Compositions and methods for treating inflammatory diseases

Abstract

The present disclosure relates to chemical entities, such as compounds or pharmaceutically acceptable salts, that inhibit inflammatory responses by inhibiting the oligomerization of apoptosis-associated speck-like proteins containing a C-terminal caspase recruitment domain (ASC). Methods of treating various disease states using compounds that inhibit the oligomerization of ASC proteins are also provided.

Description

[Technical Field]

[0001] The present invention relates to chemical entities (eg, compounds or pharmaceutically acceptable salts thereof, and / or pharmaceutical combinations containing the compounds), their use in the treatment of diseases involving inflammation, and their synthesis.

[0002] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 426,965, filed November 21, 2022, and Indian Provisional Application No. 202211051974, filed September 12, 2022, the entire contents of each of which are incorporated herein by reference.

[0003] background Inflammation is a protective immune response induced by the innate immune system in response to harmful stimuli, such as pathogens, dead cells, or irritants, and is tightly regulated by the host. Insufficient inflammation can lead to persistent pathogen infection, while excessive inflammation can cause chronic or systemic inflammatory diseases. Inflammasomes are complexes of proteins involved in the initiation and control of inflammatory responses. Excessive induction of inflammasomes leads to unwanted inflammation and inflammatory diseases. For this reason, inflammasomes have been linked to various autoinflammatory and autoimmune diseases, including inflammatory bowel disease, Crohn's disease, multiple sclerosis, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Regulating the activity of inflammasomes and their components has attracted considerable attention.

[0004] overview The present disclosure provides a compound of formula (I): [ka] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; m and n are each independently an integer having a value of 0, 1, 2, 3, or 4; X1, X2, X3, X4, X5, X6, X7, and X8 are each independently selected from the group consisting of -CH and N; and R3 is each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), -CO-alkyl, and -CO-haloalkyl; R4 is each independently hydrogen or COY or with the proviso that when X1 through X8 are -CH and R3 is hydrogen, then R4 is not hydrogen, except that when X1 through X8 are N and R1 or R2 are halo, then R4 and R3 may both be hydrogen. [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. The present invention provides a compound having the formula:

[0005] In some embodiments, the compounds of Formula I are further limited. For example, in any of the compounds of Formula I described above, R4 is not hydrogen, m is 0, and n is 1. In some embodiments, R4 is COY and Y is a substituted piperazine. In some embodiments, R4 is COY and Y is a haloalkyl. In some embodiments, R4 is hydrogen, m is 0, n is 1, and R2 is halo. In some embodiments, R4 is COY and Y is a substituted piperidine.

[0006] In some embodiments, the present disclosure provides a compound of formula I(a): [ka] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino, and m and n are each independently an integer having a value of 0, 1, 2, 3, or 4; Each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), and -CO-alkyl; R4 is each independently hydrogen or COY or with the proviso that if R3 is hydrogen then R4 is not hydrogen, except that if either R1 or R2 is halo then R4 and R3 may both be hydrogen. [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. The present invention provides a compound of the formula:

[0007] In some embodiments, the present disclosure provides a compound of formula I(b): [ka] wherein each R1 is independently selected from the group consisting of hydrogen, —CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, and C1-C6-alkyl-amino; and each m is independently an integer having a value of 0, 1, 2, 3, or 4; Each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), and -CO-alkyl; R4 is independently hydrogen or COY or [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. The present invention provides a compound of the formula:

[0008] In some embodiments, the present disclosure provides a compound of formula I(c): [ka] wherein R1 is hydrogen, m is 1, R3 is hydrogen, and each R4 is independently hydrogen or COY or [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. The present invention provides a compound of the formula:

[0009] In some embodiments, the compound is: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] is selected from the group consisting of:

[0010] In some embodiments, one or more of the above-mentioned compounds have a half maximal inhibitory concentration (IC50) value of about 2 μM. In some embodiments, the compound can reduce IL-1β expression by at least 50%. In some embodiments, the compound can treat inflammatory diseases.

[0011] In one aspect, the present disclosure provides a method for treating the disease caused by inflammation, comprising administering any of the above-mentioned compounds, thereby treating the disease.In some embodiments, the disease can be any one of inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), primary sclerosing cholangitis, primary biliary cirrhosis, alcoholic hepatitis, alcoholic cirrhosis, pancreatitis, non-alcoholic fatty liver disease, alcoholic pancreatitis, acute hepatitis, celiac disease, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, gastric ulcer, antiphospholipid syndrome, Barrett's esophagus, postoperative ileus, atrophic gastritis, peritonitis, diverticulitis, duodenal ulcer, alveolar periostitis, Crohn's disease, Alzheimer's disease, arthritis, metabolic syndrome-related obesity and multiple sclerosis. In other embodiments, diseases treatable with the compounds of the invention may be related to the brain or central nervous system (CNS), including Parkinson's disease, mechanical allodynia, spinal cord injury, Alzheimer's disease, CNS injury, anxiety, febrile seizures, depression, encephalomyelitis, cerebrovascular accidents, subarachnoid hemorrhage, hyperactive behavior, idiopathic scoliosis, middle cerebral artery occlusion, ischemic stroke, and bipolar disorder. In yet other embodiments, diseases are related to the bone, including arthritis (including rheumatoid, gouty, and psoriatic), osteoarthritis, osteopenia, osteoporosis, ankylosing spondylitis, and intervertebral disc degeneration.

[0012] Additional embodiments include diabetic retinopathy, dry eye syndrome, keratoconjunctivitis sicca, age-related macular degeneration, heart failure, myocardial infarction, myocardial reperfusion injury, coronary heart disease, myocarditis, diabetic cardiomyopathy, cardiomyopathy, myocardial fibrosis, atrial fibrillation, hypertensive disease, vasculitis, acute kidney injury, diabetic nephropathy, glomerulonephritis, IgA glomerulonephritis, chronic renal failure, lupus nephritis, nephritis, hyperuricemia, aristolochic acid nephropathy, obesity-related Included are uses of the compounds of the invention in the treatment of disease conditions involving the eye, heart and vascular system, kidney and lung, including glomerulopathy, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, emphysema, pulmonary fibrosis, cystic fibrosis, silicosis, pneumonitis, acne vulgaris, atopic dermatitis, contact dermatitis, psoriasis, dermatomyositis, lichen planus, vitiligo, epidermolysis bullosa, bullous pemphigoid, hidradenitis suppurativa, and harlequin disease. Finally, in further embodiments, treatable disease states may include alcohol abuse, cytokine release syndrome, familial Mediterranean fever, graft-versus-host disease, mastitis, sepsis, primary Sjogren's syndrome, hyperhomocysteinemia, acute chest syndrome, estrogen deficiency, painful bladder syndrome, neuropathy, allergic rhinitis, cryopyrin-associated periodic fever syndrome, Behcet's disease, mucocutaneous lymph node syndrome, autoimmune thrombocytopenia, mevalonate kinase deficiency, juvenile spondyloarthropathy, and Conn's syndrome.

[0013] Detailed Description The human body generates an inflammatory response when exposed to pathogens, tissue injury, and endogenous stressors. The inflammatory response is triggered through pattern recognition receptors (PRRs). Downstream signaling of PRRs leads to the expression of proinflammatory cytokines, such as TNFα, IL-1β, IL-6, and IL-18. Although inflammation is useful for combating pathogens, excessive inflammation can lead to chronic or systemic inflammatory diseases in which the body's immune system begins to attack its own healthy cells. However, lower levels of inflammation can be ineffective in destroying pathogens, potentially leading to persistent infection. Therefore, the level of inflammation must be tightly regulated.

[0014] Inflammatory responses are initiated and controlled by a complex of proteins called inflammasomes, found in macrophages and neutrophils. Overactive inflammasomes can lead to diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Crohn's disease, Alzheimer's disease, arthritis, and multiple sclerosis. These diseases occur when the aforementioned inflammatory cytokines induce unwanted cell death. While such cell death is a component of the immune response to ward off infection, overactivity of inflammasomes can induce unwanted cell death and ultimately lead to various autoimmune diseases, such as those mentioned above.

[0015] Without wishing to be bound by theory, a specific protein family known as apoptosis-associated speck-like proteins (ASCs containing a C-terminal caspase recruitment domain) is thought to interact with procaspase-1 and, at least in part, trigger the inflammasome response that leads to cell death (see Figure 1). ASCs regulate the assembly and activation of multiple inflammasomes. The adaptor molecule ASCs link inflammasome stimulation and assembly by providing multiple interaction surfaces through its N-terminal PYRIN-PAAD-DAPIN domain (PYD) and C-terminal caspase recruitment domain (CARD). Both the PYD and CARD domains belong to the death domain superfamily and possess a characteristic six-helix bundle fold. ASCs bring procaspase-1 monomers into close proximity, initiating caspase-1 self-cleavage and the formation of the active heterotetramer of caspase-1. Active caspase-1 proteolytically activates several proteins, including cytokines such as pro-IL-1β and pro-IL-18 (see Figure 1), inducing their release via the non-classical secretory pathway.

[0016] Some embodiments of the present invention provide first-in-class pan-inflammasome inhibitors that target ASC and have broad anti-inflammatory effects. The compounds disclosed herein inhibit ASC protein oligomerization, thereby targeting multiple inflammasome pathways to disrupt inflammasome assembly and thereby limit inflammation. Therefore, certain embodiments of the present invention have the potential to limit inflammation in a variety of gastrointestinal and other inflammatory disorders (see Figure 2).

[0017] While various embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily envision a variety of other means for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the embodiments of the present invention described herein. More generally, those skilled in the art will readily appreciate that all parameters and configurations described herein are intended to be exemplary, and that the actual parameters and / or configurations will vary depending on the particular application for which the teachings of the present invention are used.

[0018] Various inventive concepts can be embodied as one or more methods, examples of which are provided. Unless otherwise specified, acts performed as part of a method can be ordered in any suitable manner. Thus, while exemplary embodiments show acts as sequential, embodiments may be constructed that perform acts in a different order than illustrated, which may include performing some acts simultaneously.

[0019] Various aspects of the present disclosure are described in detail in the accompanying innovations. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Brief explanation of the drawings]

[0020] [Figure 1]FIG. 1 is a schematic diagram showing inflammasome assembly activation leading to caspase-1-dependent release of inflammatory cytokines, gasdermin D-mediated pyroptotic cell death, and apoptosis. [Figure 2] FIG. 1 is a schematic diagram of the mechanism of action of compounds of the present disclosure in inhibiting inflammasome activation in inflammatory disorders. [Figure 3] 1 is a graph of the reduction in IL-1β expression obtained by plotting the percentage of cytokine inhibition (IL-1β) against the concentration of compound 6. The graph shows that a dose-dependent reduction in IL-1β levels is observed under in vitro conditions. [Figure 4] 1 shows a plot of plasma IL-1β levels plotted against various increasing doses of Compound 6. The graph shows that a dose-dependent decrease in IL-1β levels is observed under in vivo conditions.

[0021] definition To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0022] In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in this specification and the appended innovations, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0023] As used herein, in some embodiments, ranges and amounts are expressed as "about" a particular value or range. About includes the exact amount. Thus, "about 5 μL" means "about 5 μL" and also means "5 μL." Generally, the term "about" refers to the normal experimental error range for the respective value known to those skilled in the art.

[0024] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0025] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or." For example, when separating items in a list, "or" or "and / or" shall be interpreted to be inclusive, i.e., to include not only at least one of the list of numbers or elements, but also two or more, and optionally, additional unlisted items. Only terms clearly indicating the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," shall refer to the inclusion of exactly one element of the list of numbers or elements. Generally, the term "or" as used herein shall be interpreted to indicate exclusive alternatives (i.e., "one or the other, but not both") only when preceded by exclusive terms such as "either," "one of," "only one of," or "exactly one of."

[0026] As used herein in the specification and claims, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are understood to be open-ended, i.e., to mean including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the U.S. Patent and Trademark Office Manual of Patent Examining Procedures, Section 2111.03.

[0027] While the foregoing discussion discloses various exemplary embodiments of the present invention, it will be apparent to those skilled in the art that various modifications may be made which will achieve some of the advantages of the present invention without departing from the true scope of the invention. Any reference to the "invention" is intended to refer to exemplary embodiments of the invention and should not be construed as referring to all embodiments of the invention unless the context requires otherwise. The described embodiments are to be considered in all respects only as illustrative and not restrictive.

[0028] As used herein, the term "ASC protein" refers to an apoptosis-associated speck-like protein that contains a C-terminal caspase recruitment domain.

[0029] "API" refers to active pharmaceutical ingredients.

[0030] The term "effective amount" or "therapeutically effective amount," as used herein, refers to the administration of a chemical entity in an amount sufficient to alleviate to some extent one or more of the symptoms of the disease or condition being treated. The results include reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to produce a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0031] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005, Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009, Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007, Pharmaceutical Preformulation and Formulation, 2nd ed; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0032] The term "pharmaceutically acceptable salt" refers to a compound formulation that does not cause significant irritation to the organism to which it is administered and does not inhibit the biological activity and properties of the compound.In certain cases, pharmaceutically acceptable salts can be obtained by reacting the compounds described herein with an acid or base.For this purpose, acids or bases or counterions listed in PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002 can be used.

[0033] As used herein, the term "IL-1β" refers to interleukin 1β (IL-1β). Increased production of IL-1β causes a number of different autoinflammatory syndromes, most notably a monogenic condition called cryopyrin-associated periodic fever syndrome (CAPS), which results from mutations in the inflammasome receptor NLRP3, which triggers the processing of IL-1β.

[0034] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). Pharmaceutical compositions facilitate administration of a compound to an organism. There are several techniques for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0035] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as a human.

[0036] The terms "treat," "treating," and "treatment" in the context of treating a disease or disorder are intended to include alleviating or arresting the disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof. As used herein, the term "treatment" refers to: (1) Prevention of disease, e.g., prevention of a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but who has not yet experienced or manifested the symptoms or symptomology of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., preventing further development of the symptoms and / or symptomology) in an individual experiencing or manifesting the symptoms or symptomology of the disease, condition, or disorder; and (3) Amelioration of a disease, e.g., amelioration of a disease, condition, or disorder (i.e., reversal of the symptoms and / or symptomology) in an individual experiencing or manifesting the symptoms or symptomology of the disease, condition, or disorder. Refers to one or more of the following.

[0037] As used in this specification and the accompanying innovations, unless otherwise specified, the following terms have the meanings indicated: "Amino" refers to the -NH2 radical. "Cyano" refers to the -CN radical. "Hydroxyl" refers to the -OH radical. "Nitro" refers to the -NO2 radical. "Oxa" refers to the -O- radical. "Oxo" refers to the =O radical. "Thioxo" refers to the =S radical. "Imino" refers to the =NH radical. "Oximo" refers to the =N-OH radical. "Halo" refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0038] The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having 1 to 15 carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl contains 1 to 13 carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl contains 5 to 15 carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., a C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., a C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., a C3-C5 alkyl). In other embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond.Unless stated otherwise specifically in the specification, alkyl groups may be selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2), and -S(O)tN(Ra)2, where t is 1 or 2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each Rf is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0039] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo.

[0040] The term "cycloalkyl," as used herein, includes cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, or 3 to 10 ring carbons, or 3 to 6 ring carbons, where the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which two rings are joined through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0041] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring system having 3 to 16 ring atoms (e.g., a 5-8-membered monocyclic, an 8-12-membered bicyclic, or an 11-14-membered tricyclic ring system), having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, where the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms if monocyclic, bicyclic, or tricyclic, respectively), and 0, 1, 2, or 3 atoms in each ring are optionally substituted. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. A heterocyclyl can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[4.1.0]heptane ...4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2 Heterocyclyl includes spirocyclic rings (e.g., spirocyclic rings in which two rings are joined by only one atom), 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which two rings are joined by only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxa ... .2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0042] As used herein, the term "cycloalkenyl" includes a partially unsaturated cyclic hydrocarbon group having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons, or 3 to 10 ring carbons, or 3 to 6 ring carbons, and the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl groups can have any degree of saturation, so long as none of the rings in the ring system is aromatic and the cycloalkenyl group as a whole is not fully saturated. Cycloalkenyls can include multiple fused and / or bridged and / or spirocyclic rings.

[0043] The term "heteroaryl," as used herein, refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms, and having 6, 10, or 14 pi electrons shared in a cyclic arrangement, wherein at least one ring in the system is aromatic (but need not be a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, and thienopyridinyl. , pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring system having 3 to 16 ring atoms (e.g., a 5-8-membered monocyclic, an 8-12-membered bicyclic, or an 11-14-membered tricyclic ring system), having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, where the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms if monocyclic, bicyclic, or tricyclic, respectively), and 0, 1, 2, or 3 atoms in each ring are optionally substituted. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. A heterocyclyl can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[4.1.0]heptane ...4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2 Heterocyclyl includes spirocyclic rings (e.g., spirocyclic rings in which two rings are joined by only one atom), 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which two rings are joined by only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxa ... .2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0044] The term "heteroalkyl" refers to an alkyl group, as defined above, where one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl. In some embodiments, the heteroalkyl contains 1, 2, or 3 heteroatoms. In some embodiments, the alkyl portion of the heteroalkyl radical is optionally substituted as defined for an alkyl group. Representative heteroalkyl groups include, but are not limited to, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2OH, -CHOCH3, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CHOCH3, -CH2CHOCH2CH2NH2, or -CH2CHOCH2CH2OH.

[0045] The term "heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0046] The term "alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc., that connects the remainder of the molecule to a radical group. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through a carbon atom in the alkylene chain or any two carbon atoms within the chain. In certain embodiments, an alkylene contains 1 to 8 carbon atoms (e.g., a C1-C8 alkylene). In other embodiments, an alkylene contains 1 to 5 carbon atoms (e.g., a C1-C5 alkylene). In other embodiments, an alkylene contains 1 to 4 carbon atoms (e.g., a C1-C4 alkylene). In other embodiments, an alkylene contains 1 to 3 carbon atoms (e.g., a C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene).Unless stated otherwise specifically in the specification, an alkylene chain may be selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2), and -S(O)tN(Ra)2, where t is 1 or 2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each Rf is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0047] The term "heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl, where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0048] "Heterocyclylalkoxy" refers to a radical attached through an oxygen atom of the formula -O-Rc-heterocyclyl, where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0049] The term "amino-alkyl" refers to a radical of the formula: -alkyl-NH2.

[0050] The term "hydroxyl-alkyl" refers to a radical of the formula: -alkyl-OH.

[0051] The term "alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0052] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group may be selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2), and -S(O)tN(Ra)2, where t is 1 or 2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each Rf is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0053] The term "aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms from 5 to 18 carbon atoms, and at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.Unless stated otherwise specifically in this specification, the term "aryl" or the prefix "ar-" (as in "aralkyl") means any of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, , optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N( and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), wherein each Ra is independently selected from hydrogen, alkyl, fluoroalkyl, aryl, aryl substituted with one or more substituents independently selected from -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)Ra (where t is 1 or 2), -Rb-S(O)ORa (where t is 1 or 2), -Rb-S(O)Ra (where t is 1 or 2), and -Rb-S(O)N(Ra)2 (where t is 1 or 2), wherein each Ra is independently selected from hydrogen, alkyl, fluoroalkyl ... and -Rb-S(O)N(Ra)2 (where t is 1 or 2), wherein each Ra is independently selected from hydrogen, alkyl, fluoroalkyl, aryl substituted with one or more substituents independently selected from -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)Ra (where t is 1 or 2), -Rb-S(O)ORa (where t is 1 or 2), and -Rb-S(O)N(Ra)2 (where t is R is independently a direct bond or a straight or branched alkylene or alkenylene chain; R is a straight or branched alkylene or alkenylene chain; and each of the foregoing substituents is unsubstituted unless otherwise indicated.

[0054] The term "aralkyl" refers to a radical of the formula -Rc-aryl, where Rc is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as described above for an aryl group.

[0055] The term "aralkenyl" refers to a radical of the formula -Rd-aryl, where Rd is an alkenylene chain as defined above. The aryl portion of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene chain portion of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0056] The term "carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including, in some embodiments, fused or bridged ring systems having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond.

[0057] In some embodiments, carbocyclyl is saturated (i.e., contains only a single C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). Fully saturated carbocyclyl radicals are also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, cycloalkyls contain 3 to 8 carbon atoms (e.g., C-C cycloalkyl). In other embodiments, cycloalkyls contain 3 to 7 carbon atoms (e.g., C-C cycloalkyl). In other embodiments, cycloalkyls contain 3 to 6 carbon atoms (e.g., C-C cycloalkyl). In other embodiments, cycloalkyls contain 3 to 5 carbon atoms (e.g., C-C cycloalkyl). In other embodiments, cycloalkyls contain 3 to 4 carbon atoms (e.g., C-C cycloalkyl). Unsaturated carbocyclyls are also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.Unless stated otherwise specifically in this specification, the term "carbocyclyl" includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heptane, Tetracyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra) is intended to include carbocyclyl radicals optionally substituted by one or more substituents independently selected from C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)tORa (where t is 1 or 2), —Rb—S(O)tRa (where t is 1 or 2) and —Rb—S(O)tN(Ra)2 (where t is 1 or 2), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain; and Rc is a straight or branched alkylene or alkenylene chain, each of the foregoing substituents is unsubstituted unless otherwise indicated.

[0058] The term "carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl, where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0059] As used herein, the term "NOAEL dose" refers to the no-observed-adverse-effect level dose, which represents the exposure level of an organism at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effects of the protocol being tested, as found by experiment or observation.

[0060] As used herein, the term "inflammatory bowel disease (IBD)" refers to inflammation of the gastrointestinal (GI) tract. Prolonged inflammation damages the GI tract. Crohn's disease and ulcerative colitis are considered common types of IBD. Common symptoms of IBD include persistent diarrhea, abdominal pain, rectal bleeding / bloody stool, weight loss, and fatigue.

[0061] As used herein, the term "irritable bowel syndrome (IBS)" refers to a disorder that affects the large intestine. Signs and symptoms include cramps, abdominal pain, bloating, gas, and diarrhea or constipation, or both. Other symptoms that are often associated include bloating, increased gas, or mucus in the stool. Symptoms are treated by managing diet, lifestyle, and reducing stress.

[0062] As used herein, the term "primary sclerosing cholangitis (PSC)" refers to a chronic liver disease in which bile ducts inside and outside the liver become inflamed and scarred, eventually narrowing or becoming blocked. In some cases, bile can back up within the liver, causing further liver damage. Liver failure can develop 10 to 15 years after diagnosis, although some PSC patients may take longer. Many PSC patients eventually require a liver transplant, typically about 10 years after the disease is diagnosed.

[0063] As used herein, the term "primary biliary cholangitis (PBC)," formerly known as primary biliary cirrhosis, is a chronic liver disease resulting from the progressive destruction of bile ducts within the liver, called intrahepatic bile ducts.

[0064] As used herein, the term "alcoholic hepatitis" refers to an inflammatory condition of the liver caused by prolonged heavy alcohol consumption.

[0065] As used herein, the term "alcoholic cirrhosis" refers to the late stage of scarring (fibrosis) of the liver caused by many forms of liver disease and conditions, such as hepatitis and chronic alcoholism.

[0066] As used herein, the term "pancreatitis" refers to inflammation of the pancreas. It can be sudden (acute) or persistent (chronic). The most common causes are alcohol abuse and solid masses in the gallbladder (gallstones). Pancreatitis caused by excessive alcohol consumption is called alcoholic pancreatitis.

[0067] As used herein, the term "non-alcoholic steatohepatitis (NASH)" refers to an advanced form of non-alcoholic fatty liver disease (NAFLD). NAFLD is caused by the accumulation of fat in the liver. When this accumulation causes inflammation and damage, it is called NASH, and can lead to scarring of the liver.

[0068] As used herein, the term "celiac disease," also known as celiac sprue or gluten-sensitive enteropathy, is an immune disorder caused by an extreme sensitivity or allergic reaction to the ingestion of gluten proteins found in wheat, barley, and rye.

[0069] As used herein, the term "antiphospholipid syndrome" refers to a condition in which the immune system mistakenly produces antibodies that attack tissues in the body. These antibodies can cause blood clots to form in the arteries and veins. Blood clots can form in the legs, lungs, and other organs such as the kidneys and spleen.

[0070] As used herein, the term "Barrett's esophagus" refers to a condition caused by repeated exposure to stomach acid. It is most commonly diagnosed in people with long-standing gastroesophageal reflux disease (GERD). Symptoms include frequent heartburn and chest pain.

[0071] As used herein, the term "postoperative ileus" refers to the prolonged loss of bowel function after a surgical procedure, usually abdominal surgery. It is a common postoperative complication, the etiology and pathophysiology of which are unknown.

[0072] As used herein, the term "atrophic gastritis" refers to chronic inflammation of the gastric mucosa, resulting in the loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissue. As a result, secretion of essential gastric substances, such as hydrochloric acid, pepsin, and intrinsic factor, is impaired, resulting in maldigestion. Vitamin B12 deficiency, which can lead to pernicious anemia, and iron malabsorption, which leads to iron deficiency anemia, are the most common causes. This may result from persistent Helicobacter pylori infection or may be autoimmune. Patients with autoimmune atrophic gastritis (type A gastritis) are statistically more likely to develop gastric cancer, Hashimoto's disease, and achlorhydria.

[0073] As used herein, the term "peritonitis" refers to inflammation of the peritoneum, the silky membrane that lines the abdominal wall and covers the organs within the abdomen, usually resulting from a bacterial or fungal infection.

[0074] As used herein, the term "diverticulitis" refers to a condition that occurs when small pouches, or sacs, form and push outward through weak areas in the colon wall, causing pain and discomfort.

[0075] As used herein, the term "duodenal ulcer" refers to a sore or peptic ulcer that occurs in the first part of the small intestine (duodenum).

[0076] As used herein, the term "alveolar periostitis" refers to a condition that occasionally occurs after tooth extraction, especially traumatic extraction, in which the exposed bone in the socket takes on a dry appearance due to disruption or loss of the blood clot. It is essentially a localized osteomyelitis without suppuration, accompanied by severe pain (alveolar pain) and a foul odor.

[0077] Ranges: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values ​​within that range. For example, description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numerical values ​​within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This is true regardless of the broadness of the range.

[0078] The present disclosure provides a compound of formula (I): Formula (I) [ka] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, and C1-C6-alkyl-amino; m and n are each independently an integer having a value of 0, 1, 2, 3, or 4; and X1, X2, X3, X4, X5, X6, X7, and X8 are each independently selected from the group consisting of -CH and N; R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), -CO-alkyl, and -CO-haloalkyl; R4 is each independently hydrogen or COY or with the proviso that when X1-X8 are -CH, if R3 is hydrogen then R4 is not hydrogen, except that when X1-X8 are N and / or R1 or R2 are halo then R4 and R3 may both be hydrogen. [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. The present invention provides a compound having the formula:

[0079] In some embodiments, in any of the above compounds, R4 is not hydrogen, m is 0, and n is 1. In some embodiments, R4 is COY and Y is a substituted piperazine. In some embodiments, R4 is COY and Y is a haloalkyl. In some embodiments, R4 is hydrogen, m is 0, n is 1, and R2 is halo. In some embodiments, R4 is COY and Y is a substituted piperidine.

[0080] In some embodiments, the compound has formula I(a): [ka] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino, and m and n are each independently an integer having a value of 0, 1, 2, 3, or 4; R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), -CO-alkyl, and -CO-haloalkyl; R4 is each independently hydrogen or COY or with the proviso that if R3 is hydrogen then R4 is not hydrogen, except that if either R1 or R2 is halo then R4 and R3 may both be hydrogen. [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. is a compound of

[0081] In some embodiments, the compound has formula I(b): [ka] wherein each R1 is independently selected from the group consisting of hydrogen, —CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, and C1-C6-alkyl-amino; and each m is independently an integer having a value of 0, 1, 2, 3, or 4; Each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), and -CO-alkyl; R4 is independently hydrogen or COY or [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. is a compound of

[0082] In some embodiments, the compound is a specific compound selected from the group consisting of compounds 1-25 above.

[0083] Preparation of compounds The compounds used in the reactions described herein are made using commercially available chemicals and / or from compounds described in the chemical literature.

[0084] In some cases, specific and similar reactants are identified through indexes of known chemicals compiled by the Chemical Abstract Service of the American Chemical Society, available in most public and university libraries, as well as online databases (for more information, contact the American Chemical Society in Washington, D.C.). Known, but uncataloged, chemicals are prepared by custom chemical synthesis companies, and many of the standard chemical supply companies (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0085] The following general reaction schemes represent processes by which the compounds of the present invention may be synthesized. In addition, specific synthetic routes to compounds 1-6 and 27-28 are described in the experimental examples herein, specifically in Example 1. Armed with knowledge of the following general reaction schemes and the specific synthetic routes provided in Example 1, one of ordinary skill in the art will be able to synthesize additional compounds within the scope of the present invention, including those of Formula I, Formula Ia, and Formula Ib, by the exercise of ordinary skill.

[0086] [ka]

[0087] Further forms of the compound labeled compound In some embodiments, the compounds described herein are present in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from that typically found in nature. In some embodiments, exemplary isotopes incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. The compounds described herein, and their metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives, containing the above isotopes and / or other isotopes of other atoms, are within the scope of the present disclosure. Certain isotopically labeled compounds, for example, compounds incorporating radioactive isotopes such as H and C, are useful in drug and / or substrate tissue distribution assays. Tritium-labeled isotopes, i.e., H and carbon-14 isotopes, i.e., C, are particularly preferred for ease of preparation and detectability. Furthermore, substitution with heavy isotopes such as deuterium, i.e., H, can confer certain therapeutic advantages due to increased metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements. In some embodiments, isotopically labeled compounds, their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives, are prepared by any suitable method.

[0088] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0089] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0090] In some embodiments, the compounds described herein have acidic or basic groups, and therefore react with some inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the present disclosure, or by separately reacting the purified compounds in free form with a suitable acid or base and isolating the salt thus formed. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0091] For example, compound 6, which is a base, can be reacted with a suitable acid, such as hydrochloric acid, to form the chloride salt of compound 6. Other suitable acids that can be used to convert compounds of the invention, such as compound 6, into pharmaceutically acceptable salts can be found in PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0092] solvate In some embodiments, the compounds described herein exist as solvates. The present disclosure provides methods of treating diseases by administering such solvates. The present disclosure further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0093] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the process of crystallization using a pharmaceutically acceptable solvent, such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or methanol. In some embodiments, the compounds provided herein exist in unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0094] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration. Typical administrations are by injection or orally. Suitable modes of administration include, but are not limited to, oral, rectal, topical, intraperitoneal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration.

[0095] Thus, provided herein are pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

[0096] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0097] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0098] In certain embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, e.g., contaminating intermediates or by-products produced during one or more steps of the synthetic method.

[0099] In some cases, exemplary pharmaceutical compositions are used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form, which contain one or more of the disclosed compounds as an active ingredient mixed with organic or inorganic carriers or excipients suitable for topical, enteral, or parenteral application. In some embodiments, the active ingredient is compounded with a conventional non-toxic pharmaceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the process or condition of a disease.

[0100] In some cases, to prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients, to form a solid preformulation composition containing a homogeneous mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition, and the composition may be readily divided into similarly effective unit dosage forms such as tablets, pills, and capsules.

[0101] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more known pharmaceutically acceptable carriers. In the case of capsules, tablets, and pills, in some embodiments, the compositions also contain buffering agents. Solid compositions of a similar type are also used as fillers for soft and hard gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, etc.

[0102] In some cases, tablets are produced by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared using binders, lubricants, inert diluents, preservatives, disintegrants, and / or surfactants or dispersants. Molded tablets are produced by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, are optionally divided or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation technology.

[0103] The compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or their mixtures, and powders.The liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.The liquid dosage forms contain, in addition to the subject composition, any inert diluents commonly used in the art.

[0104] Suspensions contain, in addition to the subject composition, optionally known suspending agents and mixtures thereof.

[0105] In some embodiments, formulations for rectal or vaginal administration are provided as suppositories prepared by mixing the subject compositions with one or more suitable non-irritating excipients or carriers that are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent(s).

[0106] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient is optionally admixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that are required in some embodiments.

[0107] In some embodiments, ointments, pastes, creams and gels contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0108] In some embodiments, powders and sprays contain, in addition to the subject compositions, known excipient mixtures of these substances. Sprays further contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, for example, butane and propane.

[0109] Alternatively, the compositions and compounds disclosed herein can be administered by aerosol. This can be achieved by preparing aqueous aerosols, liposomal formulations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. In some embodiments, sonic nebulizers are used because they minimize the exposure of the active substance to shear, which can cause degradation of the compounds contained in the subject compositions. Typically, aqueous aerosols are prepared by blending an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the specific subject composition, but typically include non-ionic surfactants. Aerosols are generally prepared from isotonic solutions.

[0110] Pharmaceutical compositions suitable for parenteral administration comprise a combination of the subject composition with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders to be reconstituted into sterile injectable solutions or dispersions immediately before use, optionally containing antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0111] Enteral pharmaceutical formulations comprising the disclosed compounds and enteric materials, as well as pharmaceutically acceptable carriers or excipients, are also contemplated. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluids at a specific pH. The small intestine is the portion of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5. Thus, the enteric material does not dissolve until a pH of, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8 or about 10.0.

[0112] In some embodiments, the dose of a composition comprising at least one compound described herein will vary depending on the condition of the patient (e.g., human), i.e., stage of disease, general health, age, and other factors used by those skilled in the medical arts to determine dosage.

[0113] In some cases, the pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented), as determined by those skilled in the medical field.The appropriate dose and the suitable duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration.In general, an appropriate dose and treatment regimen provides the composition in an amount sufficient to bring about therapeutic and / or preventive benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms).Optimal doses are generally determined using experimental models and / or clinical trials.In some embodiments, optimal doses vary depending on the patient's size, weight, or blood volume.

[0114] Example The following examples further illustrate aspects of the present invention, but do not in any way limit the teachings or disclosure of the present invention set forth herein.

[0115] List of abbreviations As used above and throughout this disclosure, the following abbreviations have the following meanings, unless otherwise indicated: ACN or MeCN acetonitrile Ac Acetyl BOC or Boc tert-butylcarbamate t-Bu tert-butyl ℃ Celsius DAST-Diethylaminosulfur trifluoride DBA or dba-dibenzylideneacetone DCE-Dichloroethane (ClCH2CH2Cl) DCM - Dichloromethane (CH2Cl2) DIPEA or DIEA - Diisopropylethylamine DMF - Dimethylformamide DMSO - Dimethyl sulfoxide Dppf or dppf-1,1'-bis(diphenylphosphino)ferrocene EA or EtOAc - Ethyl Acetate Et-ethyl EtOH - Ethanol g - grams h, hr, hrs - hours HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC - High Performance Liquid Chromatography Hz - Hertz LAH-Lithium Aluminum Anhydrous LCMS - Liquid Chromatography Mass Spectrometry m / z mass-to-charge ratio M-mol Me-methyl MeOH-methanol mg - milligram MHz - Megahertz μmol - micromolar μL - microliter mL - milliliter mmol - millimolar MS-mass spectroscopy NMR-Nuclear Magnetic Resonance PE-Petroleum Ether Ph-phenyl Prep-HPLC - Preparative High-Pressure Liquid Chromatography Prep-TLC - Preparative Thin Layer Chromatography Py-pyridine RT-retention time TEA - Triethylamine TFA - Trifluoroacetic acid THF - Tetrahydrofuran TLC - Thin Layer Chromatography XPhos-2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl It is to be understood that the

[0116] chemical synthesis Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and not optimized. Column chromatography and thin-layer chromatography (TLC) were performed on silica gel unless otherwise noted. In some embodiments, if there is a discrepancy between the reaction scheme and the written procedure, the written procedure should be followed.

[0117] Example 1 - Compound Synthesis Example 1a - Synthesis of Compounds 5 and 6 Step 1: Synthesis of methyl 2-((2-aminophenyl)amino)-5-fluorobenzoate To a stirred solution of methyl 2-bromo-5-fluorobenzoate (2 g, 8.58 mmol) in chlorobenzene (20 mL) was added benzene-1,2-diamine (597 mg, 5.52 mmol), followed by copper powder (526 mg, 8.28 mmol). The resulting mixture was refluxed for 16 h. The reaction progress was monitored by TLC (30% ethyl acetate in hexanes). The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 20% ​​ethyl acetate in hexanes to give methyl 2-((2-aminophenyl)amino)-5-fluorobenzoate as a brown solid (800 mg, 55.67%). LCMS: (M+H + =261.1)

[0118] [ka]

[0119] Step 2: Synthesis of 2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (compound 5) To a stirred solution of methyl 2-((2-aminophenyl)amino)-5-fluorobenzoate (800 mg, 3.026 mmol) in ethylene glycol (10 mL) was added potassium phosphate tripotassium (2.5 g, 9.230 mmol), and the resulting mixture was heated to 100 °C for 4 h. The reaction progress was monitored by TLC (40% ethyl acetate in hexanes). The reaction mixture was quenched with ice-cold water and then extracted with ethyl acetate. The combined organic layers were dried and evaporated, and the crude product was purified by flash column chromatography to give 2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one as a brown solid (350 mg, 25%).

[0120] [ka]

[0121] Step 3: 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one: (Compound 6) To a stirred solution of 2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (150 mg, 0.657 mmol) in dichloromethane (DCM) (10 mL), 4-dimethylaminopyridine (DMAP) (121 mg, 0.986 mmol) was added and stirred for 5 minutes. After stirring, 2-chloroacetyl chloride (74.2 mg, 0.657 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC (30% ethyl acetate in hexanes). The reaction mixture was cooled to 0°C and quenched with aqueous sodium bicarbonate, followed by extraction with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-oneimidazo[1,2-a]pyridine-6-carboxylate as an off-white solid (120 mg, 59.92%).

[0122] [ka]

[0123] [ka]

[0124] Example 1b - Synthesis of Compound 1 Synthesis of 2-fluoro-5-(2-(4-methylpiperidin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one To a solution of 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (120 mg, 0.394 mmol) in acetonitrile (6 mL) was added potassium carbonate (394 mg, 0.285 mmol) and stirred for 10 minutes, followed by the addition of 4-methylpiperidine (113 mg, 0.473 mmol). The resulting mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC (80% ethyl acetate in hexanes). The reaction mixture was concentrated under reduced pressure. The crude product was diluted with water and extracted twice with 5% MeOH in DCM. The organic layer was washed with brine solution and concentrated under reduced pressure. The crude product was purified by flash column chromatography and further purified by Prep-HPLC with formic acid buffer, concentrated at low temperature, basified with aqueous NaHCO, extracted with DCM, and the organic layer was dried over NaSO, concentrated under reduced pressure, and lyophilized to give 2-fluoro-5-(2-(4-methylpiperidin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one as a white solid (47.3 mg, 13.4%).

[0125] [ka]

[0126] [ka]

[0127] Example 1c - Synthesis of Compound 2 2-Fluoro-5-(2-(4-methylpiperazin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one To a solution of 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (120 mg, 0.394 mmol) in acetonitrile (6 mL) was added potassium carbonate (394 mg, 0.285 mmol) and stirred for 10 minutes, followed by the addition of 1-methylpiperazine (143 mg, 0.592 mmol). The resulting mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was concentrated under reduced pressure. The residue was diluted with 10% MeOH in DCM, and the organics were washed with brine solution and concentrated under reduced pressure. The crude product was purified by flash column chromatography and further purified by Prep-HPLC with formic acid buffer, concentrated under low temperature, basified with aqueous NaHCO, extracted with DCM, and the organic layer was dried over NaSO, concentrated under reduced pressure, and lyophilized to give 2-fluoro-5-(2-(4-methylpiperazin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one as a white solid (31 mg, 8.85%).

[0128] [ka]

[0129] Example 1d - Synthesis of Compound 3 2-Fluoro-5-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one To a solution of 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (120 mg, 0.394 mmol) in acetonitrile (6 mL) was added potassium carbonate (394 mg, 0.285 mmol) and stirred for 10 minutes, followed by the addition of 1-(2-fluorophenyl)piperazine (206 mg, 0.473 mmol). The resulting mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was concentrated under reduced pressure. The residue was diluted with 10% MeOH in DCM, and the organics were washed with brine solution and concentrated under reduced pressure. The crude product was purified by flash column chromatography and further purified by Prep-HPLC with formic acid buffer, concentrated at low temperature, basified with aqueous NaHCO, extracted with DCM, and the organic layer was dried over NaSO, concentrated under reduced pressure, and lyophilized to give 2-fluoro-5-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one as an off-white solid (48.3 mg, 11.32%).

[0130] [ka]

[0131] Example 1e - Synthesis of Compound 4 Step 1: 5-(2-chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one: To a stirred solution of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (200 mg, 0.952 mmol) in DCM (20 mL) was added DMAP (174 mg, 1.428 mmol), which was stirred for 5 min, followed by the addition of 2-chloroacetyl chloride (106 mg, 0.952 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The reaction progress was monitored by TLC (30% ethyl acetate in hexanes). The reaction mixture was cooled to 0 °C and quenched with saturated aqueous sodium bicarbonate solution, followed by extraction with DCM. The organics were concentrated under reduced pressure. The crude product was purified by flash column chromatography to give 5-(2-chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one as an off-white solid (120 mg, 30.32%). LCMS (M+H + =287.1)

[0132] [ka]

[0133] [ka]

[0134] Step 2: Synthesis of 5-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (Compound 4) To a solution of 5-(2-chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (100 mg, 0.349 mmol) in acetonitrile (5 mL) was added potassium carbonate (144 mg, 1.047 mmol) and stirred for 10 minutes, followed by the addition of 1-(2-fluorophenyl)piperazine (62 mg, 0.349 mmol). The resulting mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC (80% ethyl acetate in hexanes). The reaction mixture was concentrated under reduced pressure. The crude product was diluted with 5% MeOH in DCM, and the organics were washed with brine solution and concentrated under reduced pressure. The crude product was purified by flash column chromatography, and then the crude material (crude) was further purified by Prep-HPLC using formic acid buffer, concentrated under low temperature, basified with aqueous NaHCO, extracted with DCM, and the organic layer was dried over NaSO, concentrated under reduced pressure, and lyophilized to give 5-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (18.1 mg, 12%).

[0135] [ka]

[0136] Example 1f - Synthesis of Compound 27 [ka]

[0137] Step-1: Synthesis of methyl N-(tert-butoxycarbonyl)-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteinate To a stirred solution of methyl (tert-butoxycarbonyl)-L-cysteinate (0.1 g, 0.425 mmol) in dichloromethane (10 mL), triethylamine (64.5 mg, 0.637 mmol) and 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (117 mg, 0.382 mmol) were added at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with water, extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combi-Flash column chromatography eluting with 0-25% EtOAc / Hex to give methyl N-(tert-butoxycarbonyl)-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteinate (150 mg, 70.93% yield) as an off-white solid.

[0138] [ka]

[0139] Step-2: Synthesis of methyl S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteinate To a stirred solution of methyl N-(tert-butoxycarbonyl)-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteinate (110 mg, 0.218 μmol) in dichloromethane (4 mL), trifluoroacetic acid (0.5 mL) was added at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, co-distilled with DCM, and triturated with diethyl ether to give methyl S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteinate (80 mg, crude) as an off-white solid. The crude compound was used directly in the next step.

[0140] [ka]

[0141] Step-3: Synthesis of S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteine To a stirred solution of methyl S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteinate (120 mg, 0.297 mmol) in tetrahydrofuran (3 mL) and water (3 mL), lithium hydroxide (14.2 mg, 0.595 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by prep-HPLC to give S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteine ​​(32 mg, 27.58% yield) as a white solid.

[0142] [ka]

[0143] Example 1g - Synthesis of Compound 28 [ka]

[0144] Step 1: Synthesis of methylacetyl-L-cysteinate To a stirred solution of hydrogen chloride-methyl (R)-2-amino-3-captopropionate (1 / 1) (2 g, 11.7 mmol) in dichloromethane (50 mL), triethylamine (3.6 mL, 25.63 mmol) and acetic anhydride (1.3 g, 12.817 mmol) were added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by Combiflash chromatography eluting with (0–100% DCM in hexane) to give methyl acetyl-L-cysteinate (0.3 g, 11.45% yield) as a white solid.

[0145] [ka]

[0146] Step-2: Synthesis of methyl N-acetyl-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteinate To a stirred solution of methylacetyl-L-cysteinate (64 mg, 0.361 mmol) in dichloromethane (5 mL) was added triethylamine (66 mg, 0.657 mmol), followed by 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (100 mg, 0.328 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, it was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography eluting with (0-25% EtOAc / hexanes) to give methyl N-acetyl-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteinate (130 mg, 89% yield) as an off-white solid.

[0147] [ka]

[0148] Step-3: Synthesis of N-acetyl-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteine To a stirred solution of methyl N-acetyl-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteinate (120 mg, 0.269 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added lithium hydroxide (14.2 mg, 0.595 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated to remove THF, and the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by prep-HPLC to give N-acetyl-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteine ​​(50 mg, 51.8% yield) as an off-white solid.

[0149] [ka]

[0150] The synthesis of novel compounds with modifications to the core structure can be achieved using two different strategies. First, compounds 5 / 6 can be chemically modified by substitution / reaction with suitable reagents to introduce the desired modifications to the core structure. These modifications include functional group modifications and ring substitutions. Second, synthesis can be performed using commercially available key starting materials that already possess the substitutions or functional groups required for the synthesis of the core structure. The choice of reagents, reaction conditions, and protecting groups can play a crucial role in the successful implementation of these strategies. Side chains can be incorporated into the modified core structure using the same synthetic protocol as disclosed for compound 6.

[0151] Example 2 - In vitro inhibition of IL-1β production The following examples demonstrate the efficacy of compounds of the present disclosure in inhibiting the production of cytokines such as interleukin-1β in a dose-dependent manner under in vitro conditions. The procedures detailed herein can be used to test any compound of the present disclosure.

[0152] Human monocytic THP-1 cells were treated with phorbol 12-myristate 13-acetate (PMA) (100 nM) overnight to differentiate the monocytic cells into macrophages. After 24 hours of incubation, the differentiated cells were incubated with test compounds at concentrations of 0.01, 0.1, 1, 10, 30, and 50 μM for 12 hours. The cells were then washed once with PBS and primed with E. coli LPS (0.1 μg / ml) for 4 hours, followed by stimulation with ATP (5 μM) for an additional 30 minutes. The cell culture supernatant was then collected, and the OD values ​​of IL-1β levels were measured by ELISA. A standard curve of IL-1β (OD vs. concentration) was also plotted and used to determine the IL-1β concentration relative to the OD values. The inhibition rate of IL-1β was calculated using the following formula: (IL-1β concentration with LPS+ATP - IL-1β concentration with sample) / (IL-1β concentration with LPS+ATP - IL-1β concentration with DMSO) x 100 was calculated using

[0153] The IL-1β inhibition rates at different compound concentrations were plotted as a sigmoid curve, and IC50 values ​​were interpolated using Graphpad Prism. Cell death was assessed by propidium iodide staining, and OD was measured at 490 nm. Cell viability was estimated relative to the DMSO control. Figure 3 shows the IC50 value of a representative compound, compound 6, which had 99% cell viability at 10 μM, indicating that it was not toxic to cells within the tested concentration range.

[0154] Example 3 - In vivo inhibition of IL-1β production The following example demonstrates the efficacy of compounds of the present disclosure in inhibiting the production of cytokines such as interleukin-1β in a dose-dependent manner under in vivo conditions. The procedures detailed herein can be used to test any compound of the present disclosure. In this example, an LPS + ATP-induced inflammasome activation model in 8-10 week-old male Balb / c mice is used for in vivo testing.

[0155] Eight to ten week old male Balb / c mice were conditioned by intraperitoneal (ip) injection of 200 μg / kg (0.2 μg / g) LPS at t = 0 hr, followed by an ip injection of 5 mM ATP solution at t = 2 hr (2 hr after LPS challenge). Compounds of the disclosure (e.g., Compound 6) to be tested for inhibitory activity were administered by both intraperitoneal and oral routes at -1 hr. Different doses of compounds of the disclosure were given to mice after LPS priming, as shown below.

[0156] MCC950, a specific small molecule inhibitor of NLRP3 inflammasome, was used as a positive control so that the inhibitory activity of the compounds of the present disclosure could be compared with that of known inhibitors. 2.5 hours after LPS priming (or 0.5 hours after ATP administration), blood was collected by retro-orbital bleeding into a heparinized blood collection tube. The blood was centrifuged at 10,000 rpm for 5 minutes in a refrigerated centrifuge to obtain plasma. The separated plasma was used for cytokine evaluation by ELISA. A standard curve of IL-1β (OD vs. concentration) was also plotted and used to determine the IL-1β concentration relative to the OD value. The inhibition rate of IL-1β was calculated using the following formula: (IL-1β concentration in LPS+ATP control - IL-1β concentration in sample) / (IL-1β concentration in LPS+ATP control - IL-1β concentration in sham control) x 100 was calculated using

[0157] The following groups were evaluated to observe IL-1β inhibition: [Table 2]

[0158] Figure 4 shows the dose-dependent reduction of IL-1β with compound 6 in an in vivo mouse model. Interestingly, this compound showed 79% inhibition of IL-1β at 10 mg / kg i.p. and 46% inhibition of IL-1β when tested at 10 mg / kg orally. MCC950 was used as a tool compound in this assay.

[0159] Thus, compounds of the present disclosure showed significant inhibition of IL-1β production in an LPS+ATP-induced mouse model of inflammasome activation. Example 4 - Analysis of Absorption, Distribution, Metabolism and Excretion (ADME) and Pharmacokinetic (PK) Parameters ADME describes the absorption, distribution, metabolism, and excretion of drugs in the body. The following examples illustrate the process of evaluating ADME parameters of compounds of the present disclosure.

[0160] solubility analysis Seven calibration standards (i.e., 1, 5, 10, 50, 100, 200, and 300 μM) of test compounds were prepared from a 20 mM primary stock solution in DMSO. 198 μL aliquots of PBS (pH 7.4) were dispensed into duplicate wells of a MultiScreen solubility filter plate. 2 μL of test compound solution from the 20 mM primary stock solution was then added to a final concentration of 200 μM. The plate was then capped and shaken at 150 rpm for 90 minutes. At the end of the 90 minutes, samples were filtered using the MultiScreen HTS vacuum manifold assembly, and the filtrate was collected in an acceptor plate. 150 μL aliquots of the filtrate from the 96-well acceptor plate were transferred to HPLC vials and analyzed by HPLC-PDA. Solubility was determined by comparing the absorbance of the test / reference compounds to their respective DMSO calibration curves. Compound 6 was tested for solubility in phosphate buffered saline (pH-7.4) by a kinetic method, and the compound was highly soluble with a solubility of greater than 200 μM.

[0161] Metabolic stability assay in mouse, rat, and human liver microsomes Assays were performed in duplicate, with a final test concentration of 1 μM. Incubations were performed for 45 minutes, with intermediate time points at 0, 5, 15, and 30 minutes. Verapamil was used as the reference standard in this experiment. The concentration of verapamil was 1 μM. For microsome stability experiments, vials containing microsomes were thawed in an ice bath. 33 μL of microsomes (20 mg / mL) were suspended in 1165.7 μL of 100 mM potassium phosphate buffer (pH 7.4) in a propylene tube labeled "incubation mixture." Control and test compounds were placed in a similar set of incubation mixture tubes. 1.1 μL of compound 6 or verapamil (1 mM) was added to the incubation mixture to achieve a working concentration of 1.1 μM, respectively. 180 μL aliquots from the incubation mixture were used for T Control , T0, T5, T 15 , T 30 and T 45 The solution was transferred to six tubes labeled

[0162] All tubes were preincubated in a shaking water bath at 37±1°C for 5 minutes. The tubes containing 10 mM NADPH solution were also preincubated under the same conditions. After preincubation, 20 μL of 10 mM NADPH solution was added to the tubes at T0, T5, and T6. 15 , T 30 and T 45 Add to the tube and Control 20 μL of buffer solution was added to each tube to achieve a final concentration of 1 μM. At TO, the reaction was immediately quenched with 200 μL of quenching solution containing warfarin as an internal standard (IS). Similarly, at the end of each tube's incubation time (5, 15, 30, and 45 min), 200 μL of quenching solution containing warfarin as an internal standard (IS) was added to each tube to terminate the reaction. The resulting samples were centrifuged at 3220 g (relative centrifugal force) for 20 min. A 200 μL aliquot of the supernatant was taken from each reaction tube for LC-MS / MS analysis.

[0163] The calculation was performed as follows: % remaining = 100 x (PAR at a given incubation time / PAR at TO time point) Elimination rate constant (k) = (-slope) Half-life (t1 / 2) = 0.693 / k V (μL / mg) = incubation volume (μL) / protein in incubation (mg) Microsomal intrinsic clearance (mCLint) (μL / min / mg protein) = (V × 0.693) / t 1 / 2 where PAR is the peak area ratio of the analyte to the internal standard (IS).

[0164] The stability of compound 6 when incubated with the reference standard verapamil in mouse, rat and human liver microsomes is shown in the table below: [Table 3]

[0165] The reference standard, verapamil, showed extensive metabolism by liver microsomes and was well within the mCLint acceptance criteria (human: low < 8.60 and high > 47.0; rat: low < 13.2 and high > 71.9; mouse: low < 8.80 and high > 48.0). The compound tested, compound 6, showed moderate to high stability across the species tested.

[0166] Metabolic stability assay in human liver microsomes in the presence of specific cytochrome P450 inhibitors. Experiments were performed in duplicate, with a final test concentration of 1 μM. Incubation was for 45 min with intermediate time points at 0, 5, 15, and 30 min. CYP-specific reference standards and inhibitors were used in the experiments. Test concentrations of substrate were 1 μM and inhibitors were 20 μM.

[0167] The following substrates and inhibitors were used: [Table 4]

[0168] For microsome stability experiments, vials containing microsomes were thawed on the surface of an ice bath. 33 μL of microsomes (20 mg / mL) were suspended in 1165.7 μL of 100 mM potassium phosphate buffer (pH 7.4) in a propylene tube labeled "Incubation Mixture." Control and test compounds were placed in a similar set of incubation mixture tubes. 1.1 μL (1 mM) of a compound of the present disclosure, such as Compound 6, was added to the incubation mixture to achieve a working concentration of 1.1 μM, respectively. Similarly, 1.1 μL of Compound 6 (1 mM) and inhibitor (20 mM) were added to a second set of the incubation mixture to achieve working concentrations of 1.1 μM and 20 μM, respectively. 180 μL aliquots from each incubation mixture were transferred to T Control , T0, T5, T 15 , T 30 and T 45 The solution was transferred to six tubes labeled

[0169] All tubes were preincubated in a shaking water bath at 37±1°C for 5 minutes. The tubes containing 10 mM NADPH solution were also preincubated under the same conditions. After preincubation, 20 μL of 10 mM NADPH solution was added to the tubes at T0, T5, and T6. 15 , T 30 and T 45 Add to the tube and Control 20 μL of buffer solution was added to the tubes to achieve a final concentration of 1 μM. At TO, the reaction was immediately quenched with 200 μL of quenching solution containing warfarin as an internal standard (IS). Similarly, at the end of each tube's incubation time (5, 15, 30, and 45 min), 200 μL of quenching solution containing warfarin as an internal standard (IS) was added to each tube to terminate the reaction. The resulting samples were centrifuged at 3220 g for 20 min. A 200 μL aliquot of the supernatant was taken from each reaction tube for LC-MS / MS analysis. Calculations were performed as described in the previous section.

[0170] The stability of compound 6 when incubated with human liver microsomes together with CYP-specific substrates and inhibitors is shown in the table below: [Table 5]

[0171] As in the previous section, compound 6 showed moderate to high stability in human liver microsomes. Experiments were performed in human liver microsomes, targeting five different isoforms of CYPs: 3A4, 2D6, 2C9, 2C19, and IA2. Compound 6 showed approximately 35% degradation when incubated in human liver microsomes. The degradation of compound 6 was largely unchanged by co-incubation with specific CYP inhibitors. Even in the presence of specific CYP inhibitors, compound 6 degraded only 40-45%, indicating that more than one CYP is involved in the degradation of compound 6.

[0172] Example 5 - Analysis of plasma protein binding, permeability and mode of administration Plasma protein binding assay The transfer of compounds of the present disclosure, such as compound 6, from mouse, rat, and human plasma through a membrane (12 kDa cutoff) into a buffer solution is tested by the equilibrium dialyzer method at a concentration of 3 μM with shaking for 4.5 h at 37° C. Warfarin and naltrexone are used as positive controls, and the % bound, unbound fraction (fu), and recovery are calculated.

[0173] [Table 6]

[0174] Permeability assay The apical-basolateral and reverse permeabilities of compounds of the present disclosure, such as Compound 6, are determined through MDR1-transfected Madin-Darby canine kidney (MDCK) cell monolayers at a concentration of 5 μM for 60 minutes. Digoxin is used as a reference and Lucifer Yellow is used as an integrity marker. The concentration of Compound 6 is determined by LC-MS / MS. Papp, efflux ratio, and recovery are calculated. The results of the permeability assay are shown in the table below.

[0175] Based on the above results, compound 6 is a highly permeable compound (AB permeability is 26 × 10 -6 cm / sec) and is not an excretory substrate (ER<2).

[0176] Oral and intravenous pharmacokinetics in rats In rats, after administration of 10 mg / kg (oral) and 2 mg / kg (intravenous), the plasma concentration versus time profiles were analyzed by AUC at 0.25, 0.5, 1, 2, 4, 6, 10, and 24 hours for oral treatment and 0.083, 0.25, 0.5, 1, 2, 4, 6, 10, and 24 hours for intravenous treatment. 0-t , AUC 0-∞ , C max , T max ,CL,Vd,t 1 / 2 and F, as well as other key pharmacokinetic parameters.

[0177] Dose escalation to determine maximum tolerated dose (MTD) in rats The MTD study will be conducted in 8-9 week old female Sprague-Dawley rats, with four ascending doses administered orally. Rats will be analyzed for weight loss, the development of any clinical signs, morbidity, or mortality. Plasma versus time concentration profiles and, where applicable, key pharmacokinetic parameters (AUC) will be analyzed at 0.25, 0.5, 1, 2, 4, 6, 10, and 24 hours after oral administration of 30, 100, and 300 mg / kg in rats. 0-t , AUC 0-∞ , C max , T max ,CL,Vd,t 1 / 2 and F).

[0178] Example 6 - Toxicology assay in rats Compounds of the present disclosure, such as Compound 6, are evaluated in 6-8 week-old Sprague-Dawley rats (male / female) in a 4 / 14 day exploratory repeated-dose escalation toxicity study at the doses listed below. Routine parameters such as mortality, weight change, clinical signs, urinalysis, hematology, blood biochemistry, gross organ histopathology, and the no observed adverse effect level (NOAEL) are monitored. The following doses are tested to determine the optimal dose for safety and efficacy:

[0179] [Table 7]

[0180] Evaluate the following readouts: [Table 8]

[0181] The same experiment is then repeated for a 28-day GLP toxicity study following the same protocol as above.

[0182] Example 7 - Treatment of Primary Sclerosing Cholangitis Primary sclerosing cholangitis (PSC) is a chronic liver disease in which bile ducts inside and outside the liver become inflamed and scarred, eventually narrowing or becoming blocked. In PSC, inflammation causes scarring within the bile ducts. These scars harden and narrow the bile ducts, gradually causing severe liver damage. Most patients with PSC also have an inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0183] Mdr2 knockout mice are used as an animal model of primary sclerosing cholangitis. Male FVB / NJ WT and Mdr2 knockout mice aged 9-11 weeks are randomized into different groups as indicated. Compounds of the present disclosure, such as Compound 6, are administered intraperitoneally or orally daily starting at 10 weeks of age until 12 weeks of age. At 12 weeks of age, mice are sacrificed and analyzed for liver and serum bile acid accumulation, liver fibrosis, pro-inflammatory and pro-fibrotic markers. The following doses and administration routes are tested: [Table 9]

[0184] Example 8 - Treatment of Arthritis Arthritis is swelling and tenderness in one or more joints. The main symptoms of arthritis are joint pain and stiffness, which usually worsen with age. The most common types of arthritis are osteoarthritis and rheumatoid arthritis. Osteoarthritis destroys the cartilage that covers the ends of bones that form joints. Rheumatoid arthritis is a disease in which the immune system attacks joints, starting with the joint lining. Monoclonal antibody-induced arthritis models (mAb-induced RA, AIA, or CAIA) are ideal for rapid screening and evaluation of anti-inflammatory therapeutic agents.

[0185] Compounds of the present disclosure, such as Compound 6, are evaluated for their ability to treat arthritis using a monoclonal antibody-induced arthritis model. Male Balb / c mice aged 8-10 weeks are used in the assay. Mice are injected intraperitoneally (IP) with a cocktail of five monoclonal antibodies against type II collagen (1.5 mg). On day 3, an IP injection of 50 μg of lipopolysaccharide (LPS derived from Escherichia coli strain 055B5; in sterile saline) is administered.

[0186] [Table 10]

[0187] Compound 6 is administered at the doses described below from day 2 through day 10. The compound is administered by both intraperitoneal and oral routes. Paw thickness, paw weight, clinical score, joint cytokine profile, and histopathology are assessed to determine if there is an improvement in these parameters following compound administration.

[0188] Additional Embodiments 1. Formula (I) [ka] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, and C1-C6-alkyl-amino; m and n are each independently an integer having a value of 0, 1, 2, 3, or 4; and X1, X2, X3, X4, X5, X6, X7, and X8 are each independently selected from the group consisting of -CH and N; R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), -CO-alkyl, and -CO-haloalkyl; R4 is each independently hydrogen or COY or with the proviso that when X1-X8 are -CH, if R3 is hydrogen then R4 is not hydrogen, except that when X1-X8 are N and / or R1 or R2 are halo then R4 and R3 may both be hydrogen. [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. Compound.

[0189] 2. The compound according to Innovation 1, wherein R4 is not hydrogen, m is 0, and n is 1.

[0190] 3. The compound according to Innovation 2, wherein R4 is COY and Y is a substituted piperazine.

[0191] 4. The compound according to Innovation 2, wherein R4 is COY and Y is haloalkyl.

[0192] 5. The compound according to Innovation 1, wherein R4 is hydrogen, m is 0, n is 1, and R2 is halo.

[0193] 6. The compound according to Innovation 2, wherein R4 is COY and Y is a substituted piperidine.

[0194] 7. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] [Table 11-11] [Table 11-12] [Table 11-13] [Table 11-14] [Table 11-15] A compound selected from the group consisting of:

[0195] 8. The compound according to any one of Innovations 1 to 7, having an IC50 value of about 2 μM.

[0196] 9. A compound according to any one of Innovations 1 to 8, which is capable of reducing the expression of IL-1β by at least 50%.

[0197] 10. A compound according to any one of Innovations 1 to 9, capable of treating an inflammatory disease.

[0198] 11. A method for treating an inflammatory disease, comprising administering a compound according to any one of Innovations 1 to 10, thereby treating said disease.

[0199] 12. The method of innovation 11, wherein the disease is selected from the group consisting of inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), primary sclerosing cholangitis, primary biliary cirrhosis, alcoholic hepatitis, alcoholic cirrhosis, pancreatitis, non-alcoholic steatohepatitis, alcoholic pancreatitis, acute hepatitis, celiac disease, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, gastric ulcer, antiphospholipid syndrome, Barrett's esophagus, postoperative ileus, atrophic gastritis, peritonitis, diverticulitis, duodenal ulcer, alveolar periostitis, Crohn's disease, Alzheimer's disease, arthritis, and multiple sclerosis.

[0200] 13. Formula I(a) [ka] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, and C1-C6-alkyl-amino; m and n are each independently an integer having a value of 0, 1, 2, 3, or 4; Each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), and -CO-alkyl; R4 is each independently hydrogen or COY or with the proviso that if R3 is hydrogen then R4 is not hydrogen, except that if either R1 or R2 is halo then R4 and R3 may both be hydrogen. [ka] [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. Compound.

[0201] 14.Formula I(b) [ka] wherein each R1 is independently selected from the group consisting of hydrogen, —CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, and C1-C6-alkyl-amino; and each m is independently an integer having a value of 0, 1, 2, 3, or 4; Each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), and -CO-alkyl; R4 is independently hydrogen or COY or [ka] [ka] It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. Compound.

[0202] 15. The compound according to Innovation 13 or 14, which is capable of reducing the expression of IL-1β by at least 50%.

[0203] Other embodiments While specific embodiments of the subject matter have been discussed, the above specification is illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0204] The following are exemplary claims directed to the above subject matter and should not be construed as limiting the invention. Applicant reserves the right to pursue claims directed to any of the disclosed subject matter.

Claims

1. Formula (I) 【Chemical 1】 wherein R1 and R2 are each independently selected from the group consisting of hydrogen, —CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; m and n are each independently an integer having a value of 0, 1, 2, 3, or 4; and X1, X2, X3, X4, X5, X6, X7, and X8 are each independently selected from the group consisting of —CH and N; each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), —CO-alkyl, and —CO-haloalkyl; R4 is each independently hydrogen or COY or, when X1 to X8 are -CH, if R3 is hydrogen then R4 is not hydrogen, except that when X1 to X8 are N and / or R1 or R2 are halo then R4 and R3 may both be hydrogen. 【Chemistry 2-1】 【Chemistry 2-2】 It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. Compound.

2. 2. The compound of claim 1, wherein R4 is not hydrogen, m is 0, and n is 1.

3. 3. The compound of claim 2, wherein R4 is COY and Y is a substituted piperazine.

4. 3. The compound of claim 2, wherein R4 is COY and Y is haloalkyl.

5. 2. The compound of claim 1, wherein R4 is hydrogen, m is 0, n is 1, and R2 is halo.

6. 3. The compound of claim 2, wherein R4 is COY and Y is a substituted piperidine. 【Request 7】 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 A compound selected from the group consisting of:

8. 2. The compound of claim 1, having an IC50 value of about 2 μM.

9. 2. The compound of claim 1, which is capable of reducing the expression of IL-1β by at least 50%.

10. 【Chemical 3】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

11. Formula I(a) 【Chemistry 4】 wherein R1 and R2 are each independently selected from the group consisting of hydrogen, —CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; m and n are each independently an integer having a value of 0, 1, 2, 3, or 4; Each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), and —CO-alkyl; 【Chemistry 5-1】 【Chemistry 5-2】 wherein R4 is each independently one of hydrogen or COY, with the proviso that if R3 is hydrogen then R4 is not hydrogen, except that if either R1 or R2 is halo then R4 and R3 may both be hydrogen; or each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group; Compound.

12. Formula I(b) 【Chemistry 6】 wherein each R1 is independently selected from the group consisting of hydrogen, —CO-alkyl, hydroxyl, halo, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, and C1-C6-alkyl-amino; and each m is independently an integer having a value of 0, 1, 2, 3, or 4; Each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), and —CO-alkyl; Each R4 is independently hydrogen or COY or 【Chemistry 7-1】 【Chemistry 7-2】 It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. Compound.

13. Formula I(c) 【Chemistry 8】 wherein R1 is hydrogen, m is 1, R3 is hydrogen; Each R4 is independently hydrogen or COY or 【Chemistry 9-1】 【Chemistry 9-2】 It is one of the wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, and C3-C8 cyclo(halo)-alkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a 5- or 6-membered ring optionally containing at least one heteroatom selected from N, S, and O, and the 5- or 6-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted with a halo, amino, carboxyl, or alkoxy group. Compound.

14. 2-Fluoro-5-(2-(4-methylpiperidin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-Fluoro-5-(2-(4-methylpiperidin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-Fluoro-5-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(2-chloro acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-(fluoroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-(3,3,3-trifluoropropanoyl) )-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(aminoacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-[(methylamino)acetyl]-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-[(dimethylamino)acetyl]-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-[(aziridine-1- N-[2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl]methanesulfonamide, 5-acetyl-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-[(E)-2-fluoroethenyl]-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-[(Z)-2-fluoroethenyl]-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-[(1Z)-3,3,3-trifluoroprop-1-en-1-yl]-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-5,10-dihydro-11H-dibenzo[b,e][1, 4]diazepin-11-one, 5-(chloroacetyl)-2-fluoro-10-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(chloroacetyl)-2-fluoro-10-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-10-methyl-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-5-carboxylic acid, 2-fluoro-5-(morpholine-4-carbo 2-Fluoro-5-(4-methylpiperazine-1-carbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-Fluoro-5-(2-hydroxybutyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-Fluoro-5-[(oxiran-2-yl)methyl]-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one ]diazepin-11-one, 2-chloro-1-(2-fluoro-11-hydroxy-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethan-1-one, 2-amino-3-{[2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl]sulfanyl}propanoic acid, 2-acetamido-3-{[2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl]sulfanyl}propanoic acid, 2-amino-5-((1-((carboxymethyl)amino)-3-((2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)thio)-1-oxopropan-2-yl)amino)-5-oxopentanoic acid, 6-((5-(2-chloroacetyl)-2-fluoro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-yl)oxy)-3,4,5-trihydro hydroxytetrahydro-2H-pyran-2-carboxylic acid, 2-fluoro-5-(fluoroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(2-chloroethyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(3-chloro-1,1,1-trifluoropropan-2-yl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-(trifluoroacetyl)-5,10 -dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(3-chloropropanoyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(3-chlorooxiran-2-yl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-(4,4,4-trifluorobutanoyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(chloromethanesulfonyl) )-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-(2,2,2-trifluoroethanesulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-(2-chloro-1,1-difluoroethyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 11-(chloroacetyl)-3-fluoro-6,11-dihydro-5H-5λ6-dibenzo[c,f][1,2]thiazepine-5,5-dione, 11-(3-chloropropanoyl)-3-fluoro-6,11-dihydro-5H-5λ6-dibenzo[c,f][1,2,5]thiadiazepine-5,5-dione, 11-(2-chloroethyl)-3-fluoro-6,11-dihydro-5H-5λ6-dibenzo[c,f][1,2,5]thiadiazepine-5,5-dione, 3-fluoro-11-(2-fluoroethyl)-6,11-dihydro-5H-5λ6-dibenzo[c,f][1,2,5]thiadiazepine-5,5-dione, 3-fluoro-11-(fluoroacetyl)-6,11- Dihydro-5H-5λ6-dibenzo[c,f][1,2,5]thiadiazepine-5,5-dione, 11-butanoyl-3-fluoro-6,11-dihydro-5H-5λ6-dibenzo[c,f][1,2,5]thiadiazepine-5,5-dione, 1-[2-fluoro-11-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl]propan-1-one, 2-fluoro-1-[2-fluoro-11-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl]propan-1-one 1-[2-fluoro-11-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl]ethan-1-one, 1-[2-fluoro-11-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl]butan-1-one, 3-fluoro-1-[2-fluoro-11-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl]propan-1-one, 2-fluoro-5-propyl-11-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine, 5-(2-chloroethyl)- 2-fluoro-11-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine, 2-fluoro-5-(2,2,2-trifluoroethanesulfonyl)-5,10,11,11a-tetrahydro-4aH-dibenzo[b,e][1,4]diazepine, 2-fluoro-5-(2,2,2-trifluoroethanesulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-imine, 2,11,11-trifluoro-5-(2,2,2-trifluoroethanesulfonyl)-10,11-Dihydro-5H-dibenzo[b,e][1,4]diazepine, 3,3,3-trifluoro-1-(2-fluoro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)propan-1-one, 3,3,3-trifluoro-1-(2-fluoro-11-imino-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)propan-1-one, 3,3,3-trifluoro-1-(2,11,11-trifluoro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)propan-1-one, 2-fluoro-1-(2-fluoro-10,11 a compound selected from the group consisting of 2-fluoro-1-(2-fluoro-11-imino-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethan-1-one, 2-fluoro-1-(2,11,11-trifluoro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethan-1-one, and 3-chloro-1-[2-fluoro-11-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl]propan-1-one.

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