO, with a final DMSO concentration of 0.5% DMSO v / v. The cells were incubated at 37 °C and 5% CO2 for 5 hours. The plates were centrifuged at 500 g for 5 minutes at room temperature to pellet the cells, then the medium was aspirated and the cells were washed with 100 μL of PBS. The plates were centrifuged again at 500 g for 5 minutes at room temperature to pellet the cells, and the PBS was aspirated. The cells were resuspended in 100 μL of RIPA buffer containing protease inhibitor (Roche complete protease inhibitor mixture). The samples were lysed by pipetting up and down 15 times using a multi-channel pipette. The samples were diluted 1:2 in PBS containing 1% BSA and the cellular HO-1 levels were evaluated by ELISA according to the manufacturer's instructions (R&Dsystems catalog number DYC3776-5). The data were normalized relative to a reference compound control (10 μM vTv / Anteris Bach1 inhibitor) present in triplicate on each plate and expressed as activity (% reference compound).

[0459] Measurement of NLRP1 inflammasome in mouse macrophages:J774A.1 cells (ATCC catalog number TIB-67) were maintained according to the manufacturer's instructions. For NLRP1 activation, cells with passage number <12 were used. 100,000 cells / well were seeded in 70 μL of medium into a 96-well plate and allowed to attach at 37 °C and 5% CO2 for 30 minutes. The cells were stimulated with 10 μL of 3 μg / mL ultrapure LPS (Invivogen catalog number tlrl-3pelps) for a final concentration of 300 ng / mL. The cells were incubated at 37 °C and 5% CO2 for 1 hour. Compounds were prepared at 10X in medium containing 5% DMSO and then 10 μL was added to each well for a final DMSO concentration of 0.5% DMSO v / v. The cells were incubated at 37 °C and 5% CO2 for an additional 1 hour. 1 μg / mL lethal toxin (LT) of Bacillus anthracis was prepared by adding lethal factor of Bacillus anthracis (List Labs catalog number 169L) and protective antigen of Bacillus anthracis (List Labs catalog number 171E) to the medium to a final concentration of 1 μg / mL each. Each well was treated with 10 μL of LT for a final concentration of 100 ng / mL. The cells were incubated at 37 °C and 5% CO2 for an additional 3 hours. The plate was centrifuged at 500 g for 5 minutes at room temperature to pellet the cells, then the supernatant was collected and diluted 1:10 in PBS containing 1% BSA and then IL-1β was evaluated by ELISA according to the manufacturer's instructions (R&D Systems catalog number DY401). AlamarBlue cell viability reagent (ThermoFisher catalog number DAL1100) was diluted 1:10 in medium and then 100 μL was added to each cell pellet and incubated at 37 °C and 5% CO2 for 3 hours. The plate was read at 570 nm with a reference wavelength of 600 nm and viability was expressed relative to the untreated control, background corrected using medium.

[0460] Measurement of NLRC4 inflammasome in THP-1 cells: THP-1 cells overexpressing NLRC4 (Invivogen catalog number thp1-nlrc4) were maintained at 0.2–0.8x 10 6Maintenance at a density of cells / mL. For NLRC4 activation, 100,000 cells / well were seeded in a 96-well plate in 70 μL of medium and stimulated with 10 μL of ultrapure LPS (Invivogen catalog number tlrl-3pelps) at 3 μg / mL in the medium, for a final concentration of 300 ng / mL. The cells were incubated at 37 °C and 5% CO2 for 1 hour. Compounds were prepared at 10X in medium containing 5% DMSO and then 10 μL was added to each well for a final DMSO concentration of 0.5% DMSO v / v. The cells were incubated at 37 °C and 5% CO2 for an additional 1 hour. NeedleTox was prepared by mixing anthrax protective antigen (List Labs catalog number 171E) and LFn-Needle (Invivogen catalog number tlrl-ndl) to final concentrations of 1250 ng / mL and 250 ng / mL, respectively. Each well was treated with 10 μL of NeedleTox for a final concentration of 150 ng / mL. The cells were incubated at 37 °C and 5% CO2 for an additional 3 hours. The plate was centrifuged at 500 g for 5 minutes at room temperature to pellet the cells, then the supernatant was collected and diluted 1:10 in PBS containing 1% BSA and then IL-1β was evaluated by ELISA according to the manufacturer's instructions (R&D Systems catalog number DY201). Alamar Blue cell viability reagent (ThermoFisher catalog number DAL1100) was diluted 1:10 in medium and then 100 μL was added to each cell pellet and incubated at 37 °C and 5% CO2 for 3 hours. The plate was read at 570 nm with a reference wavelength of 600 nm and viability was expressed relative to an untreated control, with background correction using the medium.

[0461] Biological Example 1: Cell viability assay

[0462] The properties of each compound were analyzed in a variety of cell assays using THP-1 human monocytes. IL-1β inhibition and protection against pyroptosis were evaluated in the NLRP3 inflammasome assay. The results are provided in Table 2.

[0463] Table 2

[0464]

[0465]

[0466]

[0467] Control compounds for comparison were tested and the results are provided in Table 3.

[0468] Table 3

[0469]

[0470]

[0471] Biological Example 2: HO-1 induction assay

[0472] Each compound was evaluated for its ability to induce heme oxygenase-1 (HO-1) using THP-1 human monocytes in assays. The results are provided in Table 4.

[0473] Table 4

[0474]

[0475]

[0476]

[0477] Biological Example 3: Inhibition of ASC Oligomerization

[0478] ASC oligomerization was monitored using the ASC-GFP THP-1 reporter cell line. Once the inflammasome is activated, ASC aggregates and forms a single large "Speck" in each cell. By tagging ASC with GFP, these "Specks" are easily observable, and the percentage of cells containing the inflammasome can be evaluated. THP-1 ASC-GFP cells were differentiated overnight using PMA and then left in medium without PMA for one day. Cells were treated with the indicated drugs at dose titrations 2 hours before activation of the NLRP3 inflammasome using nigericin. Forty-five minutes after nigericin treatment, the cells were fixed in 2% paraformaldehyde and imaged on a fluorescence microscope. The percentage of ASC-GFP Speck-positive cells in each field of view was quantified.

[0479] Biological Example 4: Inhibition of Multiple Inflammasomes in Human PBMCs

[0480] The ability of the compounds of interest to inhibit multiple inflammasomes was evaluated in fresh primary human peripheral blood mononuclear cells (PBMCs). Dose titrations of the compounds were added simultaneously with the following inflammasome stimulations:

[0481] a. NLRP3: primed with LPS and then stimulated with nigericin for 2 hours.

[0482] b. NLRP1: treated overnight with talabostat (a DPP8 / 9 inhibitor)

[0483] c. NLRC4: transfected overnight with bacterial flagellin

[0484] d. AIM2: Transfect with double-stranded DNA overnight

[0485] Figure 1 The results provided in show that, compared with the control compound MCC950 (N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide sodium; CAS number 256373-96-3), the compounds of the present disclosure are effective pan-inflammasome inhibitors.

[0486] It should be understood that the embodiments of the invention disclosed herein are for illustrating the principles of the invention. Other modifications that can be employed are also within the scope of the invention. Thus, by way of example and not limitation, alternative configurations of the invention can be used in accordance with the teachings herein. Accordingly, the invention is not limited to exactly what is shown and described.

Claims

1. A compound having the following structural formula: or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof, wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; R is H, C1-C6 alkyl, phenyl, -(C1-C3 alkyl)-phenyl, heteroaryl optionally substituted by methyl, C3-C8 cycloalkyl or -(C1-C3 alkyl)-C3-C8 cycloalkyl; Each R 1 independently is halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy) or amino(C1-C6 alkyl); R 2 is H or a C1-C6 alkyl group; Each R 3 is independently halogen, 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-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)-heterocyclic group 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 , where R 8 and R 9 are independently H or C1-C6 alkyl, where each alkyl within R 8 and R 9 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 substituted by -C1-C6 alkoxy, or Two Rs 3 together with the atoms to which they are attached form a heterocycle which is optionally substituted by one or more R7s, wherein R 4 is H or a C1-C6 alkyl group; R 5 is H, C1-C6 alkyl optionally substituted by one or more R7, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(C1-C6 alkyl)-O-C1-C6 alkyl, -(C1-C6 alkyl)-O-C2-C6 alkenyl or -(C1-C6 alkyl)-O-C2-C6 alkynyl; Each R 6 is independently halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -CO2H, -CO2(C1-C6 alkyl), -CO(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl) or -CON(C1-C6 alkyl)2; and Each R 7 is independently halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -CO2H, -CO2(C1-C6 alkyl), -CO(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl) or -CON(C1-C6 alkyl)2, or two R 7 groups together with the carbon to which they are attached form =O; provided that the compound is not 2-[(1-methyl-1H-benzoimidazol-2-yl)amino]-5-benzooxazolecarboxylic acid.

2. The compound according to claim 1, wherein R is H, C1-C3 alkyl, phenyl, benzyl, methylpyrazolyl, cyclopropyl or cyclopropylmethyl.

3. The compound according to claim 1 or claim 2, wherein R is H or methyl.

4. The compound according to claim 1 or claim 2, wherein R is methyl, and the compound has the following formula:

5. The compound according to any one of claims 1 to 4, wherein m is 1 or 2.

6. The compound according to any one of claims 1 to 4, wherein m is 1.

7. The compound according to claim 6, which has the following formula:

8. The compound according to claim 6, which has the following formula: Such as 9. The compound according to claim 6, which has the following formula:

10. The compound according to claim 6, which has the following formula: Such as 11. The compound according to any one of claims 1 to 10, wherein R 1 is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl.

12. The compound according to any one of claims 1 to 10, wherein R 1 is independently halogen, C1-C6 alkyl or C1-C6 haloalkyl.

13. The compound according to any one of claims 1 to 10, wherein R 1 is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl.

14. A compound according to any one of claims 1 to 10, wherein R 1 is independently halogen.

15. The compound according to any one of claims 1 to 10, wherein at least one R 1 is a halogen.

16. The compound according to any one of claims 1 to 8, which has the following formula: Such as 17. The compound according to any one of claims 1 to 10, wherein R 2 is H or C1-C3 alkyl.

18. The compound according to any one of claims 1 to 10, wherein R 2 is H or methyl.

19. The compound according to any one of claims 1 to 10, wherein R 2 is H.

20. The compound according to any one of claims 1 to 8, which has the following formula:

21. The compound according to any one of claims 1 to 8, which has the following formula:

22. The compound according to any one of claims 1 to 21, wherein n is 1 or 2.

23. The compound according to any one of claims 1 to 21, wherein n is 1.

24. The compound according to claim 23, which has the following formula: Such as 25. The compound according to claim 23, which has the following formula: such as 26. The compound according to claim 23, which has the following formula:

27. The compound according to claim 23, which has the following formula:

28. A compound according to any one of claims 1 to 27, wherein R 3 is -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)-heterocycloalkyl 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 which is optionally substituted with one or more R7.

29. The compound according to any one of claims 1 to 27, wherein R 3 is -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)-heterocyclic group optionally substituted with one or more R7, -(C1-C6 alkyl)-C3-C8 cycloalkyl optionally substituted with one or more R7, -COH, -CO2H, -CO2(C1-C6 alkyl), -CO(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl) or -CON(C1-C6 alkyl)2.

30. A compound according to any one of claims 1 to 27, wherein 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 atom to which they are attached form a heterocycle which is optionally substituted with one or more R7.

31. A compound according to any one of claims 1 to 27, wherein 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.

32. A compound according to any one of claims 1 to 27, wherein 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.

33. The compound according to any one of claims 1 to 27, wherein R 3 is -C1-C6 alkyl-NR 4 R 5 .

34. The compound according to any one of claims 1 to 33, wherein R 4 is a C1-C6 alkyl group and R 5 is a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, –(C1-C6 alkyl)-O-C1-C6 alkyl group, –(C1-C6 alkyl)-O-C2-C6 alkenyl group or –(C1-C6 alkyl)-O-C2-C6 alkynyl group, which is optionally substituted by one or more R7 groups.

35. A compound according to any one of claims 1 to 33, wherein R 4 is a C1-C6 alkyl group and R 5 is a C1-C6 alkyl group optionally substituted with one or more R7 groups.

36. The compound according to any one of claims 1 to 33, wherein R 4 is a C1-C3 alkyl group and R 5 is a C1-C3 alkyl group.

37. A compound according to any one of claims 1 to 33, wherein R 4 is methyl and R 5 is methyl optionally substituted with one or more R7s.

38. A compound according to any one of claims 1 to 27, wherein the two Rs 3 together with the atoms to which they are attached form a heterocycle which is optionally substituted by one or more R7s.

39. A compound according to any one of claims 1 to 27, wherein R 3 is selected from: H, -CH2Cl, -C(O)H, -OCH3, -CO2CH3, or two Rs 3 together with the atoms to which they are attached form 40. A compound according to any one of claims 1 to 27, wherein R 3 is 41. A compound according to any one of claims 1 to 28, wherein R 3 is 42. The compound according to claim 23 or 23, which has the following formula: Such as 43. A compound according to claim 42 or 42, wherein R 1 is independently halogen, C1-C6 alkyl or C1-C6 haloalkyl.

44. A compound according to any one of claims 1 to 27, wherein R 3 is -CONR 8 R 9 , wherein R 8 and R 9 are independently H or C1-C6 alkyl, wherein each alkyl within R 8 and R 9 is independently substituted by one, two or three halogens, cyano, hydroxy, C1-C3 alkoxy, amino, mono- or di-(C1-C3 alkyl)amino, amino-C1-C3 alkoxy, mono- or di-(C1-C3 alkyl)amino-C1-C3 alkoxy, hydroxy-C1-C3 alkoxy or C1-C6 alkoxy-C1-C6 alkoxy.

45. A compound according to any one of claims 1 to 27, wherein R 3 is -CONHR 9 , wherein R 9 is C1-C6 alkyl substituted by one, two or three halogen, cyano, hydroxy, C1-C3 alkoxy, amino or mono- or di(C1-C3 alkyl)amino.

46. A compound according to any one of claims 1 to 27, wherein R 3 is -CONHR 9 , wherein R 9 is C1-C6 alkyl substituted by hydroxy-C1-C3 alkoxy or C1-C6 alkoxy-C1-C6 alkoxy.

47. A compound according to any one of claims 1 to 27, wherein R 3 is -CONHR 9 , wherein R 9 is a C1-C6 alkyl group substituted with a hydroxy-C1-C3 alkoxy group.

48. A compound according to any one of claims 1 to 27, wherein R 3 is -CONHR 9 , wherein R 9 is C1-C6 alkyl substituted by amino-C1-C3 alkoxy.

49. The compound according to claim 1, which is: 5-((dimethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo [d]oxazol-2-amine; 5-((ethyl(methyl)amino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine; 5-((Diethylamino)methyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo [d]oxazol-2-amine; 5-((Dimethylamino)methyl)-N-(5-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzo [d]imidazol-2-yl)benzo[d]oxazol-2-amine; 5-(Azetidin-1-ylmethyl)-N-(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-2-amine; 5-((Dimethylamino)methyl)-N-(1-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxa zol-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]oxazol-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-ben zo[d]imidazol-2-yl)benzo[d]oxazol-2-amine; N-(2-(2-Hydroxyethoxy)ethyl)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)benzo[d]oxazole-5-carboxamide; or a pharmaceutically acceptable salt thereof.

50. A pharmaceutical composition comprising a compound according to any one of claims 1-44 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

51. A method of treating an inflammatory condition in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-49 or a pharmaceutical composition according to claim 50.

52. The method according to claim 51, wherein the inflammatory condition is inflammatory bowel disease, Crohn's disease and colitis, an arthritis disease or a neurodegenerative disease.

53. The method according to claim 51, wherein the inflammatory condition is an infectious disease, an immune disease, a blood disorder, cancer, an ocular, pulmonary and systemic inflammatory condition.

54. The method according to claim 51, wherein the condition is a metabolic, fibrotic, kidney disorder or a neurological disease.

55. A compound according to any one of claims 1-49, wherein the compound binds to the transcriptional repressor Bach1 or is an HO-1 inducer.

56. A method for increasing the activity or amount of HO-1 in a human subject, the method comprising: Administering to a human subject an effective amount of a compound according to any one of claims 1-49 or a pharmaceutical composition according to claim 50.

57. A method of activating transcription factor Nrf2 in a human subject, comprising: Administering to a human subject an effective amount of a compound according to any one of claims 1-49 or a pharmaceutical composition according to claim 50. A method for reducing the amount of reactive oxygen species in a human subject, comprising: Administering to a human subject an effective amount of a compound according to any one of claims 1-49.

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