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, for example, inhibiting oligomerization of apoptosis-related spot-like proteins containing the C-terminal caspase recruitment domain (ASC). Methods of treating various disease states using the compounds that inhibit 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 compositions containing the same), their use in treating diseases involving inflammation, and their synthesis.

[0002] Related applications

[0003] This application claims priority to U.S. Provisional Application No. 63 / 426,965, filed on November 21, 2022, and Indian Provisional Application No. 202211051974, filed on September 12, 2022, the contents of each of which are incorporated herein by reference in their entirety. Background Art

[0004] Inflammation is a protective immune response produced by the innate immune system in response to harmful stimuli such as pathogens, dead cells or irritants, and is strictly regulated by the host. Insufficient inflammation can lead to persistent infection with pathogens, while excessive inflammation can cause chronic or systemic inflammatory diseases. Inflammasomes are protein complexes that play a role in initiating and controlling inflammatory responses. Excessive triggering of inflammasomes leads to unnecessary inflammation and inflammatory diseases. Therefore, inflammasomes are associated with a variety of autoinflammatory and autoimmune diseases, including neurodegenerative diseases such as inflammatory bowel disease, Crohn's disease, multiple sclerosis, Alzheimer's disease and Parkinson's disease. It is interesting to control inflammation by regulating the activity of inflammasomes and their components. Summary of the Invention

[0005] The present disclosure provides compounds having formula (I):

[0006]

[0007] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m and n are integers each independently having a value of 0, 1, 2, 3 or 4, wherein X1, X2, X3, X4, X5, X6, X7 and X8 are each independently selected from the group consisting of -CH and N; wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl(C1-C6), -CO-alkyl and -CO-haloalkyl,

[0008] wherein each R4 is independently one of hydrogen or COY, provided that when R3 is hydrogen and when X1-X8 is -CH, R4 is not hydrogen, except that when X1-X8 is N and when R1 or R2 is halogen, R4 and R3 may both be hydrogen; or R4 is

[0009]

[0010]

[0011] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0012] In some embodiments, the compounds of Formula I are further limited. For example, in any of the foregoing compounds of Formula I, 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 halogen. In some embodiments, R4 is COY and Y is a substituted piperidine.

[0013] In some embodiments, the present disclosure provides compounds of Formula I(a)

[0014]

[0015] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m and n are each independently integers having a value of 0, 1, 2, 3 or 4,

[0016] wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6) and -CO-alkyl,

[0017] wherein R4 is each independently one of hydrogen or COY, provided that when R3 is hydrogen R4 is not hydrogen, except that when R1 or R2 is halogen, R4 and R3 may both be hydrogen: or R4 is

[0018]

[0019]

[0020] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0021] In some embodiments, the present disclosure provides compounds of Formula I(b)

[0022]

[0023] wherein R1 is each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m is an integer each independently having a value of 0, 1, 2, 3 or 4,

[0024] wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6) and -CO-alkyl,

[0025] wherein R4 is each independently hydrogen or COY or one of the following:

[0026]

[0027]

[0028] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0029] In some embodiments, the present disclosure provides compounds of formula I(c)

[0030]

[0031] wherein R1 is hydrogen and m is 1, wherein R3 is hydrogen, and wherein each R4 is independently hydrogen or COY or one of:

[0032]

[0033]

[0034] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or poly-substituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0035] In some embodiments, the compound is selected from the group consisting of:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044] In some embodiments, one or more of the aforementioned compounds have a half-maximal inhibitory concentration (IC50) value of about 2 μM. In some embodiments, the compound is capable of reducing the expression of IL-1β by at least 50%. In some embodiments, the compound can treat inflammatory diseases.

[0045] In one aspect, the present disclosure provides a method for treating a disease caused by inflammation, comprising administering any of the aforementioned compounds and thereby treating the disease. In some embodiments, the disease can be any of inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), primary sclerosing cholangitis, primary biliary cirrhosis, alcoholic hepatitis, alcoholic cirrhosis, pancreatitis, nonalcoholic steatohepatitis, alcoholic pancreatitis, acute hepatitis, celiac disease, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers, gastric ulcers, antiphospholipid syndrome, Barrett's esophagus, postoperative ileus, atrophic gastritis, peritonitis, diverticulitis, duodenal ulcer, alveolar periostitis, Crohn's disease, Alzheimer's disease, arthritis, metabolic syndrome-associated obesity, and multiple sclerosis. In other embodiments, the diseases that can be treated with the compounds of the present invention may involve 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 accident, subarachnoid hemorrhage, hyperactive behavior, idiopathic scoliosis, middle cerebral artery occlusion, ischemic stroke and bipolar disorder. In other embodiments, the diseases involve bone, including arthritis (including rheumatoid arthritis, gouty arthritis, psoriatic arthritis), osteoarthritis, osteopenia, osteoporosis, ankylosing spondylitis and intervertebral disc degeneration.

[0046] Additional embodiments relate to the use of the compounds of the present invention to treat disease states associated with the eye, heart and vascular system, kidneys and lungs, including 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, cardiac fibrosis, atrial fibrillation, hypertensive disorders, vasculitis, acute kidney injury, diabetic nephropathy, glomerulonephritis, IgA glomerulonephritis, Chronic renal failure, lupus nephritis, nephritis, hyperuricemia, aristolochic acid nephropathy, obesity-related glomerulopathy, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, emphysema, pulmonary fibrosis, cystic fibrosis, silicosis, pneumonia, acne vulgaris, atopic dermatitis, contact dermatitis, psoriasis, dermatomyositis, lichen planus, vitiligo, epidermolysis bullosa, bullous pemphigoid, hidradenitis suppurativa, harlequinfetus. Finally, in additional embodiments, treatable disease states may include alcohol abuse, cytokine release syndrome, familial Mediterranean fever, graft-versus-host disease, mastitis, sepsis, primary Sjögren's syndrome, hyperhomocysteinemia, acute chest syndrome, estrogen deficiency, painful bladder syndrome, neuropathy, allergic rhinitis, cold pyridine-associated periodic syndrome, Bechet Disease, mucocutaneous lymph node syndrome, autoimmune thrombocytopenia, mevalonate kinase deficiency, juvenile spondyloarthropathy, and Conn's syndrome. DETAILED DESCRIPTION

[0047] The human body mounts an inflammatory response when exposed to pathogens, tissue damage, and endogenous stressors. The inflammatory response is triggered by pattern recognition receptors (PRRs). Signaling downstream of PRRs leads to the expression of proinflammatory cytokines such as TNFα, IL-1β, IL-6, IL-18, and others. Inflammation can be used to fight pathogens, but 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 lead to ineffective pathogen destruction, resulting in persistent infection. Therefore, the level of inflammation needs to be tightly regulated.

[0048] The inflammatory response is initiated and controlled by protein complexes called inflammasomes, which are found in macrophages and neutrophils. When inflammasomes are overactive, diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Crohn's disease, Alzheimer's disease, arthritis, and multiple sclerosis can result. These diseases occur when the proinflammatory cytokines mentioned above trigger unwanted cell death. While this cell death is an integral part of the immune response to fight infection, excessive inflammasome activity triggers unwanted cell death, thereby triggering a variety of autoimmune diseases, such as those mentioned above.

[0049] Without being bound by theory, it is believed that a specific family of proteins called apoptosis-associated speck-like proteins (containing a C-terminal caspase recruitment domain, abbreviated as ASC) interact with procaspase-1 to at least partially trigger the inflammasome response that leads to cell death. (See Figure 1 ). ASC regulates the assembly and activation of multiple inflammasomes. The adaptor molecule ASC plays a role in the stimulation and assembly of linked inflammasomes 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 have a characteristic six-helix bundle fold. ASC brings monomers of pro-caspase-1 into proximity, which triggers caspase-1 autocleavage and the formation of active heterotetrameric 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 nonclassical secretory pathway.

[0050] Some embodiments of the present invention provide first-in-class pan-inflammasome inhibitors targeting ASC with broad anti-inflammatory effects. The compounds disclosed herein inhibit ASC protein oligomerization, which in turn disrupts inflammasome assembly, thereby limiting inflammation by targeting multiple inflammasome pathways. Therefore, certain embodiments of the present invention have the potential to limit inflammation in various gastrointestinal and other inflammatory conditions (see Figure 2 ).

[0051] Although various inventive embodiments have been described and illustrated herein, those skilled in the art will readily conceive of various other means for performing the functions and / or obtaining the results and / or one or more advantages described herein, and each of these variations and / or modifications is considered to be within the scope of the inventive embodiments 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 actual parameters and / or configurations will depend on one or more specific applications in which the teachings of the present invention are used.

[0052] Various inventive concepts can be embodied as one or more methods, examples of which have been provided. Unless otherwise specified, the acts performed as part of a method can be ordered in any suitable manner. Thus, embodiments can be constructed in which acts are performed in an order different from that shown, which can include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Various aspects of the present disclosure are specifically described in the accompanying innovations. A better understanding of the features and advantages of the present disclosure will be obtained by referring to the following detailed description and the accompanying drawings, which set forth illustrative embodiments utilizing the principles of the present disclosure, wherein:

[0054] Figure 1 is a schematic diagram showing activation of inflammasome assembly leading to caspase-1-dependent release of proinflammatory cytokines, gasdermin D-mediated pyroptosis, and apoptosis.

[0055] Figure 2 is a schematic diagram of the mechanism of action of compounds of the present disclosure in inhibiting inflammasome activation in inflammatory disorders.

[0056] Figure 3 Graph showing reduction in IL-1β expression, obtained by plotting percent cytokine inhibition (IL-1β) versus the concentration of compound 6. The graph shows that there is a dose-dependent reduction in IL-1β levels under in vitro conditions.

[0057] Figure 4 Shown is a graph showing the amount of plasma IL-1β plotted against various increasing doses of compound 6. The graph shows that there is a dose-dependent reduction in IL-1β levels under in vivo conditions.

[0058] definition

[0059] 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.

[0060] In this application, unless otherwise specifically stated, the use of the singular includes the plural. It must be noted that, as used in the specification and the accompanying inventions, 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 otherwise stated. Furthermore, the use of the term "include" as well as other forms such as "including," "comprising," and "containing" are not limiting.

[0061] As used herein, in some embodiments, ranges and amounts are expressed as "about" a particular value or range. Approximately also includes an exact amount. Thus, "about 5 μL" means "about 5 μL" as well as "5 μL." Generally, the term "about" refers to the usual experimental error range for the corresponding value known to those of ordinary skill in the art.

[0062] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0063] 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" should be interpreted as inclusive, that is, including multiple elements or at least one of the listed items, but also including more than one, and optionally, additional unlisted items. Only terms that clearly indicate the contrary, such as "only one" or "exactly one", or when used in the claims, "consisting of..." will refer to including exactly one element of a plurality or a plurality of elements. In general, the term "or" as used herein should only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by an exclusive term such as "either", "one of", "only one of" or "exactly one of".

[0064] As used herein in the specification and claims, all transitional phrases such as "comprises," "comprising," "carrying," "having," "containing," "involving," "maintaining," "consisting of," and the like are to be construed as open-ended, i.e., meaning including, but not limited to, "consisting of." Only the transitional phrases "consisting of" and "consisting essentially of" are to be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0065] Although the above discussion discloses various exemplary embodiments of the present invention, it should be clear that those skilled in the art can make various modifications to achieve some of the advantages of the present invention without departing from the true scope of the present invention. Any reference to "the present invention" is intended to refer to exemplary embodiments of the present invention and should not be construed as referring to all embodiments of the present invention unless the context requires otherwise. The described embodiments are to be considered in all respects only as illustrative and not restrictive.

[0066] As used herein, the term "ASC protein" refers to an apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain.

[0067] “API” means active pharmaceutical ingredient.

[0068] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a chemical entity administered to alleviate to some extent one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0069] 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 and suitable for contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, 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.

[0070] The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with an acid or base. For this purpose, acids or bases or counterions described in P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002, can be used.

[0071] As used herein, the term "IL-1β" refers to interleukin 1β (IL-1β). Increased production of IL-1β due to mutations in the inflammasome receptor NLRP3, which triggers IL-1β processing, causes a number of different autoinflammatory syndromes, most notably a monogenic disorder known as cryopyrin-associated periodic syndrome (CAPS).

[0072] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients") such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents. Pharmaceutical compositions facilitate administration of the compound to an organism. Various techniques exist in the art for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0073] The term "subject" refers to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., to refer to a mammalian subject, e.g., a human.

[0074] In the context of treating a disease or condition, the term "treat" is intended to include alleviating or eliminating 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 "treat" refers to one or more of the following:

[0075] (1) Prevention of disease, e.g., preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who does not yet experience or exhibit the pathology or symptoms of the disease.

[0076] (2) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., preventing further development of the pathology and / or symptoms); and

[0077] (3) ameliorating a disease, condition, or disorder, e.g., improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or symptoms).

[0078] As used in the specification and appended descriptions, the following terms have the meanings indicated below unless specified to the contrary.

[0079] "Amino" refers to a -NH2 group.

[0080] "Cyano" refers to a -CN group.

[0081] "Hydroxy" refers to an -OH group.

[0082] "Nitro" refers to a -NO2 group.

[0083] "Oxa" refers to an -O- group.

[0084] "Oxo" refers to a =0 group.

[0085] "Thioxo" refers to a =S group.

[0086] "Imino" refers to a =NH group.

[0087] "Oximo" refers to a =N-OH group.

[0088] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0089] The term "alkyl" refers to a straight or branched chain hydrocarbon group 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, the alkyl group contains 1 to 13 carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group contains one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group contains one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (e.g., C5-C15 alkyl). In other embodiments, the alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group contains three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the 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), 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra), -C(O)Ra, -C(O)ORa, -C(O)N(Ra), -N(Ra)C(O)ORf, -OC(O)-NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (wherein t is 1 or 2), -S(O)tORa (wherein t is 1 or 2), -S(O)tRf (wherein t is 1 or 2), and -S(O)tN(Ra)2 (wherein 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.

[0090] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halogens.

[0091] As used herein, the term "cycloalkyl" 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, wherein 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. Cycloalkyls also include spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by 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.

[0092] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic non-aromatic ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system), if monocyclic, having 1-3 heteroatoms, if bicyclic, having 1-6 heteroatoms, or if tricyclic or polycyclic, having 1-9 heteroatoms selected from O, N or S (e.g., carbon atoms and 1-3, 1-6 or 1-9 heteroatoms if monocyclic, bicyclic or tricyclic, respectively, wherein 0, 1, 2 or 3 heteroatoms per ring), wherein 0, 1, 2 or 3 atoms per ring may be substituted by substituents. Examples of heterocyclyls include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl and the like. Heterocyclyls may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclic groups 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[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[3.2.1]octane, 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 spirocycles (e.g., spirobicycles in which the 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-oxaspiro[3.5] ... Spiro[2.2]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.

[0093] As used herein, the term "cycloalkenyl" includes partially unsaturated cyclic hydrocarbon groups 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, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The cycloalkenyl group may have any degree of saturation, provided that none of the rings in the ring system are aromatic; and the cycloalkenyl group is not generally fully saturated. The cycloalkenyl group may include a plurality of fused and / or bridged and / or spirocycles.

[0094] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having from 5 to 20 ring atoms, or 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 pi electrons shared in the cyclic array; wherein at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, such as tetrahydroisoquinolinyl, such as tetrahydroquinolinyl), and at least one ring in the system contains one or more heteroatoms independently selected from N, O, and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinoline 1,3-dihydrobenzo[b][1,4]dioxolyl, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiine, isoindolyl, etc. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furanyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazolyl and pyrimidinyl. The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic non-aromatic ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system), if monocyclic, having 1-3 heteroatoms, if bicyclic, having 1-6 heteroatoms, or if tricyclic or polycyclic, having 1-9 heteroatoms selected from O, N or S (e.g., carbon atoms and 1-3, 1-6 or 1-9 heteroatoms, respectively, if monocyclic, bicyclic or tricyclic), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by substituents. Examples of heterocyclyls include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl and the like. Heterocyclyls may include multiple fused and bridged rings.Non-limiting examples of fused / bridged heterocyclic groups 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[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[3.2.1]octane, 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 spirocycles (e.g., spirobicycles in which the 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-oxo[1,2-diazaspir ... 1-oxaspiro[2.2]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-oxo-9-azaspiro[5.5]undecane, etc.

[0095] The term "heteroalkyl" refers to an alkyl group as defined above, wherein the one or more backbone atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N (alkyl)-, sulphur or a combination thereof). Heteroalkyl is connected to the remainder of the molecule at the carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group. In some embodiments, the heteroalkyl group comprises 1, 2 or 3 heteroatoms. In some embodiments, the alkyl moiety of the heteroalkyl group is optionally substituted as defined for the alkyl group. Representative heteroalkyl groups include but are not limited to -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2OCH2CH2NH2 or -CH2CH2OCH2CH2OH.

[0096] The term "heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, wherein Rc is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0097] The term "alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group consisting only of carbon and hydrogen, containing no unsaturation and having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. In some embodiments, the connection point between the alkylene chain and the rest of the molecule and the group is through a carbon in the alkylene chain or through any two carbons in the chain. In certain embodiments, the alkylene group comprises 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene group comprises 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene group comprises 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene group comprises 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene group comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in the specification, the alkylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxygen, sulfur, imino, oxime, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)R, -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 (wherein t is 1 or 2), -S(O)tRf (wherein t is 1 or 2), and -S(O)tN(Ra)2 (wherein 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.

[0098] The term "heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl, wherein Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkyl is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkyl is optionally substituted as defined above for the heterocyclyl.

[0099] "Heterocyclylalkoxy" refers to a group bonded 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 group at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy is optionally substituted as defined above for a heterocyclyl.

[0100] The term "amino-alkyl" refers to a radical of the formula: -alkyl-NH2.

[0101] The term "hydroxy-alkyl" refers to a radical of the formula: -alkyl-OH.

[0102] The term "alkoxy" refers to a group bonded through an oxygen atom of the formula -O-alkyl, wherein alkyl is an alkyl chain as defined above.

[0103] The term "alkenyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having 2 to 12 carbon atoms. In certain embodiments, the alkenyl group comprises 2 to 8 carbon atoms. In other embodiments, the alkenyl group comprises 2 to 4 carbon atoms. The alkenyl group is connected to the remainder of the molecule by a single bond, such as vinyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra), -C(O)Ra, -C(O)ORa, -C(O)N(Ra), -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 (wherein t is 1 or 2), -S(O)tRf (wherein t is 1 or 2), and -S(O)tN(Ra)2 (wherein 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.

[0104] 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 5 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π electron system according to the Hückel theory. Ring systems derived from aryl include, but are not limited to, radicals such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (e.g., in "aralkyl") is meant to include aryl groups optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, 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- Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (wherein t is 1 or 2), -Rb-S(O)tORa (wherein t is 1 or 2), -Rb-S(O)tRa (wherein t is 1 or 2), and -Rb-S(O)tN(Ra)2 (wherein t is 1 or 2), where each Rb is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), 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, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0105] 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 alkylene chains. The aryl portion of the aralkyl radical is optionally substituted as described above for aryl radicals.

[0106] The term "aralkenyl" refers to a radical of the formula -Rd-aryl, wherein Rd is an alkenylene chain as defined above. The aryl portion of the aralkenyl radical is optionally substituted as described above for aryl. The alkenylene chain portion of the aralkenyl radical is optionally substituted as defined above for alkenylene.

[0107] The term "carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, and in some embodiments, includes a fused or bridged ring system having 3 to 15 carbon atoms. In certain embodiments, the carbocyclyl comprises 3 to 10 carbon atoms. In other embodiments, the carbocyclyl comprises 5 to 7 carbon atoms. The carbocyclyl is connected to the rest of the molecule by a single bond.

[0108] In some embodiments, carbocyclyl is saturated (i.e., containing only a single C-C bond) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclyl is also referred to as "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, cycloalkyl comprises three to eight carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, cycloalkyl comprises three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, cycloalkyl comprises three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, cycloalkyl comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). Unsaturated carbocyclyl is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyls include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in the specification, the term "carbocyclyl" is intended to include carbocyclyl groups that are optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, oxygen, sulfur, 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, -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)C(O)Ra, -Rb-N(Ra)S(O)tRa (wherein t is 1 or 2), -Rb-S(O)tORa (wherein t is 1 or 2), -Rb-S(O)tRa (wherein t is 1 or 2), and -Rb-S(O)tN(Ra)2 (wherein t is 1 or 2), where 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, and where each of the above substituents is unsubstituted unless otherwise specified.

[0109] The term "carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl, wherein Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0110] As used herein, the term "NOAEL dose" refers to the no-observed-adverse-effect level dose. It represents the exposure level of an organism found experimentally or by observation at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effect of the test regimen.

[0111] As used herein, the term "inflammatory bowel disease (IBD)" refers to inflammation of the gastrointestinal (GI) tract. Long-term inflammation can lead to damage to 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 stools, weight loss, and fatigue.

[0112] As used herein, the term "irritable bowel syndrome (IBS)" refers to a condition that affects the large intestine. Signs and symptoms include cramping, abdominal pain, bloating, flatulence, diarrhea, constipation, or both. Other commonly associated symptoms include bloating and increased gas or mucus in the stool. Symptoms are managed through diet, lifestyle changes, and stress reduction.

[0113] As used herein, the term "primary sclerosing cholangitis (PSC)" refers to a chronic liver disease in which the bile ducts inside and outside the liver become inflamed and scarred and eventually narrow or become blocked. In some cases, bile accumulates in the liver and causes further liver damage. Liver failure may develop 10-15 years after diagnosis, but for some PSC patients, this may take longer. Many PSC patients ultimately require a liver transplant, usually about 10 years after being diagnosed with the disease.

[0114] As used herein, the term "primary biliary cholangitis (PBC)", formerly known as primary biliary cirrhosis, is a chronic liver disease caused by the progressive destruction of bile ducts in the liver (called intrahepatic bile ducts).

[0115] As used herein, the term "alcoholic hepatitis" refers to an inflammatory condition of the liver caused by heavy alcohol consumption over a long period of time.

[0116] As used herein, the term "alcoholic cirrhosis" refers to the advanced stage of liver scarring (fibrosis) caused by various forms of liver disease and disorders, such as hepatitis and chronic alcoholism.

[0117] As used herein, the term "pancreatitis" refers to inflammation of the pancreas. It may be sudden (acute) or ongoing (chronic). The most common causes are alcohol abuse and lumps of solid matter in the gallbladder (gallstones). Pancreatitis caused by excessive drinking is called alcoholic pancreatitis.

[0118] 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 a buildup of fat in the liver. When this buildup leads to inflammation and damage, it is called NASH, which can cause scarring of the liver.

[0119] 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 gluten found in the consumption of wheat, barley, and rye.

[0120] 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 arteries and veins. Blood clots can form in the legs, lungs, and other organs, such as the kidneys and spleen.

[0121] As used herein, the term "Barrett's esophagus" is a disease that develops due to repeated exposure to stomach acid. It is most often diagnosed in people with long-term gastroesophageal reflux disease (GERD). Frequent heartburn and chest pain are symptoms.

[0122] As used herein, the term "postoperative ileus" refers to the prolonged loss of bowel function following surgery (usually abdominal surgery). It is a common postoperative complication whose etiology and pathophysiology are unclear.

[0123] As used herein, the term "atrophic gastritis" refers to a chronic inflammation of the gastric mucosa of the stomach, which leads to the loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissue. As a result, the secretion of essential substances such as hydrochloric acid, pepsin, and intrinsic factor by the stomach is impaired, leading to digestive problems. The most common are vitamin B12 deficiency, which may lead to pernicious anemia; and iron malabsorption, which leads to iron deficiency anemia. It can be caused by persistent infection with Helicobacter pylori or be of autoimmune origin. Patients with autoimmune atrophic gastritis (type A gastritis) are statistically more likely to develop gastric cancer, Hashimoto's thyroiditis, and achlorhydria.

[0124] As used herein, the term "peritonitis" refers to inflammation of the peritoneum (the filamentous membrane that lines the abdominal wall and covers the organs within the abdomen), usually caused by bacterial or fungal infection.

[0125] As used herein, the term "diverticulitis" refers to a condition that occurs when small pouches or sacs form and push outward through weak spots in the colon wall, causing pain and discomfort.

[0126] As used herein, the term "duodenal ulcer" refers to an ulcer or peptic ulcer that develops in the first part of the small intestine (duodenum).

[0127] As used herein, the term "alveolar periostitis" refers to a condition that sometimes occurs after tooth extraction, particularly after traumatic extraction, resulting in a dry appearance of exposed bone in the tooth socket due to the breakdown or loss of a blood clot. It is essentially a focal osteomyelitis without suppuration and is associated with severe pain (dry socket) and a foul odor.

[0128] Range: Throughout this disclosure, various aspects of the invention may be presented in range format. It should be understood that descriptions in range format are merely for convenience and brevity and should not be construed as inflexible limitations on the scope of the invention. Thus, descriptions of ranges should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, descriptions of ranges 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 numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the range.

[0129] The present disclosure provides compounds having formula (I):

[0130] Formula (I)

[0131]

[0132] wherein R1 and R2 are each independently selected from hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m and n are integers each independently having a value of 0, 1, 2, 3 or 4, wherein X1, X2, X3, X4, X5, X6, X7 and X8 are each independently selected from the group consisting of -CH and N;

[0133] wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6), -CO-alkyl and -CO-haloalkyl,

[0134] wherein R4 is each independently one of hydrogen or COY, provided that when X1-X8 is -CH and when R3 is hydrogen, R4 is not hydrogen, except that when X1-X8 is N and / or R1 or R2 is halogen, R4 and R3 may both be hydrogen; or R4 is

[0135]

[0136]

[0137] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0138] In some embodiments, in any of the foregoing 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 halogen. In some embodiments, R4 is COY and Y is a substituted piperidine.

[0139] In some embodiments, the compound has Formula I(a)

[0140]

[0141] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m and n are each independently integers having a value of 0, 1, 2, 3 or 4,

[0142] wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6), -CO-alkyl and -CO-haloalkyl,

[0143] wherein R4 is each independently one of hydrogen or COY, provided that when R3 is hydrogen, R4 is not hydrogen, except that when R1 or R2 is halogen, R4 and R3 may both be hydrogen; or R4 is

[0144]

[0145]

[0146] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0147] In some embodiments, the compound has formula I(b)

[0148]

[0149] wherein R1 is each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m is an integer each independently having a value of 0, 1, 2, 3 or 4,

[0150] wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6) and -CO-alkyl,

[0151] wherein R4 is each independently hydrogen or COY or one of the following:

[0152]

[0153]

[0154] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0155] In some embodiments, the compound is a specific compound selected from the group consisting of compounds 1-25 above.

[0156] Preparation of compounds

[0157] Compounds used in the reactions described herein were prepared using commercially available chemicals and / or from compounds described in the chemical literature.

[0158] In some cases, specific and similar reactants were identified by indexing known chemicals prepared by the Chemical Abstracts service of the American Chemical Society (which is available in most public and university libraries) and by online databases (contact the American Chemical Society in Washington, D.C. for more details). Chemicals that are known but not commercially available in the catalog are prepared by custom chemical synthesis laboratories, many of which provide custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0159] The following general reaction schemes represent methods by which the compounds of the present invention can be synthesized. In addition, specific synthetic routes for compounds 1-6 and 27-28 are described in the experimental examples herein, particularly in Example 1. With the understanding of the following general reaction schemes and the specific synthetic routes provided in Example 1, those skilled in the art can synthesize additional compounds within the scope of this specification, including Formula I, Formula Ia, and Formula Ib, by applying ordinary techniques.

[0160]

[0161] Other forms of compounds

[0162] Labeled compounds

[0163] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, but the fact is that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. In some embodiments, examples of isotopes incorporated into the 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 aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotope-labeled compounds, for example those incorporating radioactive isotopes such as 3H and 14C, can be used for drug and / or substrate tissue distribution assays. Tritiated (i.e. 3H) and carbon-14 (i.e. 14C) isotopes are particularly preferred because they are easy to prepare and detectable. In addition, substitution with heavy isotopes such as deuterium (i.e. 2H) produces certain therapeutic advantages caused by greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, isotope-labeled compounds, their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives are prepared by any suitable method.

[0164] 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.

[0165] Pharmaceutically acceptable salts

[0166] In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0167] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of several 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 disclosed compounds, or by reacting the purified compound in free form with a suitable acid or base separately and isolating the salt thus formed. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0168] For example, compound 6 as a base can be reacted with a suitable acid such as hydrochloric acid to form a chloride salt of compound 6. Other suitable acids that can be used to convert compounds of the present invention, such as compound 6, into pharmaceutically acceptable salts can be found in P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0169] Solvates

[0170] In some embodiments, the compounds described herein exist as solvates. The present disclosure provides methods for treating diseases by administering such solvates. The present disclosure also provides methods for treating diseases by administering such solvates as pharmaceutical compositions.

[0171] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. 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 methods 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 an organic solvent including, but not limited to, dioxane, tetrahydrofuran, or methanol. In some embodiments, the compounds provided herein exist in unsolvated as well as solvated forms. Generally, for the purposes of the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

[0172] Pharmaceutical composition

[0173] 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 selected route of administration. Typical administration is by injection or oral administration. Suitable forms 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.

[0174] Thus, provided herein is a pharmaceutical composition comprising at least one compound described herein, a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof and 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 is not harmful to the recipient (i.e., subject) of the composition.

[0175] 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.

[0176] 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.

[0177] 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, such as contaminating intermediates or by-products produced, for example, during one or more steps of the synthetic methods.

[0178] In some cases, exemplary pharmaceutical compositions are used in the form of pharmaceutical preparations, for example, in solid, semisolid or liquid form, which include one or more disclosed compounds as active ingredients, mixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral application. In some embodiments, the active ingredients are mixed with conventional non-toxic, pharmaceutically acceptable carriers, for example, for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0179] To prepare solid compositions such as tablets, in some cases, the main 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 evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0180] In solid dosage forms (capsules, tablets, pills, dragees, powders, granules, etc.) for oral administration, the subject composition is mixed with one or more known pharmaceutically acceptable carriers. In the case of capsules, tablets and pills, in some embodiments, the composition also comprises a buffer. Similar types of solid compositions are also used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, etc.

[0181] In some cases, tablet is made by compression or molding, optionally with one or more auxiliary ingredients. Use binding agent, lubricant, inert diluent, preservative, disintegrant and / or surfactant or dispersant to prepare compressed tablet. Prepare molded tablet by molding the mixture of the subject composition moistened with inert liquid diluent in a suitable machine. Tablet and other solid dosage forms, such as dragee, capsule, pill and granule, optionally with coating and shell (such as other coatings known to enteric coating and pharmaceutical formulation field) score or preparation.

[0182] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, the liquid dosage form may contain an optional inert diluent commonly used in the art.

[0183] In addition to the subject composition, the suspension optionally contains known suspending agents and mixtures thereof.

[0184] In some embodiments, formulations for rectal or vaginal administration are presented as suppositories, which are 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.

[0185] 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 mixed under sterile conditions with a pharmaceutically acceptable carrier and, in some embodiments, any preservatives, buffers, or propellants desired.

[0186] In some embodiments, ointments, pastes, creams, and gels contain, in addition to the subject compositions, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0187] In some embodiments, powders and sprays contain, in addition to the subject composition, known excipient mixtures of these substances. Sprays also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0188] Alternatively, compositions and compounds disclosed herein are administered by aerosol. This is achieved by preparing aqueous aerosols, liposome preparations or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellants) suspensions can be used. Sonic wave sprayers are used because they minimize the exposure of reagents to shear, and in some embodiments, shearing causes the degradation of the compound contained in the subject composition. Typically, aqueous aerosols are prepared by preparing an aqueous solution or suspension of the subject composition together with a conventional pharmaceutically acceptable carrier and stabilizer. Carrier and stabilizer vary with the requirements of the specific subject composition, but typically include nonionic surfactants. Aerosols are typically prepared by isotonic solutions.

[0189] Pharmaceutical compositions suitable for parenteral administration comprise a combination of the subject compositions with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders for reconstitution 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.

[0190] Also contemplated are enteral pharmaceutical formulations comprising the disclosed compounds and enteric materials and pharmaceutically acceptable carriers or excipients thereof. An enteric material is a polymer that is substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluid at a specific pH. The small intestine is the portion of the gastrointestinal tract (intestines) 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 is insoluble, for example, until the pH is 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.

[0191] In some embodiments, the dosage of a composition comprising at least one compound as described herein varies depending on the condition of the patient (e.g., human), i.e., the stage of the disease, general health, age, and other factors that one skilled in the medical art would use to determine dosage.

[0192] In some cases, pharmaceutical composition is used in a manner suitable for the disease to be treated (or prevention) determined by medical field technicians. Suitable dosage and suitable duration of application and frequency will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of active ingredient and the method of administration. Usually, suitable dosage and treatment regimen provide compositions (for example, improved clinical results, such as more frequent complete or partial relief, or longer disease-free and / or total survival, or the alleviating of symptom severity) in an amount that is enough to provide treatment and / or prevention benefit. Optimal dose is usually determined using experimental models and / or clinical trials. In some embodiments, optimal dose depends on patient's body weight, weight or blood volume.

[0193] Example

[0194] The following examples further illustrate aspects of the present invention. However, they are in no way intended to limit the teachings or disclosures of the invention set forth herein.

[0195] List of abbreviations

[0196] As used above and throughout this disclosure, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings:

[0197] ACN or MeCN acetonitrile

[0198] Acetyl

[0199] BOC or BOC tert-butyl carbamate

[0200] t-Bu tert-butyl

[0201] ℃ degrees Celsius

[0202] DAST-Diethylaminosulfur trifluoride

[0203] DBA or dba-dibenzylideneacetone

[0204] DCE-dichloroethane (ClCH2CH2Cl)

[0205] DCM-dichloromethane (CH2Cl2)

[0206] DIPEA or DIEA-diisopropylethylamine

[0207] DMF-dimethylformamide

[0208] DMSO-dimethyl sulfoxide

[0209] Dppf or dppf-1,1'-bis(diphenylphosphino)ferrocene

[0210] EA or EtOAc-ethyl acetate

[0211] Et-ethyl

[0212] EtOH-ethanol

[0213] g-gram

[0214] h, hr, hrs - hours

[0215] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0216] HPLC-High Performance Liquid Chromatography

[0217] Hz-Hertz

[0218] LAH-lithium aluminum anhydride

[0219] LCMS-Liquid Chromatography Mass Spectrometry

[0220] m / z mass-to-charge ratio

[0221] M-Moore

[0222] Me-methyl

[0223] MeOH-methanol

[0224] mg-milligram

[0225] MHz-megahertz

[0226] μmol-micromole

[0227] μl-microliter

[0228] mL-milliliter

[0229] mmol-millimolar

[0230] MS-Mass Spectrometry

[0231] NMR - Nuclear Magnetic Resonance

[0232] PE-petroleum ether

[0233] Ph-phenyl

[0234] prep-HPLC - Preparative High Pressure Liquid Chromatography

[0235] prep-TLC - preparative thin layer chromatography

[0236] Py-pyridine

[0237] RT - retention time

[0238] TEA-triethylamine

[0239] TFA-trifluoroacetic acid

[0240] THF-Tetrahydrofuran

[0241] TLC-Thin Layer Chromatography

[0242] XPhos-2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0243] Chemical synthesis

[0244] Unless otherwise stated, reagents and solvents obtained from commercial suppliers were used. Anhydrous solvents and oven-dried glassware were used for synthetic transformations that were sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times are approximate and not optimized. Unless otherwise stated, column chromatography and thin layer chromatography (TLC) were performed on silica gel. In some embodiments, in the event of a discrepancy between the reaction scheme and the written procedure, the written procedure should be followed.

[0245] Example 1 - Synthesis of Compounds

[0246] Example 1a - Synthesis of Compounds 5 and 6

[0247] Step 1: Synthesis of methyl 2-((2-aminophenyl)amino)-5-fluorobenzoate

[0248] 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 hours. The progress of the reaction was monitored by TLC (30% ethyl acetate / hexane). 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 / hexane to give methyl 2-((2-aminophenyl)amino)-5-fluorobenzoate as a brown solid (800 mg, 55.67%). LCMS: (M+H + =261.1)

[0249] 1H NMR (400MHz, DMSO): δ8.58(s,1H),7.58(dd,J=9.7,3.0Hz,1H),7.25(td,J=8.8,3.0Hz,1H),7. 00(dd,J=16.4,7.9Hz,2H),6.81(d,J=7.9Hz,1H),6.65–6.51(m,2H),4.92(s,2H),3.87(s,3H).

[0250] Step 2: Synthesis of 2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (Compound 5)

[0251] 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 (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 hexane). 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 obtain 2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one as a brown solid (350 mg, 25%).

[0252] 1 H NMR (400MHz, DMSO): δ10.00 (s, 1H), 7.85 (s, 1H), 7.38 (dd, J=9.6, 3.1Hz, 1H), 7.24 (td, J=8.5, 3.1Hz, 1H), 7.08–6.81 (m, 5H). LCMS: (M+H + =229.1).

[0253] Step 3: 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one: (Compound 6)

[0254] To a stirred solution of 2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (150 mg, 0.657 mmol) in dichloromethane (DCM) (10 mL) was added 4-dimethylaminopyridine (DMAP) (121 mg, 0.986 mmol) and stirred for 5 min, followed by the addition of 2-chloroacetyl chloride (74.2 mg, 0.657 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 ethane). The reaction mixture was cooled to 0 ° C, quenched with aqueous sodium bicarbonate solution, and then extracted 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 afford 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one imidazo[1,2-a]pyridine-6-carboxylate as an off-white solid (120 mg, 59.92%).

[0255] LCMS (M+H + =305.1). 1 H NMR (400MHz, DMSO): δ11.03–10.65(m,1H),8.00–7.61(m,1H),7.65–7.12(m,6H),4.47–3.92(m,2H).

[0256]

[0257] Example 1b - Synthesis of Compound 1

[0258] Synthesis of 2-fluoro-5-(2-(4-methylpiperidin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one

[0259] To a solution of 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-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 h. The progress of the reaction was monitored by TLC (80% ethyl acetate in hexane). The reaction mixture was concentrated under reduced pressure. The crude product was diluted with water, extracted twice with 5% MeOH in DCM, and 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 preparative HPLC using formic acid buffer, concentrated at low temperature, basified with aqueous NaHCO3 solution, extracted with DCM, and the organic layer was dried over Na2SO4, 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%).

[0260] 1 H NMR (400MHz, CD3OD_SPE): δ7.91–6.99(m,7H),3.29–2.99(m,2H),2.92–2.39(m,2H),2.10–1.85(m,2H),1.67–0.98(m,5H),0.90(s,3H).LCMS(M+H + =368.1).

[0261]

[0262] Example 1c - Synthesis of Compound 2

[0263] 2-Fluoro-5-(2-(4-methylpiperazin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one

[0264] To a solution of 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-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 h. 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, the organic matter was washed with brine solution, and concentrated under reduced pressure. The crude product was purified by flash column chromatography and further purified by preparative HPLC using formic acid buffer, concentrated at low temperature, basified with aqueous NaHCO3 solution, extracted with DCM, and the organic layer was dried over Na2SO4, 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%).

[0265] 1 H NMR (400MHz, CD3OD_SPE): δ7.71–7.35(m,5H),7.37–7.15(m,2H),3.16(dt,J=18.7,15.1Hz,2H),2.67–2.26(m,11H).LCMS(M+H + =369.1).

[0266] Example 1d-Synthesis of Compound 3

[0267] 2-Fluoro-5-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one

[0268] To a solution of 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-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 h. 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, the organic matter was washed with brine solution, and concentrated under reduced pressure. The crude product was purified by flash column chromatography and further purified by preparative HPLC using formic acid buffer, concentrated at low temperature, basified with aqueous NaHCO3 solution, extracted with DCM, and the organic layer was dried over Na2SO4, 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%).

[0269] 1 H NMR (400MHz, MeOD): δ7.81–7.15(m,7H),7.17–6.80(m,4H),3.44(dd,J=32.6 ,17.9Hz,0.4H),3.30–3.08(m,2H),3.01(s,4H),2.69–2.28(m,4H).LCMS(M+H + =449.1).

[0270] Example 1e - Synthesis of Compound 4

[0271] Step 1: 5-(2-chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one:

[0272] 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 minutes, and then 2-chloroacetyl chloride (106 mg, 0.952 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC (30% ethyl acetate in hexanes). The reaction mixture was cooled to 0°C, quenched with saturated aqueous sodium bicarbonate solution, and then extracted with DCM. The organics were concentrated under reduced pressure. The crude product was purified by flash column chromatography to 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)

[0273] 1 H NMR (400MHz, T MeOD): δ8.11–7.11(m,8H), 4.36–3.97(m,2H).

[0274]

[0275] 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)

[0276] To a solution of 5-(2-chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-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 h. The reaction progress was monitored by TLC (80% ethyl acetate in hexane). The reaction mixture was concentrated under reduced pressure. The crude product was diluted with 5% MeOH in DCM, the organic matter was washed with brine solution and concentrated under reduced pressure. The crude product was purified by flash column chromatography, and then further purified by preparative HPLC using a formic acid buffer, concentrated at low temperature, basified with aqueous NaHCO3 solution, extracted with DCM, and the organic layer dried over Na2SO4, 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%).

[0277] 1 H NMR (400MHz, MeOD): δ8.01–7.76(m,1H),7.76–7.55(m,2H),7.49(t,J=15.5Hz,2H),7.45–7.20(m,3H),7.14– 6.88(m,4H),3.50–3.35(m,0.8H),3.32–3.11(m,1.6H),2.95(d,J=31.2Hz,4H),2.68–2.22(m,4H).LCMS(M+H + =431.1)

[0278] Example 1f-Synthesis of Compound 27

[0279]

[0280] Step-1: Synthesis of N-(tert-butoxycarbonyl)-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteine ​​methyl ester

[0281] To a stirred solution of (tert-butoxycarbonyl)-L-cysteine ​​methyl ester (0.1 g, 0.425 mmol) in dichloromethane (10 mL) was added triethylamine (64.5 mg, 0.637 mmol) and 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (117 mg, 0.382 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After the starting material was completed, the reaction mixture was diluted with water and 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 N-(tert-butoxycarbonyl)-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteine ​​methyl ester as an off-white solid (150 mg, 70.93% yield).

[0282] 1H-NMR (400MHz, DMSO-d6): δ10.8 (d, J=31.6Hz, 1H), 7.84-7.63 (m, 1H), 7.62-7.48 (m, 3H), 7.47-7.37 (m ,1H),7.33-7.18(m,3H),4.2-4.02(m,1H),3.60(s,3H),3.48-3.28(m,2H),2.92-2.6(m,2H),1.36(s,9H)

[0283] Step-2: Synthesis of S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteine ​​methyl ester

[0284] To a stirred solution of N-(tert-butoxycarbonyl)-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-5-yl)-2-oxoethyl)-L-cysteine ​​methyl ester (110 mg, 0.218 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.5 mL) at 0 ° C, and the reaction mixture was stirred at 0-room temperature for 3 h. The reaction progress was monitored by TLC. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, co-distilled with DCM, and triturated with ether to obtain S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-5-yl)-2-oxoethyl)-L-cysteine ​​methyl ester (80 mg, crude product) as an off-white solid. The crude compound was carried out to the next step as it was.

[0285] 1H-NMR (400MHz, DMSO-d6): δ10.82(d,J=32.4Hz,1H),8.44(brs,3H),7.88-7.67(m,1H),7.62-7.46(m,3H),7. 45-7.38(m,1H),7.37-7.2(m,3H),4.29(d,J=6Hz,1H),3.8-3.52(m,4H),3.33-3.22(m,1H),3.15-2.85(m,2H)

[0286] LCMS: m / z (m+H, 404.32, 426) (Na adduct)

[0287] 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

[0288] To a stirred solution of S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteine ​​methyl ester (120 mg, 0.297 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added lithium hydroxide (14.2 mg, 0.595 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by preparative 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 ​​as a white solid (32 mg, 27.58% yield).

[0289] 1H-NMR (400MHz, D2O): δ7.7-7.58(m,1H),7.57-7.23(m,5H),7.28(d,J=7.6Hz,1H),3.9-3.78(m,1H),3.6-3.4(m,2H),3.1-2.8(m,2H)

[0290] LCMS: m / z (m+H, 390.44)

[0291] Example 1g-Synthesis of Compound 28

[0292]

[0293] Step-1: Synthesis of acetyl-L-cysteine ​​methyl ester

[0294] At 0 ℃, triethylamine (3.6mL, 25.63mmol) and acetic anhydride (1.3g, 12.817mmol) were added dropwise to a stirred solution of hydrogen chloride-(R)-2-amino-3-mercaptopropionic acid methyl ester (1 / 1) (2g, 11.7mmol) in dichloromethane (50mL). The reaction mixture was stirred at room temperature for 3h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water (100mL) and extracted with DCM (3×100mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by combi-flash chromatography and eluted with (0-100% DCM in hexane) to give acetyl-L-cysteine ​​methyl ester (0.3g, yield -11.45%) as a white solid.

[0295] 1H-NMR (400MHz, CDCL3): δ6.36 (s, 1H), 4.95-4.87 (m, 1H), 3.8 (s, 3H), 3.03-2.99 (m, 2H), 2.07 (s, 3H), 1.32 (t, J = 8.8Hz, 1H).

[0296] Step-2: 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 ​​methyl ester

[0297] To a stirred solution of acetyl-L-cysteine ​​methyl ester (64 mg, 0.361 mmol) in dichloromethane (5 mL) was added triethylamine (66 mg, 0.657 mmol) at 0°C, followed by 5-(2-chloroacetyl)-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (100 mg, 0.328 mmol). 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, the mixture 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 combi-flash column chromatography eluting with (0-25% EtOAc in hexanes) to afford N-acetyl-S-(2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl)-L-cysteine ​​methyl ester (130 mg, 89% yield) as an off-white solid.

[0298] 1H-NMR (400MHz, DMSO-d6): δ10.81(d,1H),8.4-8.25(m,1H),7.85-7.64(m,1H),7.6-7.49(m,3H) ,7.48-7.18(m,3H),4.5-4.3(m,1H),3.61(s,3H),3.52-3.2(m,2H),3.0-2.7(m,2H),1.82(s,3H)

[0299] 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

[0300] To a stirred solution 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 ​​methyl ester (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-room temperature 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 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by preparative 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.

[0301] 1H-NMR (400MHz, DMSO-d6): δ12.79(brs,1H),10.8(d,1H),8.24-8.1(m,1H),7.9-7.6(m,1H),7. 6-7.3(m,4H),7.29-7.15(m,2H),4.42-4.2(m,1H),3.5-3.2(m,2H),3-2.62(m,2H),1.81(s,3H)

[0302] LCMS: (m / z, m+H, 432.1)

[0303] The synthesis of new compounds with modified core structures can be achieved using two different strategies. First, compounds 5 / 6 are chemically modified by substitution / reaction with suitable reagents to introduce the desired modifications into the core structure. These modifications include functional group modifications and ring substitutions. Secondly, commercially available key starting materials that already have the substitutions or functional groups necessary to synthesize the core structure are used for synthesis. The selection of reagents, reaction conditions, and protecting groups plays a crucial role in the successful implementation of these strategies. Side chains can be incorporated into the modified core structure using the same synthetic scheme disclosed for compound 6.

[0304] Example 2 - Inhibition of IL-1β production in vitro

[0305] 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 in vitro. The procedures detailed herein can be used to test all compounds of the present disclosure.

[0306] Human mononuclear THP-1 cells were treated with phorbol 12-myristate 13 acetate (PMA) (100 nM) overnight to differentiate monocytes into macrophages. Then, after standing for 24 hours, the differentiated cells were incubated with test compounds at concentrations of 0.01, 0.1, 1, 10, 30 and 50 mM for 12 hours. The cells were then washed once with PBS and triggered with E. coli LPS (0.1 μg / ml) for 4 hours, followed by stimulation with ATP (5 μM) for another 30 minutes. The cell culture supernatant was then collected and the OD value of IL-1β levels was measured by ELISA. A standard curve (OD to concentration) of IL-1β was also drawn and used to determine the IL-1β concentration of the OD value. The percentage inhibition of IL-1β was calculated using the following formula:

[0307]

[0308] The percentage inhibition of IL-1β at different compound concentrations was plotted in a sigmoidal curve, and IC50 values ​​were interpolated in Graphpad Prism. Cell death was assessed by propidium iodide staining and OD was measured at 490 nm. Cell viability was estimated relative to DMSO control. Figure 3 The IC50 value of a representative compound, Compound 6, is shown, which had 99% cell viability at 10 μM, indicating that it was non-toxic to cells within the concentration range tested.

[0309] Example 3 - Inhibition of IL-1β production in vivo

[0310] 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 vivo conditions. The procedures detailed herein can be used to test all compounds of the present disclosure. The examples were tested in vivo using an LPS+ATP-induced inflammasome activation model in 8-10 week old male Balb / c mice.

[0311] 8-10 week old male Balb / c mice were challenged with 200 μg / kg (0.2 μg / g) LPS by intraperitoneal (ip) injection at t=0 hours, followed by an intraperitoneal injection of 5 mM ATP solution at t=2 hours (2 hours after LPS challenge). Compounds of the present disclosure being tested for inhibitory activity (e.g., Compound 6) were administered intraperitoneally and orally at -1 hour. As shown below, different doses of compounds of the present disclosure were administered to mice after LPS induction.

[0312] MCC950, a specific small molecule inhibitor of NLRP3 inflammasome, was used as a positive control to be able to compare the inhibitory activity of the compounds disclosed herein with known inhibitors. 2.5 hours after LPS induction (or 0.5 hours after ATP administration), blood was collected in heparinized blood collection tubes by retroorbital bleeding. The blood was centrifuged at 10,000 rpm for 5 minutes in a refrigerated centrifuge to obtain plasma. The separated plasma was used to evaluate cytokines by ELISA. A standard curve of IL-1β (OD versus concentration) was also drawn and used to determine the IL-1β concentration of the OD value. The percentage inhibition of IL-1β was calculated using the following formula:

[0313]

[0314] The following groups were evaluated and observed for IL-1β suppression:

[0315] Group dose Route of administration N % IL-1β inhibition Sham operation control - - 6 - LPS control - - 6 - LPS+ATP - - 6 - MCC950 20 mg / kg intraperitoneally 6 95％ Compound 6 1 mg / kg intraperitoneally 6 52％ Compound 6 10 mg / kg intraperitoneally 6 79％ Compound 6 10 mg / kg oral 6 46％

[0316] Figure 4 Compound 6 demonstrated a dose-dependent reduction in IL-β in an in vivo mouse model. Notably, the compound exhibited 79% inhibition of IL-1β at 10 mg / kg intraperitoneal dose and 46% inhibition of IL-1β at 10 mg / kg oral dose. MCC950 was used as a tool compound in this assay.

[0317] Therefore, the compounds of the present disclosure showed significant inhibition of IL-1β production in the LPS+ATP-induced inflammasome activation mouse model.

[0318] Example 4 - Analysis of Absorption, Distribution, Metabolism and Excretion (ADME) and Pharmacokinetic (PK) Parameters

[0319] ADME describes the absorption, distribution, metabolism, and excretion of a drug in the body. The following examples describe methods for evaluating ADME parameters of the disclosed compounds.

[0320] Solubility analysis

[0321] 7 horizontal calibration standards (i.e. 1, 5, 10, 50, 100, 200 and 300 μM) of the test compound were prepared from the 20mM primary stock solution in DMSO. 198 μL PBS (pH-7.4) aliquots were distributed in duplicate wells of a multi-sieve solubility filter plate. Subsequently, 2 μL test compound solutions from the 20mM primary stock solution were added to give a final concentration of 200 μM, the cover plate was vibrated at 150 rpm for 90 minutes. At the end of 90 minutes, the sample was filtered using the MultiScreen HTS vacuum manifold assembly, and the filtrate was collected in a receiving plate. 150 μL filtrate aliquots from the above-mentioned 96-well receptor plate were transferred to HPLC vials and analyzed by HPLC-PDA. Solubility was determined by comparing the absorbance of the test / reference compound with the corresponding DMSO calibration curve. The solubility of compound 6 in phosphate buffered saline (pH 7.4) was tested by kinetic method. The compound was highly soluble with a solubility of >200 μM.

[0322] Metabolic stability assays in mouse, rat, and human liver microsomes

[0323] The test was performed in duplicate with a final test concentration of 1 μM. The incubation was carried out for 45 minutes with intermediate time points of 0, 5, 15 and 30 minutes. Verapamil was used as the reference standard for the experiment. The concentration of verapamil was 1 μM. For the microsomal stability experiment, the vial containing the microsomes was thawed in an ice bath. 33 μL of microsomes (20 mg / mL) was suspended in 1165.7 μL of 100 mM potassium phosphate buffer (pH 7.4) in a propylene tube labeled as incubation mixture. The control and test compounds will have a similar set of incubation mixture tubes. 1.1 μL of compound 6 or verapamil (1 mM) was added to the above incubation mixture to obtain a working concentration of 1.1 μM. 180 μL aliquots from the incubation mixture were transferred to a propylene tube labeled T 对照 、T0、T5、T 15 、T 30 and T 45 of 6 test tubes.

[0324] All tubes were pre-incubated at 37±1°C in a shaking water bath for 5 minutes. NADPH solution (10 mM) tubes were similarly pre-incubated under similar conditions. After pre-incubation, the tubes were heated to T0, T5, T 15 、T 30 and T 45 Add 20 μL of NADPH solution (10 mM) to the tube and 对照20 μ L buffer was added to the tube to make the final concentration reach 1 μ M respectively. Immediately, T0 was quenched with 200 μ L quenching solution containing warfarin as internal standard (IS). Similarly, at the end of the incubation period (5, 15, 30 and 45 minutes) of each test tube, 200 μ L quenching solution containing warfarin as internal standard (IS) was added to each test tube to terminate the reaction. The obtained sample was centrifuged at 3220 g (relative centrifugal force) for 20 minutes. The supernatant (200 μ L) from each reaction tube was taken for LC-MS / MS analysis.

[0325] The calculation is as follows:

[0326] Remaining % = 100 x (PAR at designated incubation time / PAR at T0)

[0327] Elimination rate constant (k) = (- gradient)

[0328] Half-life (t1 / 2) = 0.693 / k

[0329] V (μL / mg) = incubation volume (μL) / protein in incubation (mg)

[0330] Microsomal intrinsic clearance (mCLint) (μL / min / mg protein) = (V*0.693) / t1 / 2

[0331] Where PAR is the peak area ratio of the analyte to the internal standard (IS)

[0332] The stability of compound 6 in mouse, rat and human liver microsomes when incubated with reference standard verapamil is shown in the following table:

[0333]

[0334] The reference standard verapamil showed extensive metabolism by liver microsomes, well within the mCLint acceptance criteria (human: <8.60 low and >47.0 high, rat: 13.2 low and >71.9 high, mouse: <8.80 low and >48.0 high). Tested Compounds Compound 6 showed moderate to high stability among the tested materials.

[0335] Metabolic stability determination of human liver microsomes in the presence of specific cytochrome P450 inhibitors

[0336] Experiments 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. CYP-specific reference standards and inhibitors were used in this experiment. The test concentration for substrates was 1 μM, and for inhibitors was 20 μM.

[0337] The following substrates and inhibitors were used:

[0338] CYPs substrate inhibitors 3A4 Midazolam Ketoconazole 2D6 Butofurol Quinidine 2C9 Diclofenac Sulfadiazole 2C19 Omeprazole Nootkatone 1A2 Phenacetin Furanophylline

[0339] For the microsome stability experiment, the vial containing the microsomes was 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 as incubation mixture. The control and test compounds will have a similar set of incubation mixture tubes. 1.1 μL of a compound of the present disclosure, such as compound 6 (1 mM), was added to the above-mentioned incubation mixture to obtain a working concentration of 1.1 μM, respectively. Similarly, 1.1 μL of compound 6 (1 mM) and inhibitor (20 mM) were added to the second set of above-mentioned incubation mixtures to obtain working concentrations of 1.1 μM and 20 μM, respectively. 180 μL aliquots were transferred from the corresponding incubation mixtures to a tube labeled T 对照 、T0、T5、T 15 、T 30 and T 45 of 6 test tubes.

[0340] All tubes were pre-incubated at 37±1°C in a shaking water bath for 5 minutes. NADPH solution (10 mM) tubes were similarly pre-incubated under similar conditions. After pre-incubation, the tubes were heated to T0, T5, T 15 、T 30 and T 45 Add 20 μL of NADPH solution (10 mM) to the tube and 对照 20 μ L buffer was added to the tube to reach a final concentration of 1 μ M. Immediately, T0 was quenched with 200 μ L quenching solution containing warfarin as an internal standard (IS). Similarly, at the end of the incubation period (5, 15, 30, and 45 minutes) of each test tube, 200 μ L quenching solution containing warfarin as an internal standard (IS) was added to each test tube to terminate the reaction. The resulting sample was centrifuged at 3220 g for 20 minutes. The supernatant (200 μ L) from each reaction tube was taken and analyzed by LC-MS / MS. Calculation was performed as described in the previous section.

[0341] The stability of compound 6 when incubated with CYP-specific substrates and inhibitors in human liver microsomes is shown in the following table:

[0342]

[0343]

[0344] Compound 6 exhibited moderate to high stability in human liver microsomes, as shown in the previous section. Experiments were conducted in human liver microsomes targeting five different CYP isoforms: CYP 3A4, 2D6, 2C9, 2C19, and IA2. Compound 6 showed approximately 35% degradation when incubated in human liver microsomes. Even when co-incubated with a specific CYP inhibitor, the degradation of Compound 6 did not change significantly. Even in the presence of a specific CYP inhibitor, the degradation of Compound 6 was between 40-45%, indicating that more than one CYP is involved in the degradation of Compound 6.

[0345] Example 5 - Analysis of plasma protein binding, permeability and administration mode

[0346] Plasma protein binding test

[0347] The movement of compounds of the present disclosure, such as Compound 6, from mouse, rat, and human plasma through the membrane toward buffer (12 kDa cutoff) was tested by the equilibrium dialyzer method at a concentration of 3 μM at 37° C. for 4.5 hours with shaking. Warfarin and naltrexone were used as positive controls, and the % bound, fraction unbound (fu), and percent recovery were calculated.

[0348]

[0349] Permeability determination

[0350] The permeability of compounds of the present disclosure (e.g., Compound 6) from the apical to the basal direction and vice versa was determined by measuring a concentration of 5 μM for 60 minutes through Madin-Darby canine kidney (MDCK) cell monolayers transfected with MDR1. Digoxin was used as a reference and Lucifer Yellow was used as an integrity marker. The concentration of Compound 6 was determined by LC-MS / MS. Papp, efflux ratio, and recovery percentage were calculated. The results of the permeability assay are shown in the table below.

[0351] Based on the above results, compound 6 is a highly permeable compound (AB permeability is 26×10 -6 cm / sec) and is not an efflux substrate (ER<2).

[0352] Oral and intravenous pharmacokinetics in rats

[0353] Plasma concentration versus time curves and key pharmacokinetic parameters, such as AUC, were determined in rats at 0.25, 0.5, 1, 2, 4, 6, 10, and 24 hours after oral administration of 10 mg / kg (oral) and 2 mg / kg (intravenous), and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 10, and 24 hours after intravenous treatment. 0-t , AUC 0-∞ 、C max、T max , CL, Vd, t 1 / 2 and F.

[0354] Dose escalation for determination of the maximum tolerated dose (MTD) in rats

[0355] The MTD study was conducted in 8-9 week old female Sprague Dawley rats with oral administration of four ascending doses. The rats were analyzed for weight loss, the appearance of any clinical signs, pathological symptoms or mortality. The plasma concentration-time relationship and key pharmacokinetic parameters (if applicable) (AUC) were determined 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).

[0356] Example 6 - Toxicology Assays in Rats

[0357] A preliminary 4 / 14 day repeated dose escalation toxicity study of compounds of the present disclosure (e.g., Compound 6) was performed in 6-8 week old Sprague Dawley rats (male / female) at the following doses. General parameters such as mortality, weight change, clinical signs, urinalysis, hematology, blood biochemistry, gross organ histopathology, and no observed side effect level (NOAEL dose) were monitored. The following doses were tested to determine the optimal dose for safety and efficacy.

[0358] Group dose Route of administration N Sham operation control - - 6 Compound 6 25 mg / kg oral 6 Compound 6 50 mg / kg oral 6 Compound 6 100mg / kg oral 6 Compound 6 300mg / kg oral 6 Compound 6 800mg / kg oral 6

[0359] Evaluate the following readings:

[0360]

[0361] The same experiment was then repeated following the same protocol as above for a 28-day GLP toxicity study.

[0362] Example 7 - Treatment of Primary Sclerosing Cholangitis

[0363] Primary sclerosing cholangitis (PSC) is a chronic liver disease in which bile ducts within and outside the liver become inflamed, scarred, and eventually narrowed or blocked. In PSC, inflammation leads to scarring within the bile ducts. This scarring hardens and narrows the ducts, gradually causing severe liver damage. Most people with PSC also have inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0364] Mdr2 knockout mice are used as an animal model for primary sclerosing cholangitis. Male FVB / NJ WT and Mdr2 knockout mice aged 9-11 weeks were randomly divided into different groups as shown. Starting from 10 to 12 weeks of age, compounds of the present disclosure, such as Compound 6, were administered intraperitoneally or orally daily. At 12 weeks of age, mice were sacrificed and analyzed for liver and serum bile acid accumulation, liver fibrosis, pro-inflammatory and pro-fibrotic markers. The following doses and routes of administration were tested:

[0365] Group dose Route of administration N Sham operation control - - 6 Pathological control - - 6 Compound 6 1 mg / kg intraperitoneally 6 Compound 6 10 mg / kg intraperitoneally 6 Compound 6 30 mg / kg intraperitoneally 6 Compound 6 10 mg / kg oral 6 Compound 6 30 mg / kg oral 6

[0366] Example 8 - Treatment of Arthritis

[0367] 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 causes the breakdown of cartilage that covers the ends of bones that form the joints. Rheumatoid arthritis is a disease in which the immune system attacks the joints, starting with the lining of the joints. Monoclonal antibody-induced arthritis models (mAb-induced RA, AIA, or CAIA) are ideal models for rapidly screening and evaluating anti-inflammatory therapeutics.

[0368] The ability of compounds of the present disclosure, such as Compound 6, to treat arthritis was evaluated using a monoclonal antibody-induced arthritis model. Male Balb / c mice aged 8-10 weeks were used in the assay. A mixture of 5 monoclonal antibodies against type II collagen (1.5 mg) was injected intraperitoneally (IP) into the mice. On day 3, 50 μg of lipopolysaccharide (LPS from E. coli strain 055B5; in sterile saline) was injected IP.

[0369] Group dose Route of administration N Sham operation control - - 6 Pathological control - - 6 Compound 6 1 mg / kg intraperitoneally 6 Compound 6 10 mg / kg intraperitoneally 6 Compound 6 30 mg / kg intraperitoneally 6 Compound 6 10 mg / kg oral 6 Compound 6 30 mg / kg oral 6

[0370] Compound 6 will be administered at the following doses from day 2 to day 10. The compound will be administered via intraperitoneal and oral routes. Paw thickness, paw weight, clinical scores, joint cytokine profiles, and histopathology will be assessed to determine if these parameters improve after compound administration.

[0371] Additional Implementations

[0372] 1. A compound of formula (I)

[0373]

[0374] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m and n are each independently integers having a value of 0, 1, 2, 3 or 4, wherein X1, X2, X3, X4, X5, X6, X7 and X8 are each independently selected from the group consisting of -CH and N;

[0375] wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6), -CO-alkyl and -CO-haloalkyl,

[0376] wherein R4 is each independently one of hydrogen or COY, provided that when X1-X8 is -CH and when R3 is hydrogen, R4 is not hydrogen, except that when X1-X8 is N and / or R1 or R2 is halogen, R4 and R3 may both be hydrogen; or R4 is

[0377]

[0378]

[0379] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0380] 2. The compound according to innovation 1, wherein R4 is not hydrogen, m is 0 and n is 1.

[0381] 3. The compound according to Innovation 2, wherein R4 is COY, and Y is a substituted piperazine.

[0382] 4. The compound according to Innovation 2, wherein R4 is COY and Y is a haloalkyl group.

[0383] 5. The compound according to Innovation 1, wherein R4 is hydrogen, m is 0, n is 1 and R2 is halogen.

[0384] 6. The compound according to Innovation 2, wherein R4 is COY, and Y is a substituted piperidine.

[0385] 7. A compound selected from the group consisting of:

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394] 8. The compound according to any one of Innovations 1-7, wherein the compound has an IC50 value of about 2 μM.

[0395] 9. The compound according to any one of Innovations 1 to 8, wherein the compound is capable of reducing the expression of IL-1β by at least 50%.

[0396] 10. The compound according to any one of Innovations 1-9, wherein the compound is capable of treating inflammatory diseases.

[0397] 11. A method for treating an inflammatory disease, comprising the step of administering the compound according to any one of Inventions 1 to 10, thereby treating the disease.

[0398] 12. The method according to 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.

[0399] 13. A compound of formula I(a)

[0400]

[0401] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl (C1-C6), trihaloalkyl (C1-C6), haloalkoxy, amino, and C1-C6-alkyl-amino;

[0402] wherein m and n are integers each independently having a value of 0, 1, 2, 3 or 4,

[0403] wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6) and -CO-alkyl,

[0404] wherein R4 is each independently one of hydrogen or COY, provided that when R3 is hydrogen, R4 is not hydrogen, except that when R1 or R2 is halogen, R4 and R3 may both be hydrogen; or R4 is

[0405]

[0406]

[0407] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0408] 14. A compound of formula I(b)

[0409]

[0410] wherein R1 is each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m is an integer each independently having a value of 0, 1, 2, 3 or 4,

[0411] wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6) and -CO-alkyl,

[0412] wherein R4 is independently one of hydrogen or COY, or

[0413]

[0414]

[0415] wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

[0416] 15. The compound according to any one of innovations 13 or 14, wherein the compound is capable of reducing the expression of IL-1β by at least 50%.

[0417] Other Implementations

[0418] While specific embodiments of the subject matter have been discussed, the above description is illustrative rather than restrictive. Many variations will become apparent to those skilled in the art upon reading this specification and the following claims. The full scope of the invention should be determined by reference to the full scope of the claims and their equivalents and the description, as well as such variations.

[0419] The following are exemplary claims directed to the above-described subject matter and should not be construed as limiting the invention; applicants reserve the right to assert claims to any disclosed subject matter.

Claims

1. A compound of formula (I) wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m and n are each independently integers having a value of 0, 1, 2, 3 or 4, wherein X1, X2, X3, X4, X5, X6, X7 and X8 are each independently selected from the group consisting of -CH and N; wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6), -CO-alkyl and -CO-haloalkyl, wherein R4 is each independently one of hydrogen or COY, provided that when X1-X8 is -CH and when R3 is hydrogen, R4 is not hydrogen, except that when X1-X8 is N and / or R1 or R2 is halogen, R4 and R3 may both be hydrogen; or R4 is wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono-substituted or poly-substituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

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

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

4. The compound according to claim 2, wherein R4 is COY, and Y is a haloalkyl group.

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

6. The compound of claim 2, wherein R4 is COY and Y is a substituted piperidine.

7. A compound selected from the group consisting of:

8. The compound of claim 1, wherein the compound has an IC50 value of about 2 μM.

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

10. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

11. A compound of formula I(a) wherein R1 and R2 are each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m and n are each independently integers having a value of 0, 1, 2, 3 or 4, wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6) and -CO-alkyl, wherein each R4 is independently one of hydrogen or COY, provided that when R3 is hydrogen, R4 is not hydrogen, except that when R1 or R2 is halogen, R4 and R3 may both be hydrogen; or wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

12. A compound of formula I(b) wherein R1 is each independently selected from the group consisting of hydrogen, -CO-alkyl, hydroxy, halogen, haloalkyl(C1-C6), trihaloalkyl(C1-C6), haloalkoxy, amino, C1-C6-alkyl-amino; wherein m is an integer each independently having a value of 0, 1, 2, 3 or 4, wherein R3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, trihaloalkyl (C1-C6) and -CO-alkyl, wherein R4 is each independently hydrogen or COY or one of the following: wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

13. A compound of formula I(c) wherein R1 is hydrogen and m is 1, wherein R3 is hydrogen, and wherein R4 is independently one of hydrogen or COY, or wherein each Y is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cyclo-(halo)-alkyl, and wherein the alkyl or cycloalkyl group is optionally substituted with a five-membered or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the five-membered or six-membered ring is optionally mono- or polysubstituted with C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 aminoalkyl, C1-C6 aminoalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with halogen, amino, carboxyl or alkoxy.

14. A compound selected from the group consisting of: 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-chloroacetyl)-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-trifluoropropionyl)-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)-1,1-dapoxetine]-1 1,4]diazepin-11-one, 5-[(dimethylamino)acetyl]-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 5-[(aziridin-1-yl)acetyl]-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 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 ][1,4]diazepin-11-one, 2-fluoro-5-[(E)-2-fluorovinyl]-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-[(Z)-2-fluorovinyl]-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-one4]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]diazepin-5-carboxylic acid, 2-fluoro-5-(morpholine-4-carbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 2-fluoro-5-(4-methylpiperazine-1-carbonyl)-5,10-dihydro 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, 2-chloro-1-(2-fluoro-11-hydroxy-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethane-1-one, 2-amino-3-{[2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)methyl]- )-2-oxoethyl]thiol}propanoic acid, 2-acetylamino-3-{[2-(2-fluoro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)-2-oxoethyl]thiol}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-trihydroxytetrahydro-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-trifluoropropane-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-chloropropionyl)-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-trifluorobutyryl)-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]diazepine-11-one, 11-(chloroacetyl)-3-fluoro-6,11-dihydro-5H-5λ6-dibenzo[c,f][1,2]thiazepine-5,5-dione, 11-(3-chloropropionyl)-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-butyryl-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]diazepine-5-yl]propan-1-one, 2-fluoro-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]diazepin, 5-(2-chloroethyl)-2-fluoro-11-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin, 2-fluoro-5-(2,2,2-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]diazepine-11-imine, 2,11,11-trifluoro-5-(2,2,2-trifluoroethanesulfonyl)-10,11-dihydro-5 H-dibenzo[b,e][1,4]diazepine, 3,3,3-trifluoro-1-(2-fluoro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-5-yl)propan-1-one, 3,3,3-trifluoro-1-(2-fluoro-11-imino-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-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-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl)ethane-1-one, 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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