Inhibitors of interleukin-1 receptor-associated kinases 1 and 4

Abstract

The present disclosure provides compounds that are inhibitors of interleukin-1 receptor-associated kinases 1 and 4 (IRAK1 and IRAK4), and their use in the treatment of medical disorders such as autoimmune disorders, cancer, and pain disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 055,970, filed June 24, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to compounds for the treatment of medical disorders, more particularly to compounds that are inhibitors of interleukin-1 receptor-associated kinases 1 and 4 (IRAK1 and IRAK4), and uses thereof. [Background technology]

[0003] Interleukin receptor-associated kinase 4 (IRAK4) is an essential functional member of the IRAK family, an intracellular serine-threonine kinase consisting of IRAK1, IRAK2, IRAK3, and IRAK4 (see S. Li et al., PNAS, 99 (2002), p. 5567). IRAK4 is a downstream signaling mediator of the proinflammatory IL-1 family of receptors and pathogen-sensing and innate immune signaling Toll-like receptors (TLRs). TLRs are activated by endogenous pathogens, which are associated with necrotic cell death and tissue damage, key features of chronic inflammatory processes. Aberrant expression of IRAK4 contributes to chronic inflammatory diseases such as rheumatoid arthritis and lupus. Aberrant signaling of the IRAK4 pathway, due to activating mutations in the MyD88 adaptor protein, has also been implicated in malignancies. Due to its proximity to immune signaling receptors (TLRs and IL-1R), therapeutic targeting of IRAK4 has generated significant interest for the regulation of autoimmune and inflammatory diseases. Therapeutics targeting IRAK4 have also been suggested to be useful in controlling high-risk malignancies such as pancreatic cancer (D. Zhang et al. Clin. Canc. Res. (2016): doi:10.1158 / 1078-0432. CCR-16-1121), colitis-induced tumorigenesis and chemoresistance in colorectal cancer (Q. Li et al. JCI Insight 4(19), (2019), e130867).

[0004] According to the National Institutes of Health (NIH), 23.5 million Americans (more than 7% of the population) suffer from various forms of autoimmune diseases, and this rate is on the rise (see NIH Autoimmune Diseases Coordinating Committee: Autoimmune Diseases Research Plan, March 2005). In one aspect, autoimmune diseases can lead to the production of antibodies that attach to the body's own cells, tissues, and organs instead of fighting infection. Autoimmune diseases can occur almost anywhere in the body, and some can affect multiple sites. Autoimmune diseases are also characterized by inadequate treatment and significant unmet medical needs. Similarly, more than 1.5 million new cancer cases were diagnosed in 2012, many of which are directly or indirectly caused by abnormalities in IRAK4 signaling. There is a clear need for the development of new therapeutic approaches targeting the IRAK family, particularly IRAK1 and IRAK4, for the treatment of immune disorders and malignancies. Summary of the Invention

[0005] The present disclosure provides compounds that are inhibitors of interleukin receptor-associated kinases 1 and 4 (IRAK1 and IRAK4), and methods for treating disorders associated with aberrant expression or signaling of IRAK1 and / or IRAK4 using the compounds described herein.

[0006] Thus, in one aspect, a compound of formula I: [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided, wherein all variables are further defined herein.

[0007] Also provided are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0008] In another aspect, a method for treating a medical disorder in a subject associated with abnormal expression or signaling of IRAK1 and / or IRAK4, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0009] In some embodiments, the medical disorder comprises cancer. In some embodiments, the medical disorder comprises an autoimmune disorder. In another aspect, the medical disorder comprises a pain disorder, e.g., neuropathic pain or nociceptive pain.

[0010] The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0011] [Figure 1A] 1 shows the synthesis scheme and chemical structure of UR241-1. [Figure 1B] 1 shows the in silico predicted interaction between UR241-2 and IRAK-1. [Figure 1C] 1 shows the in silico predicted interaction between UR241-2 and IRAK-4. [Figure 1D] 1 shows that UR241-2 dose-dependently inhibited IL1b-induced NF-kB activity in the human leukemia THP-1 reporter cell line. [Figure 1E] UR241-2 inhibited IL1b signaling events in THP-1 cells at 10 and 30 minutes [hIL-1β 10 ng / mL, UR241-2 4 μM, WB 30 μg / lane]. [Figure 1F]Figure 1 shows UR241-2 (4 uM) inhibition with and without MCC950 (100 nM) of colony forming activity in methylcellulose cultures of murine MLL-AF9 leukemia. [Figure 2A] The effects of IRAK-1 and -4 inhibitors in the THP-1 NF-kB assay are shown. THP-1 cells (1e4 cells / 0.1 mL / well) seeded in a 96-well white plate were treated with 0.4% vehicle (DMS), 10 ng / mL hIL-1β, and 20 μM IKK2 inhibitor. Figure 2A: UR241-1. Figure 2B: PF06650833. Figures C and D: UR241-2 batches 1 and 3 (B1, B3). Cells were pretreated with drug for 30 minutes and then treated with hIL-1β for an additional 6 hours. [Figure 2B] (as above) [Figure 2C] (as above) [Figure 2D] (as above) [Figure 3] This figure shows the effect of UR241-1 and UR241-2, representative compounds disclosed herein, on MAP kinase expression in THP-1 cells. Whole cell lysates of THP-1 cells were treated with vehicle, hIL-1B (10 ng / mL), UR241-1 (10 μM), or UR241-2 (4 μM) for 10 and 30 minutes. 30 μg of protein was electrophoresed and probed for phospho- / native p65, phospho-p38, pAKT, and GAPDH. [Figure 4A] The effects of MCC950 (control), UR241-1, and UR241-2 on the in vitro colony-forming ability of THP-1 cells are shown. MCC-950 (Figure 4A0), UR241-1 (Figure 4B), and UR241-2 (Figure 4C) dose-dependently suppressed colony formation by THP-1 cells. [Figure 4B] (as above) [Figure 4C] (as above) [Figure 5A]Figure 5 shows the relative inhibition of NF-kB reporter activity in stably transfected THP-1 cells by treatment with UR241-1 (Figure 5A), PF06650833 (Figure 5B), UR241-2, batch 1 (Figure 5C), and UR241-2, batch 3 (Figure 5D). [Figure 5B] (as above) [Figure 5C] (as above) [Figure 5D] (as above) [Figure 6A] The effects of UR241-1 and UR241-2 on the in vitro colony-forming ability of MDS-L cells are shown in Fig. 6A. UR241-1 and (Fig. 6B) UR241-2 dose-dependently suppressed colony formation by MDS-L cells. [Figure 6B] (as above) [Figure 7A] 7A, 7B, and 7C show that treatment with UR241-2 (FIG. 7A), PF-06650833 (FIG. 7B, control), and MCC950 (FIG. 7C, control) inhibited colony formation of MDS-L cells in vitro. [Figure 7B] (as above) [Figure 7C] (as above) [Figure 8A] Figure 8 shows the inhibition of NF-kB reporter activity in PANC-1 pancreatic cancer cells by UR241-1 (Figure 8A), UR241-2, batch 1 (Figure 8B), UR241-2, batch 2 (Figure 8C), and UR241-2, batch 3 (Figure 8D). [Figure 8B] (as above) [Figure 8C] (as above) [Figure 8D] (as above)

[0012] Like reference symbols in the various drawings indicate like elements. DETAILED DESCRIPTION OF THE INVENTION

[0013] Numerous modifications and other embodiments of the compounds, compositions, and methods disclosed herein will occur to one skilled in the art to which the disclosed compounds, compositions, and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is understood, therefore, that the disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptations of the aspects described herein. These variations and adaptations are within the teachings of the present disclosure and are intended to be encompassed by the scope of the claims herein.

[0014] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0015] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has individual components and features that may be readily separated and combined with any feature of the other several embodiments without departing from the scope and spirit of the disclosure.

[0016] Any recited method can be performed in the order of events recited or in any other order that is logically possible. That is, unless expressly stated otherwise, it is not intended that any method or aspect described herein be construed as requiring that its steps be performed in a particular order. Thus, unless specifically stated in the claims or in this specification that steps are limited to a particular order, no order is intended to be implied in any respect. This applies to all possible implicit principles of interpretation, including logical considerations regarding the arrangement or operational flow of steps, the plain meaning derived from grammatical structure or punctuation, or the number or type of aspects described herein.

[0017] All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. The publication dates provided herein may be different from the actual publication dates, which may require independent confirmation.

[0018] It should also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the disclosed compounds, compositions, and methods belong. Furthermore, terms as defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of this specification and related art, and should not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0019] Prior to describing the various aspects of this disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in this disclosure.

[0020] definition As used herein, "comprising" is interpreted as specifying the presence of the stated features, integers, steps, or components, but does not exclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Furthermore, each of the terms "by," "comprising," "comprises," "comprised of," "including," "includes," "included," "involving," "involved," "involved," and "such as" are used in their open, non-limiting sense and may be used interchangeably. Furthermore, the term "comprising" is intended to include examples and embodiments encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of."

[0021] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "compound," a "pharmaceutical composition," or a "medical disorder" includes, but is not limited to, two or more such compounds, pharmaceutical compositions, or medical disorders, etc.

[0022] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in range format. It is further understood that the endpoints of each range are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values ​​disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself. For example, if a value of "10" is disclosed, then "about 10" is also disclosed. Ranges can be expressed herein from one particular value and / or to another particular value using "about." Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms a further aspect. For example, if a value of "10" is disclosed, then "about 10" is also disclosed.

[0023] As used herein, the terms "about," "approximate," "at or about," and "substantially" mean that the amount or value in question may be an exact value or a value that will provide an equivalent result or effect as recited in the claims or taught herein. That is, it will be understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximated and / or made larger or smaller, as desired, to provide an equivalent result or effect, reflecting tolerances, conversion factors, rounding, measurement errors, etc., and other factors known to those skilled in the art. In some circumstances, it may not be possible to reasonably determine a value that will provide an equivalent result or effect. In such cases, as used herein, "about" and "at or about" are generally understood to mean a variation of ±10% of the nominal value indicated, unless otherwise indicated or inferred. In general, any amount, size, formulation, parameter, or other quantity or characteristic is "about," "approximately," or "in the region of," whether or not expressly stated as such. When "about," "approximately," or "in the region of" is used before a quantitative value, it is understood that the parameter also includes the particular quantitative value itself, unless specifically stated otherwise.

[0024] As used herein, "effective amount" may refer to an amount of a disclosed compound or pharmaceutical composition provided herein sufficient to produce a beneficial or desired biological, emotional, medical, or clinical response in a cell, tissue, system, animal, or human. An effective amount may be administered in one or more administrations, applications, or dosages. The term may also encompass within its scope an amount effective to enhance or restore substantially normal physiological function.

[0025] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result, or an amount that has an effect on undesired symptoms but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the specific composition used, the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, the excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or concomitantly with the specific compound used, and similar factors that are within the knowledge and expertise of medical practitioners and well known in the medical field. When treating a particular disease or condition, in some cases, the desired response may be to inhibit the progression of the disease or condition. As such, this may involve only temporarily slowing the progression of the disease. However, in some cases, it may be desirable to permanently halt the progression of the disease. This can be monitored by routine diagnostic methods known to those skilled in the art for any particular disease. The desired response to treatment of a disease or condition may also be to delay or prevent the onset of the disease or condition.

[0026] For example, it is well within the knowledge of those skilled in the art to start administering a compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration purposes. As a result, a single-dose composition can contain such an amount or further fractions thereof to make up the daily dose. The dosage can be adjusted by an individual physician in the event of any contraindications. In general, it is preferable to use the maximum amount of the pharmacological agent of the present invention (alone or in combination with other therapeutic agents), i.e., the highest safe dose based on sound medical judgment. However, those skilled in the art will understand that a patient may insist on a lower dosage or tolerated dose for medical reasons, psychological reasons, or virtually any other reason.

[0027] Response to a therapeutically effective amount of the disclosed compounds or pharmaceutical compositions can be measured by determining physiological effects, such as a reduction or absence of disease symptoms after administration of a therapeutic or pharmacological agent. Other assays will be known to those skilled in the art and could be employed to measure the level of response. The therapeutic amount can be varied, for example, by increasing or decreasing the amount of the disclosed compounds and / or pharmaceutical compositions, by changing the disclosed compounds and / or pharmaceutical compositions administered, by changing the route of administration, by changing the timing of administration, etc. Doses can be varied and can be administered in one or more doses daily, for one or several days. Guidance can be found in the literature regarding appropriate doses for a given class of pharmaceutical products.

[0028] As used herein, the term "prophylactically effective amount" refers to an amount effective to prevent the development or onset of a disease or condition.

[0029] As used herein, the terms "prevent" or "prevention" refer to preventing, avoiding, impeding, eliminating, stopping, or impeding something from happening, especially by prior action. Unless otherwise specified, when inhibit or prevent is used herein, it is understood that the use of the other two words is also expressly disclosed.

[0030] As used herein, "optional" or "optionally" means that a subsequently described event or circumstance may or may not occur, and the description includes cases where said event or circumstance occurs and cases where it does not occur.

[0031] As used interchangeably herein, a "subject," "individual," or "patient" can refer to a vertebrate, such as a mammal (e.g., a human). A "subject" can also refer to a cell, a cell population, a tissue, an organ, or an organism, preferably a human and components thereof.

[0032] As used herein, the terms "treating" and "treatment" can generally refer to obtaining a desired pharmacological and / or physiological effect. The effect may be, but is not necessarily, prophylactic, in that a disease, such as a medical disorder, symptom, or condition thereof is prevented or partially prevented. The effect may be therapeutic, in that a disease, condition, symptom, or side effects resulting from a disease, disorder, or condition are partially or completely cured. As used herein, the term "treatment" can include any treatment of a medical disorder in a subject, particularly a human, and can include any one or more of the following: (a) preventing the occurrence of a disease in a subject who is predisposed to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, i.e., arresting the progression of the disease; and (c) palliating the disease, i.e., reducing or ameliorating the disease and / or its symptoms or condition. As used herein, the term "treatment" can refer to therapeutic treatment only, prophylactic treatment only, or both therapeutic and prophylactic treatment. Those in need of treatment (i.e., subjects in need thereof) can include those already with the disorder and / or those in whom a disorder is to be prevented. As used herein, the term "treating" can include inhibiting a disease, disorder, or condition, e.g., preventing its progression, as well as alleviating a disease, disorder, or condition, e.g., causing regression of the disease, disorder, and / or condition. Treating a disease, disorder, or condition can include ameliorating at least one symptom of a particular disease, disorder, or condition, even if the underlying pathophysiology is unaffected; for example, administering a painkiller can treat pain in a subject even though the painkiller does not treat the cause of the pain.

[0033] As used herein, "dose," "unit dose," or "dosage" can refer to physically discrete units suitable for subject administration, each unit containing a predetermined quantity of a disclosed compound and / or pharmaceutical composition thereof calculated to produce a desired response or responses associated with its administration.

[0034] As used herein, "therapeutic" can refer to treating, curing, and / or ameliorating a disease, disorder, condition, or side effect, or reducing the rate of progression of a disease, disorder, condition, or side effect.

[0035] chemical definition Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0036] The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers such as rotamers, as if each were expressly stated, unless otherwise indicated or excluded by context.

[0037] A dash ("-") that is not between two letters or symbols indicates the point of attachment of the substituent. For example, -(C=O)NH is attached through the carbon of the keto (C=O) group.

[0038] As used herein, the term "substituted" means that any one or more hydrogens on the specified atom or group are replaced with a site selected from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom and the resulting compound is stable. For example, if the substituent is oxo (i.e., =O), two hydrogens on the atom are replaced. For example, an oxo-substituted pyridyl group is pyridine. Combinations of substituents and / or variables are permissible only if they result in a stable compound or useful synthetic intermediate. A stable active compound refers to a compound that can be isolated and formulated into a dosage form with a shelf life of at least one month. A stable manufacturing intermediate or active compound precursor is stable if it is not decomposed within the time required for reaction or other use. A stable moiety or substituent is one that does not decompose, react, or decay within the time required for use. Non-limiting examples of unstable moieties are those that attach heteroatoms in an unstable configuration, as typically known and identifiable to those skilled in the art.

[0039] Any suitable group may be present at a "substituted" or "optionally substituted" position that results in a stable molecule and satisfies the intended objectives of the present invention, including, but not limited to, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, silyl, sulfoxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0040] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. In certain embodiments, alkyl is C1-C2, C1-C3, or C1-C6 (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length). As used herein, specified ranges refer to alkyl groups having the length of each member of the range described as a separate species. For example, as used herein, C1-C6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is described as a separate species; as used herein, C1-C4 alkyl refers to an alkyl group having 1, 2, 3, or 4 carbon atoms, each of which is described as a separate species. C0-C n When alkyl is used herein in connection with another group, such as (C-C cycloalkyl)C-C alkyl, or —C-C(C-C cycloalkyl), the indicated group, in this case cycloalkyl, is either directly attached by a single covalent bond (C alkyl) or is attached by an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms. Alkyl can also be attached through other groups, such as heteroatoms, such as —O—C-C alkyl(C-C cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentene, 3-methylpentene, 2,2-dimethylbutane, and 2,3-dimethylbutane. In one embodiment, alkyl groups are optionally substituted as described herein.

[0041] "Cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be fused or bridged together. Non-limiting examples of typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In one embodiment, cycloalkyl groups are optionally substituted as described herein.

[0042] "Alkenyl" refers to a straight- or branched-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, each of which may be independently cis or trans and may occur at any stable point along the chain. Non-limiting examples include C2-C4 alkenyl and C2-C6 alkenyl (i.e., having 2, 3, 4, 5, or 6 carbons). As used herein, a given range represents an alkenyl group with each member of the range recited as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one embodiment, an alkenyl group is optionally substituted as described herein.

[0043] "Alkynyl" refers to a straight- or branched-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain, such as C2-C4 alkynyl or C2-C6 alkynyl (i.e., having 2, 3, 4, 5, or 6 carbons). As used herein, a given range represents an alkynyl group with each member of the range recited as a separate species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In one embodiment, an alkynyl group is optionally substituted as described herein.

[0044] "Alkoxy" refers to an alkyl group as defined above covalently bonded through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an "alkylthio" or "thioalkyl" group refers to an alkyl group as defined above with the specified number of carbon atoms covalently bonded through a sulfur bridge (-S-). In one embodiment, an alkoxy group is optionally substituted as described herein.

[0045] "Alkanoyl" is an alkyl group as defined above covalently attached through a carbonyl (C=O) bridge. The carbonyl carbon is included in the carbon number; for example, a C2 alkanoyl is a CH3(C=O)- group. In one embodiment, the alkanoyl group is optionally substituted as described herein.

[0046] "Haloalkoxy" denotes a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).

[0047] "Halo" or "halogen" independently refer to either fluoro, chloro, bromo, or iodo.

[0048] "Aryl" refers to an aromatic group containing only carbon in the aromatic ring or rings. In one embodiment, an aryl group contains 1 to 3 separate or fused rings, no heteroatoms as ring members, and 6 to 14 or 18 ring atoms. Where indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 4- to 7-membered or 5- to 7-membered saturated or partially unsaturated cyclic group, optionally containing 1, 2, or 3 heteroatoms independently selected from N, O, B, P, Si, and S, to form, for example, a 3,4-methylenedioxyphenyl group. Examples of aryl groups include phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described herein.

[0049] The term "heterocycle" refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, O, and S. The term heterocycle includes monocyclic 3- to 12-membered rings and bicyclic 5- to 16-membered ring systems, which may include fused, bridged, or spiro-bicyclic systems. It does not include rings containing -OO-, -OS-, and -SS- moieties. Examples of saturated heterocyclic groups include saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl), saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclic radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydrobenzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofurinyl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1 Examples of heterocyclic rings include, but are not limited to, 2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-benzo[d]isothazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Bicyclic heterocycles also include groups in which a heterocyclic radical is fused to an aryl radical, with the point of attachment being the heterocycle. Bicyclic heterocycles also include heterocyclic radicals fused to a carbocyclic radical.Representative examples include, but are not limited to, partially unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms such as indoline and isoindoline, partially unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated fused heterocyclic groups containing 1 to 2 oxygen atoms or 1 to 2 sulfur atoms.

[0050] "Heteroaryl" refers to a stable monocyclic, bicyclic, or polycyclic aromatic ring containing 1 to 3, or in some embodiments 1, 2, or 3, heteroatoms selected from N, O, S, B, and P (typically selected from N, O, and S), with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic ring system containing at least one 5-, 6-, or 7-membered aromatic ring containing 1 to 3, or in some embodiments 1 to 2 heteroatoms selected from N, O, S, B, or P, with the remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 to 6 ring atoms. In some embodiments, the bicyclic heteroaryl group is an 8- to 10-membered heteroaryl group, i.e., a group containing 8 or 10 ring atoms in which one 5-, 6-, or 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring, where the point of attachment is at the aromatic ring. When the total number of S atoms and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In one embodiment, the total number of S atoms and O atoms in the heteroaryl group is 2 or less. In another embodiment, the total number of S atoms and O atoms in the heteroaryl group is 1 or less. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolinyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, triazolylthiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

[0051] "Pharmaceutically acceptable salts" are derivatives of the disclosed compounds in which the parent compound is modified by making its inorganic and organic non-toxic pharmaceutically acceptable acid or base addition salts. Salts of the present compounds can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (e.g., hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where feasible. Salts of the present compounds further include solvates of the compounds and salts of the compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include salts acceptable for human consumption and quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic acids. Examples of such salts include salts derived from inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as salts derived from acids such as, for example, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) 1-4 Included are salts prepared from organic acids such as —COOH, or salts using a different acid that produces the same counterion. Additional lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17 thed., Mack Publishing Company, Easton, PA., p. 1418 (1985).

[0052] Compounds of Formula I The present disclosure provides compounds that are inhibitors of interleukin-1 receptor-associated kinases 1 and 4 (IRAK1 and IRAK4). The disclosed compounds are useful for treating medical disorders associated with aberrant expression or signaling of IRAK1 and / or IRAK4, such as inflammatory disorders or cancer.

[0053] Thus, in one aspect, a compound of formula I: [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided, During the ceremony, X 1 is NR a , O, or S; X 2 are N, CH, and CR 1 is selected from X 3 and X 4 are independently N, CH, and CR 2 is selected from X 5 , O, NR a , S, and CR b R c is selected from X 6 is NR a , -CR d R e -, S, and O; X 7 is a bond or NR a and R ais selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, a 4-10 membered monocyclic or bicyclic heterocycle, a 5-10 membered monocyclic or bicyclic aryl, or a 5-10 membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted, valence permitting, with one or more Y groups; R b and R c is independently, at each occurrence, hydrogen, halo, nitro, cyano, C-C alkyl, C-C haloalkyl, C-C cycloalkyl, 4-10 membered monocyclic or bicyclic heterocycle, 5-10 membered monocyclic or bicyclic aryl, C(O)R z , -S(O)R z , and -S(O)R z each of which may be optionally substituted, valence permitting, with one or more Y groups; R 1 , R 2 , and R 3 is independently, at each occurrence, halo, nitro, cyano, azido, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, (4-10 membered monocyclic or bicyclic heterocycle)-(C-C alkyl), (5-10 membered monocyclic or bicyclic aryl)-(C-C alkyl), (5-10 membered monocyclic or bicyclic heteroaryl)-(C-C alkyl), -OR x , -SR x , -NR x R y , -C(O)R z , -S(O)R z , and -S(O)R z each of which may be optionally substituted, valence permitting, with one or more Y groups; m is 0, 1, or 2; n is 0, 1, or 2; o is 0, 1, 2, 3, or 4; R 4 teeth, [ka] is selected from X 8 are N, CH, and CR 5 is selected from X 9 is selected from S, S(O), and S(O)2; R 5 is independently, at each occurrence, halo, nitro, cyano, azido, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, (4-10 membered monocyclic or bicyclic heterocycle)-(C-C alkyl), (5-10 membered monocyclic or bicyclic aryl)-(C-C alkyl), (5-10 membered monocyclic or bicyclic heteroaryl)-(C-C alkyl), -OR x , -SR x , -NR x R y , -C(O)R z , -S(O)R z , and -S(O)R z each of which may be optionally substituted, valence permitting, with one or more Y groups; p is 0, 1, 2, 3, or 4; X 10 is NR a and X 11 is -(CR d R e ) q wherein q is 1 or 2; R d and R e is independently, at each occurrence, hydrogen, halo, nitro, cyano, azido, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, (4-10 membered monocyclic or bicyclic heterocycle)-(C-C alkyl), (5-10 membered monocyclic or bicyclic aryl)-(C-C alkyl), (5-10 membered monocyclic or bicyclic heteroaryl)-(C-C alkyl), -OR x , -SR x , -NRx R y , -C(O)R z , -S(O)R z , and -S(O)R z each of which may be optionally substituted, valence permitting, with one or more Y groups; R 6 is -S(O)2R z is selected from R x and R y is independently selected at each occurrence from hydrogen, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, (4-10 membered monocyclic or bicyclic heterocycle)-(C-C alkyl), (5-10 membered monocyclic or bicyclic aryl)-(C-C alkyl), and (5-10 membered monocyclic or bicyclic heteroaryl)-(C-C alkyl), each of which can be optionally substituted, valence permitting, with one or more Y groups; R z is independently, at each occurrence, hydrogen, halo, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, (4-10 membered monocyclic or bicyclic heterocycle)-(C-C alkyl), (5-10 membered monocyclic or bicyclic aryl)-(C-C alkyl), (5-10 membered monocyclic or bicyclic heteroaryl)-(C-C alkyl), -OR x , -SR x , and -NR x R y each of which may be optionally substituted, valence permitting, with one or more Y groups; Y is independently, at each occurrence, selected from halo, hydroxy, amino, cyano, -CHO, -COOH, -CONH, C-C alkyl, C-C alkanoyl, (mono- or di-C-C alkylamino)C-C alkyl, C-C haloalkyl, hydroxyC-C alkyl, ester, carbamate, urea, sulfonamide, -C-C alkyl(4- to 10-membered monocyclic or bicyclic heterocycle), -C-C alkyl(5- to 10-membered monocyclic or bicyclic heteroaryl), -C-C alkyl(C-C cycloalkyl), O-C-C alkyl(C-C cycloalkyl), B(OH), phosphate, phosphonate, and C-C haloalkoxy.

[0054] In some embodiments of Formula I, X 1 is NR a In some embodiments of Formula I, X 1 is O. In some embodiments of Formula I, X 1 is S. In some embodiments of Formula I, X 1 is NH.

[0055] In some embodiments of Formula I, X 2 is N. In some embodiments of Formula I, X 2 is CH. In some embodiments of Formula I, X 2 is CR 1 is.

[0056] In some embodiments of Formula I, [ka] teeth, [ka] is selected from.

[0057] In some embodiments of Formula I, X 3 is N. In some embodiments of Formula I, X 3is CH. In some embodiments of Formula I, X 3 is CR 2 is.

[0058] In some embodiments of Formula I, X 4 is N. In some embodiments of Formula I, X 4 is CH. In some embodiments of Formula I, X 4 is CR 2 is.

[0059] In some embodiments of Formula I, [ka] teeth, [ka] is selected from.

[0060] In some embodiments of Formula I, X 5 is O. In some embodiments of Formula I, X 5 is NR a In some embodiments of Formula I, X 5 is S. In some embodiments of Formula I, X 5 is CR b R c is.

[0061] In some embodiments of Formula I, X 6 is NR a In some embodiments of Formula I, X 6 is NH. In some embodiments of Formula I, X 6 is O. In some embodiments of Formula I, X 6 Ha-CR d R e In some embodiments of Formula I, X 6 is CH2. In some embodiments of Formula I, X 6 is S.

[0062] In some embodiments of Formula I, [ka] teeth, [ka] is selected from.

[0063] In some embodiments, [ka] teeth, [ka] is selected from.

[0064] In some embodiments of Formula I, X 7 is a bond. In some embodiments of Formula I, X 7 is NR a In some embodiments of Formula I, X 7 is NH.

[0065] In some embodiments of Formula I, R 4 teeth [ka] is.

[0066] In some embodiments of Formula I, R 4 teeth [ka] is.

[0067] In some embodiments of Formula I, [ka] teeth, [ka] is selected from.

[0068] In some embodiments of Formula I, [ka] teeth, [ka] is selected from.

[0069] In some embodiments of Formula I, the compound is [ka] is selected from the group consisting of:

[0070] In some embodiments of Formula I, the compound is [ka] [ka] is selected from the group consisting of:

[0071] In some embodiments of Formula I, the compound is [ka] [ka] is selected from the group consisting of:

[0072] Representative examples of compounds of formula I are: [ka] [ka] Including, but not limited to:

[0073] The present disclosure also includes compounds of Formula I that are enriched with at least one desired isotopic substitution of an atom at or above the natural abundance of that isotope.

[0074] Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, e.g., 2 H, 3 H, 11 C. 13 C. 15 N, 17 O. 18 O. 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 In one embodiment, the radioisotope-labeled compounds are used in metabolic studies ( 14 C), reaction rate studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including measuring the tissue distribution of drugs and substrates, or for radiotherapy of patients. 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by following the procedures disclosed herein, substituting readily available isotopically labeled reagents with non-isotopically labeled reagents.

[0075] As a general, non-limiting example, isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3H) can be optionally used anywhere in the structures described that achieves the desired result. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C may also be used. In one embodiment, isotope substitution refers to the replacement of hydrogen with deuterium at one or more positions on a molecule to improve the performance of the molecule as a drug, e.g., pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, deuterium can be attached to a carbon in the distribution of bond cleavage during metabolism (α-deuterium kinetic isotope effect) or can be attached to a carbon next to or near the site of bond cleavage (β-deuterium kinetic isotope effect).

[0076] Isotopic substitution, e.g., deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen has been replaced with deuterium. In certain embodiments, the isotope is enriched at any position of interest by 80, 85, 90, 95, or 99% or more. In some embodiments, deuterium is enriched at a desired position by 80, 85, 90, 95, or 99%. Unless otherwise specified, enrichment at any point is above natural abundance, and in one embodiment, is sufficient to alter the detectable properties of the compound as a drug in humans.

[0077] The compounds of the present disclosure may form solvates with solvents, including water. Thus, in one embodiment, the present invention includes solvated forms of the active compounds. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. "Hydrate" refers to a molecular complex of the disclosed compound with water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, for example, DO, d6-acetone, or d6-DMSO. Solvates may be in liquid or solid form.

[0078] As used herein, a "prodrug" refers to a compound that is converted into a parent drug upon administration to a host in vivo. As used herein, the term "parent drug" refers to any of the compounds currently described herein. Prodrugs can be used to achieve any desired effect, including enhancing the properties of the parent drug or improving the pharmaceutical or pharmacokinetic properties of the parent drug, including increasing the half-life of the drug in vivo. Prodrug strategies offer options for tailoring the conditions for producing a parent drug in vivo. Non-limiting examples of prodrug strategies include covalent attachment of a removable group or removable portion of a group, such as, but not limited to, acylation, phosphorylation, phosphonylation, phosphoramido derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydrides. In certain embodiments, prodrugs render the parent compound more lipophilic. In certain embodiments, prodrugs can be provided with multiple prodrug moieties in a linear, branched, or cyclic fashion. For example, non-limiting embodiments include the use of bivalent linker moieties such as dicarboxylic acids, amino acids, diamines, hydroxycarboxylic acids, hydroxyamines, dihydroxy compounds, or other compounds with at least two functional groups that can link a parent compound to another prodrug moiety and are generally biodegradable in vivo. In some embodiments, 2, 3, 4, or 5 prodrug biodegradable moieties are covalently attached to the parent compound in a permuted, branched, or cyclic fashion.Non-limiting examples of prodrugs according to the present disclosure include those that form an ester between a carboxylic acid on the parent drug and a hydroxylated prodrug moiety; those that form an amide between a carboxylic acid on the parent drug and an amine prodrug; those that form an amide between an amino on the parent drug and a carboxylic acid prodrug moiety; those that form a sulfonamide between an amino on the parent drug and a sulfonic acid; those that form a sulfonamide between a sulfonic acid on the parent drug and an amino on the prodrug moiety; those that form an ester between a hydroxyl group on the parent drug and a carboxylic acid on the prodrug moiety; those that form an ester between a hydroxyl on the parent drug and a hydroxylated prodrug moiety; those that form a phosphonate ester between a phosphonic acid on the parent drug and a hydroxylated prodrug moiety; those that form a phosphate ester between a hydroxyl on the parent drug and a hydroxylated prodrug moiety; those that form a phosphonate ester between a hydroxyl on the parent drug and a phosphonic acid on the prodrug; those that form a phosphate ester between a hydroxyl on the parent drug and a phosphate prodrug moiety; and those that form a carboxylic acid on the parent drug and the structure HO—(CH)—O—(C—). 24 Prodrugs of HO-(CH2)2-S-(C2- alkyl) that form esters with the carboxylic acid on the parent drug; 24 alkyl) prodrugs that form thioesters; hydroxyl groups on the parent drug and the structure HO-(CH2)2-O-(C2- 24 alkyl) prodrugs that form ethers; hydroxyl groups on the parent drug and the structure HO-(CH2)2-O-(C2- 24 alkyl) that form thioethers; and carboxylic acids, oximes, hydrazides, hydrazines, amines, or hydroxyls on the parent compound with a prodrug moiety that is a biodegradable polymer or oligomer, including, but not limited to, polylactic acid, polylactic-co-glycolide, polyglycolide, polyethylene glycol, polyanhydrides, polyesters, polyamides, or peptides.

[0079] In some embodiments, prodrugs are provided by attaching a natural or unnatural amino acid to a suitable functional site on the parent compound, such as an oxygen, nitrogen, or sulfur, typically an oxygen or nitrogen, in a manner such that the amino acid is usually cleaved in vivo to provide the parent drug. Amino acids can be used alone or covalently attached (linear, branched, or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve desired performance, such as increased half-life, lipophilicity, or other drug delivery or pharmacokinetic properties. The amino acid can be any compound having an amino group and a carboxylic acid, including aliphatic, alkyl, aromatic, heteroaliphatic, heteroalkyl, heterocyclic, or heteroaryl amino acids.

[0080] Treatment method In one aspect, a method is provided for the treatment of a medical disorder associated with aberrant expression or signaling of IRAK4.

[0081] In another aspect, there is also provided a method for treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Representative examples of inflammatory disorders include peritonitis, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type 1), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, and chronic inflammatory bowel disease. Rohn's disease, psoriasis, atopic dermatitis, graft-versus-host disease, osteoporosis, multiple myeloma-related bone disorder, leukemia and related disorders, myelodysplastic syndromes, acute myeloid leukemia, clonal hematopoiesis, anemia of chronic disease, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple sclerosis, sepsis, septic shock, dysentery, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis , AIDS-associated encephalitis, HIV-associated encephalitis, aging, alopecia, nerve damage due to stroke, ulcerative colitis, infectious hepatitis, juvenile diabetes, lichen planus, acute dermatomyositis, eczema, primary cirrhosis, uveitis, Behçet's disease, atopic skin disease, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis, nephrotic syndrome, burns, bronchitis, tendonitis, bursitis, polyarteritis nodosa, thyroiditis, Hodgkin's disease, These include rheumatic fever, sarcoidosis, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling following injury, allergic rhinitis, endotoxic shock syndrome, and atherosclerosis, psoriatic arthritis, vasculitis, polymyalgia rheumatica, Wegener's granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, ocular inflammatory disease, and ataxia-telangiectasia.

[0082] In another aspect, there is also provided a method for treating organ fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Representative examples of organ fibrosis that may be treated include renal fibrosis, pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, Crohn's disease, liver fibrosis, cardiac fibrosis, scleroderma, or progressive massive fibrosis.

[0083] Malignant tumors that can be treated using the compounds of the present disclosure include ovarian, fallopian tube, primary peritoneal, endometrial, and uterine cancers, including all their associated histological subtypes, such as, but not limited to, serous carcinoma, endometrioid carcinoma, clear cell carcinoma, undifferentiated carcinoma, poorly differentiated carcinosarcoma (MMMT), sarcoma germ cell tumor, and sex cord stromal tumor.

[0084] Carcinomas contemplated for treatment by the methods of the present invention include acinar carcinoma, lobular carcinoma, follicular adenocarcinoma, carcinoma adenomatous, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basoid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armored carcinoma, skin carcinoma, cylindrical carcinoma, columnar cell carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, medullary carcinoma, supraocular carcinoma, epidermoid carcinoma, epithelial adenocarcinoma epitheliate adenoids, ulcer carcinoma, carcinoma fibrosum, gelatinous carcinoma, colloid carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, pilomatrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in epidermis, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, medullary carcinoma medullary carcinoma, medullary carcinoma, melanoma melanodes, melanotonic carcinoma, mucinouscarcinoma, mucinous carcinoma, carcinoma mucocullare, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, melanoma, carcinoma nigrum, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, ovarian cancer, papillary carcinoma, periportal carcinoma, pre-invasive carcinoma, prostate cancer, renal cell carcinoma of the kidney, renal cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solandoid carcinoma These include, but are not limited to, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, and choriocarcinoma.

[0085] The present invention also provides methods and agents for treating sarcoma. Sarcoma is a rare mesenchymal neoplasm that occurs in bone and soft tissue. Different types of sarcoma are recognized, including liposarcoma (including myxoid liposarcoma and pleomorphic liposarcoma), leiomyosarcoma, rhabdomyosarcoma, neurofibrosarcoma, malignant peripheral nerve sheath tumor, Ewing's sarcoma (including skeletal, extraskeletal, or non-skeletal Ewing's sarcoma), primitive neuroectodermal tumor (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoid tumor, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) (skeletal and extraskeletal), and chondrosarcoma.

[0086] Optionally, the cancer being treated is a refractory or responsive cancer.

[0087] In another important aspect, the compounds of the present invention can also be used to treat immunogenic cancers. Examples of immunogenic cancers include malignant melanoma and renal cell carcinoma, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acute lymphoblastic leukemia, Burkitt's lymphoma, myeloma, immunocytoma, acute promyelocytic leukemia, chronic myeloid / acute lymphoblastic leukemia, acute leukemia, B-cell acute lymphoblastic leukemia, anaplastic large cell leukemia, myelodysplastic syndrome / acute myeloid leukemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia (AML), common (pre-B) acute lymphoblastic leukemia, malignant melanoma, T-cell lymphoma, leukemia, B-cell lymphoma, epithelial malignancies, lymphoid malignancies, gynecological cancers, biliary adenocarcinoma, and ductal adenocarcinoma.

[0088] The present disclosure also provides a method for inhibiting angiogenesis in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Angiogenesis, the rapid proliferation of epithelial cells that leads to the formation of new blood vessels, supports tumor progression and survival. As a secondary effect, angiogenesis can damage various organs and tissues, including the eyes, skin, heart, blood vessels, lungs, gastrointestinal tract, and genitourinary tract. Methods and techniques for assessing angiogenesis are known to those skilled in the art.

[0089] Also provided is a method for inhibiting tumor cell growth in a subject in need thereof, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0090] Also provided is a method for sensitizing tumor cells to treatment with an additional therapeutic agent, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0091] In another aspect, there is provided a method for IL1b-induced activation of NF-κB in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0092] In another aspect, methods are provided for effecting stem cell mobilization and / or stem cell engraftment in a subject by administering an agent described herein, alone or in combination with an additional therapeutic agent.

[0093] In another aspect, there is provided a method for treating a pain disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Representative examples of pain disorders that may be treated include, but are not limited to, inflammatory pain (including infection-induced inflammatory pain, including but not limited to influenza, SARS, or the common cold), post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

[0094] In some embodiments, the pain disorder comprises neuropathic pain or nociceptive pain. Neuropathic pain is pain caused by injury or disease affecting the somatic nervous system. Neuropathic pain is typically characterized by abnormal sensations (dysesthesia) or pain from stimuli that are not normally painful (allodynia). Neuropathic pain can result from disorders of the peripheral system or the central nervous system, e.g., the brain or spinal cord. Central neuropathic pain is seen in cases of spinal cord injury, multiple sclerosis, and stroke. Peripheral neuropathic pain is seen in patients with diabetes (diabetic neuropathy), shingles infection, HIV infection, nutritional deficiencies, exposure to toxins, distant manifestations of malignant tumors, immune-mediated disorders, and physical trauma to nerve trunks. In cancer, neuropathic pain can occur when a tumor directly compresses a peripheral nerve or as a side effect of chemotherapy (chemotherapy-induced peripheral neuropathy), radiation therapy, or surgery.

[0095] The compounds described herein can be administered in combination with other therapies, such as, for example, radiation therapy, surgery, conventional chemotherapy, one or more checkpoint inhibitors, or in combination with one or more additional therapies. For example, the compounds described herein can be administered before, after, or simultaneously with a chemotherapeutic and / or cytotoxic agent. Co-administration can be in the form of a fixed combination containing two or more active ingredients, or by simultaneously administering two or more compounds formulated independently.For example, chemotherapeutic and / or cytotoxic agents that may be administered include alkylating agents (e.g., chlorambucil, cyclophosphamide, ccnu, melphalan, procarbazine, thiotepa, bcnu, and busulfan), antimetabolites (e.g., 6-mercaptopurine and 5-fluorouracil), anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone), antitumor antibiotics (e.g., bleomycin), monoclonal antibodies (e.g., alemtuzumab, bevacizumab, cetuximab, gemtuzumab, ibritumomab), and the like. omab), panitumumab, rituximab, tositumomab, and trastuzumab), platinum (e.g., cisplatin, oxaliplatin, and carboplatin), plant alkaloids (e.g., vincristine), topoisomerase I or II inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide) Examples of glutathione antagonists include, but are not limited to, vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine, and vindesine), taxanes (e.g., paclitaxel and docetaxel), epipodophyllotoxins (e.g., etoposide and teniposide), nucleoside analogs, and angiogenesis inhibitors (e.g., Avastin (beracizumab), a humanized monoclonal antibody specific for VEGF-A). Examples of glutathione antagonists include, but are not limited to, buthionine sulfoximine, cyclophosphamide, ifosfamide, actinomycin d, and N-(4-hydroxyphenyl)retinamide (4-HPR).Examples of angiogenesis inhibitors include 2-methoxyestradiol (2-ME), AG3340, angiostatin, antithrombin III, anti-VEGF antibodies, batimastat, bevacizumab (avastatin), BMS-275291, CA1, canstatin, combretastatin, combretastatin-A4 phosphate, CC-5013, captopril, celecoxib, dalteparin, EMD 121974, endostatin, erlotinib, gefitinib, genistein, halofuginone, ID1, ID3, IM862, imatinib mesylate, inducible protein 10, interferon-alpha, interleukin-12, lavendustin-a, LY317615 or AE-941, marimastat, maspin, medroxyprogesterone acetate, Meth-1, Meth-2, Neovastat, osteopontin cleavage product, PEX, pigment epithelial growth factor Examples of angiogenesis inhibitors include, but are not limited to, PEG-4, platelet factor 4, prolactin fragment, proliferin-related protein (PRP), PTK787 / ZK222584, recombinant human platelet factor 4 (rPF4), restin, squalamine, SU5416, SU6668, suramin, taxol, tecogalan, thalidomide, tetrathiomolybdate (TM), thrombospondin, TNP-470, troponin I, vasostatin, VEGF1, VEGF-TPvAP, and ZD6474. In some embodiments, the angiogenesis inhibitor is a VRGF antagonist. The VEGF antagonist can be a VEGF-binding molecule. The VEGF-binding molecule can be a VEGF antibody or an antigen-binding fragment thereof. One example of a VEGF antagonist is NeXstar.

[0096] Chemotherapeutic agents that can be combined with the compounds disclosed herein include DNA damaging agents, including topoisomerase inhibitors (e.g., etoposide, camptothecin, topotecan, irinotecan, teniposide, mitoxantrone), anti-microtubule agents (e.g., vincristine, vinblastine), antimetabolites (e.g., cytarabine, methotrexate, hydroxyurea, 5-fluorouracil, fluoridine, 6-thioguanine, 6-mercaptompurine, fludarabine, pentostatin, chloramphenicol ... These include, but are not limited to, cisplatin, mecholorethamine, cyclophosphamide, ifosphamide, melphalan, chlorambucil, busulfan, thiotepa carmustine, lomustine, carboplatin, dacarbazine, procarbazine, and DNA strand break inducers (e.g., bleomycin, doxorubicin, daunorubicin, idarubicin, mitomycin C).

[0097] Other chemotherapeutic agents that can be combined with the compounds described herein include synthetic, semi-synthetic, and naturally occurring agents. Important chemotherapeutic agents include avicin, aclarubicin, acodazole, acronin, adzelesin, adriamycin, aldesleukin, alitretinoin, allopurinol sodium (allopurinol sodium), altretamine, ambomycin, amethanthrone acetate, aminoglutethimide, amsacrine, anastrazole, annonaceous acetogenins, anthramycin, asimycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bexarotene, bicalutamide, bisantrene, visnafide, bizelesin, bleomycin, brequinar, bropirimine, bullatacin, busulfan, cabergoline, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedefingol, chlorambucil, Celecoxib, ciloremycin, cisplatin, cladribine, crisnatol, cyclophosphamide, cytarabine, dacarbazine, DACA, dactinomycin, daunorubicin, daunomycin, decitabine, denileukin, dexorumaplatin, dezaguanine, diaziclone, docetaxel, doxorubicin, droloxifene, duazomycin, edatrexate, eflornithine, elsamitrucin, estra Mustine, Etanidazole, Etoposide, Etoprine, Fadrozole, Fazarabine, Fenretinide, Floxuridine, Fludarabine, Fluorouracil, Flurocitabine, 5-FdUMP, Foskidone, Fosteuecine, FK-317, FK-973, FR-66979, FR-900482, Gemcitabine, Gemtuzumab, Ozogamicin, Gold Aul 98, goserelin, guanaconazole, hydroxyurea, idarubicin, ilmofosine, interferon alpha and analogs, iproplatin, irinotecan, lanreotide, letrozole, leuprolide, liarozole, lometrexol, lomustine, losoxantrone, masoprocol, maytansine, mechlorethamine, megastrol, melengestrol, melphalan, menogaril,Metoprine, maturedepa, mitindomide, mitocalcin, mitogillin, mitomalacin, mitomycin, mitomycin C, mitospel, mitotane, mitoxantrone, mycophenolic acid, nocodazole, nogalamycin, oprelvekin, ormaplatin, oxisuran, paclitaxel, pamidronate, pegaspargase, periomycin, pentamstine, peplomycin, perfosfamide, pipobroman, piposulfan, piroxantrone, plicamycin, promestane, porfimer , porfiromycin, prednimustine, procarbazine, puromycin, pyrazofurin, ribopurine, rituximab, rogletimide, rolliniastatin, safingol, samarium, semustine, cinthrazene, sfarfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin, squamocin, squamotacin, streptonigrin, streptozocin, SrC12, sulfofenur, tallysomycin taxane, toxoid, tecogran, tegafur, Teloxantrone, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thiotepa, Thymitaq, tiazofurin, tirapazamine, tomudex, Top-53, topotecan, toremixifme, trastuzumab, trestron, triciribine, trimetrexate, trimetrexate glucuronate, triptorelin, tuburosol, uracil mustard, uredepa, valur Bicine, vapreotide, vinblastine, vincristine, vindesine, vinepidine, vinglisinate, vinleurosine, vinorelbine, vinrocidine, vinzolidine, vorozole, zeniplatin, zinostatin, zorubicin, 2-chlorodeoxyrubicin, 2'-deoxyformycin, 9-aminocamptothecin, raltitrexed, N-propargyl-5,8-didezafolic acid, 2-chloro-2'arabinofluoro-2'deoxyadenosine, 2-chloro-2'-deoxyadenosine, anisomycin, trichostatin, hPRL-G129R,CEP-751, linomide, sulfur mustard, nitrogen mustard, N-methyl-N-nitrosourea, fotemustine, streptozotocin, decarbazine, mitozolomide, temozolomide, AZQ, ormaplatin, CI-973, DWA21 These include, but are not limited to, 14R, JM216, JM335, bisplatinum, tomudex, azecitidine, cytravincin, gemcitabine, 6-mercaptopurine, hypoxanthine, temiposide, CPT-11, doxorubicin, daunorubicin, epirubicin, darubicin, losoxantrone, amsacrine, pyrazoloacridine, all-trans-retinol, 14-hydroxy-retro-retinol, all-trans-retinoic acid, N-(4-hydroxyphenyl)retinamide, 13-cis-retinoic acid, 3-methyl-TTNEB, 9-cis-retinoic acid, fludarabine, and 2-Cda.

[0098] Other chemotherapeutic agents that can be combined with the compounds described herein include 20-epi, 1,25-dihydroxyvitamin-D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adozelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonists D, antarelix, anti-dorsal morphogenetic protein-1, anti-androgens, anti-estrogens, Antineoplaston, antisense oligonucleotide, aphidicolin, apoptosis gene modulator, apoptosis regulator, apurinic acid, ara-cdp-dl-PTBA, arginine aminase, asulaculin, atamestane, atlimustine, axinamastine 1 and axinamastine 2, axinamastine 3, azasetron, azatoxin, azatyrosine, baccatin III derivative, balanol, BCR / ABL antagonist, benzochlorin, benzoylsaurosporine, beta-lactam derivative, beta-arretin. Perillyl alcohol, phenozenomyein, phenyl acetate, phosphatase inhibitors, picibanil, pilocarbine and its salts or analogues, pirarbucin, piritrexim, prasetin A, plasminogen activator inhibitors, platinum complexes, phenylethyl isothiocyanate and its analogues, platinum compounds, platinum triamine complexes, podophylotoxin, porfimer sodiumsodium), porphyromycin, propyl bisacridone, prostaglandin J2, proteasome inhibitors, protein A-based immunomodulators, PKC inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyrazoloacridine, pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein tranaferase inhibitors, ras inhibitors; ras-GAP inhibitors, demethylated reterliptin, rhenium Re 186 etidronate etidronate, rhizoxine, ribozyme, RII retinamide, rogletimide, rosagliatazone and its analogs and derivatives, rohitukine, romurtide, roquinimex, rubiginone B1, ruboxyl, safingol, saintopin, SarCNU, sarcophytol A, sargrmostim, sdi1 mimetics, semustine, senescence derived inhibitor 1 1), sense oligonucleotides, signal transduction inhibitors, signal transduction modulators, single-chain antigen binding proteins, sizofiran, sobuzoxane, borocaptan sodium, sodium phenylacetate, sorberol, somatomedin binding proteins, sonermin, sparfosic acidacid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitors, stem cell division inhibitors, stipiamide, stromelysin, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, suramin, swainsonine, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide methiodide), tauromustine, tazarotene, tecogalan sodium, tegafur, tellurapyrilium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalidomide, thiocoraline, thrombopoietin and its mimetics, thymalfasin, thymopoietin receptor agonists, thymotrin, thyroid-stimulating hormone, tin ethyl etiopurin etiopurpin, tirapazamine, titanocene and its salts, topotecan, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, tricribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector systems, red blood cell gene therapy, velaresol, veramine, verdin, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorub, and zinostatin.

[0099] Additional chemotherapeutic agents that can be combined with the compounds described herein include antiproliferative agents (e.g., piritrexim isothiocyanate), antiprostatic hyperplasia agents (sitoglucide), benign prostatic hyperplasia therapeutic agents (e.g., tomsulosin, RBX2258), prostatic growth inhibitors (pentomone), and radioactive agents: fibrinogen 1125, fludeoxyglucose F18, fluorodopa F18, insulin 1125, iobenguane 1123, lodipamide sodium 1131, iodoantipyrine 1131, iodocholesterol 1131, iodopyracet 1125, iofetamine HCl 1123, Iomethin 1131, 1131), Iothalamate sodium 1125, Iothalamate sodium 1131, Iotyrosine 1131, Liothyronine 1125, Merosproprol Hgl 97, Iodobenzoguanine methyl (MIBG-I131 or MIBGI 123), Selenomethionine Se75, Technetium Tc99m furifosmin, Technetium Tc99m gluceptate, Tc99m biscisate, Tc99m disofenin, Tc99m gluceptate, Tc99m lidofenin, Tc99mMebrofenin, Tc99m medronate and its sodium salt, Tc99m mertiatide, Tc99m oxidronate, Tc99m pentetate and its salt, Tc99m sestambi, Tc99m siboroxime, Tc99m succinimide succimer, Tc99m sulfur colloid, Tc99m teboroxime, Tc99m tetrofosmin, Tc99m tiatide, thyroxine 1125, thyroxine 1131, tolpovidone 1131, triolein 1125 and threolin 1125, and threolin 131, MIBG-I123 and MIBG1131.

[0100] In some embodiments, the compounds described herein are administered in combination with one or more immune checkpoint inhibitors, kinase inhibitors, tubulin inhibitors, or topoisomerase inhibitors.

[0101] In some embodiments, the compounds described herein are administered in combination with one or more immune checkpoint inhibitors. Immune checkpoint inhibitors include any agent that blocks or inhibits an inhibitory pathway of the immune system in a statistically significant manner. Exemplary immune checkpoint targets for blockage or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (a member of the CD2 family of molecules expressed on all NK, gamma delta, and memory CD8+ (alpha beta) T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Immune checkpoint inhibitors include antibodies, or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (a CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (a PD-1 blocker), nivolumab (an anti-PD1 antibody), CT-011 (an anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (an anti-PDL1 antibody), BMS-936559 (an anti-PDL1 antibody), MPLDL3280A (an anti-PDL1 antibody), MSB0010718C (an anti-PDL1 antibody), and yervoy / ipilimumab (an anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0102] In one embodiment, the present invention covers the use of compounds of the present invention with one or more additional therapeutic agents that block the interaction between the immune checkpoint receptor programmed cell death protein 1 (PD-1) and its ligand, PD-L1. See, for example, A. Mullard, "New checkpoint inhibitors ride the immunotherapy tsunami," Nature Reviews: Drug Discovery (2013), 12:489-492. PD-1 is expressed on T cells and regulates T cell activity. Specifically, when PD-1 is not bound to PDL-1, T cells can engage and kill target cells. However, when PD-1 is bound to PDL-1, it stops T cells from engaging and killing target cells. Furthermore, unlike other checkpoints, PD-1 acts in close proximity to such PDL-1 and is directly overexpressed on cancer cells, which leads to increased binding to PD-1-expressing T cells.

[0103] In another aspect, the compounds of the present disclosure can be used in combination with antibodies that can act as PD-1 agonists, thereby modulating immune responses controlled by PD-1. In one embodiment, the anti-PD-1 antibody can be an antigen-binding fragment. The anti-PD-1 antibodies disclosed herein can bind to human PD-1 and stimulate the activity of PD-1, thereby inhibiting the function of immune cells that express PD-1. In some embodiments, compounds of the present disclosure may be used in combination with one or more PD-1 inhibitors selected from pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, nivolumab, AMP-224, or AMP-514. In some embodiments, compounds of the present disclosure may be used in combination with one or more PD-L1 inhibitors selected from atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, or BMS-986189.

[0104] In some embodiments, compounds of the present disclosure may be used in combination with one or more therapeutic agents that inhibit CTLA-4. Suitable anti-CTLA4 antagonist agents for use herein include anti-CTLA4 antibodies, human anti-CTLA4 antibodies, murine anti-CTLA4 antibodies, mammalian anti-CTLA4 antibodies, humanized anti-CTLA4 antibodies, monoclonal anti-CTLA4 antibodies, polyclonal anti-CTLA4 antibodies, chimeric anti-CTLA4 antibodies, MDX-010 (ipilimumab), tremelimumab, anti-CD28 antibodies, anti-CTLA4 adnectins, anti-C These include, but are not limited to, TLA4 domain antibodies, single chain anti-CTLA4 fragments, heavy chain anti-CTLA4 fragments, light chain anti-CTLA4 fragments, inhibitors of CTLA4 that stimulate the costimulatory pathway, antibodies disclosed in PCT Publication No. 2001 / 014424, antibodies disclosed in PCT Publication No. 2004 / 035607, antibodies disclosed in U.S. Patent Publication No. 2005 / 0201994, and antibodies disclosed in granted European Patent No. 1212422B1. Additional CTLA-4 antibodies are described in U.S. Patent Nos. 5,811,097, 5,855,887, 6,051,227, and 6,984,720; PCT Publication Nos. 01 / 14424 and 00 / 37504; and U.S. Patent Publication Nos. 2002 / 0039581 and 2002 / 086014. Other anti-CTLA-4 antibodies that can be used in the methods of the invention include those disclosed in WO 98 / 42752; U.S. Patent Nos. 6,682,736 and 6,207,156; Hurwitz et al., Proc. Natl. Acad. Sci. USA, 95(17):10067-10071 (1998); Camacho et al., J. Clin. Oncology, 22(145):Abstract No. 2505 (2004) (antibody CP-675206); Mokyr et al., Cancer Res., 58:5301-5304 (1998), and U.S. Patent Nos. 5,977,318, 6,682,736, 7,109,003, and 7,132,281.Additional anti-CTLA4 antagonists include, but are not limited to, any inhibitor that can disrupt the ability of the CD28 antigen to bind to its cognate ligand, inhibit the ability of CTLA4 to bind to its cognate ligand, enhance T cell responses via the costimulatory pathway, disrupt the ability of B7 to bind to CD28 and / or CTLA4, disrupt the ability of B7 to activate the costimulatory pathway, disrupt the ability of CD80 to bind to CD28 and / or CTLA4, disrupt the ability of CD80 to activate the costimulatory pathway, disrupt the ability of CD86 to bind to CD28 and / or CTLA4, disrupt the ability of CD86 to activate the costimulatory pathway, and disrupt the costimulatory pathway from being activated in general. This necessarily includes small molecule inhibitors of CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway; antibodies directed against CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway; antisense molecules directed against CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway; adnectins directed against CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway; RNAi inhibitors (both single-stranded and double-stranded) of CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway; other anti-CTLA4 antagonists.

[0105] In some embodiments, the compounds of the present disclosure can be used in combination with one or more therapeutic agents that inhibit TIM-3. Blocking TIM-3 activation by its ligand results in increased Th1 cell activation. Furthermore, TIM-3 has been identified as an important inhibitory receptor expressed by exhausted CD8+ T cells. TIM-3 has also been reported as a key regulator of nucleic acid-mediated antitumor immunity. In one example, TIM-3 has been shown to be upregulated on tumor-associated dendritic cells (TADCs).

[0106] Method of administration The compounds used in the methods described herein can be administered by any suitable method and technique currently known or expected to become known to those skilled in the art. For example, the active ingredients described herein can be formulated in a physiologically acceptable or pharmaceutically acceptable form and administered by any suitable route known in the art, including, for example, oral and parenteral routes of administration. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. The administration of the active ingredients of these compositions can be a single administration or can be continuous and at distinct intervals that can be easily determined by those skilled in the art.

[0107] The compositions described herein that include active compounds and certain excipients may be useful for a variety of medical and non-medical applications. For example, pharmaceutical compositions that include active compounds and excipients may be useful for treating and preventing mycobacterial infections.

[0108] "Excipients" include any and all solvents, diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., appropriate for the particular dosage form desired. General considerations in formulation and / or manufacturing can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0109] Exemplary excipients include, but are not limited to, any non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any kind. Some examples of materials which may function as excipients include, but are not limited to, sugars such as lactose, glucose, sucrose, and the like; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffers, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, and perfuming agents; preservatives and antioxidants can also be present in the compositions, according to the judgment of the formulator. As will be appreciated by those skilled in the art, excipients may be selected based on what the composition is useful for. For example, in pharmaceutical or cosmetic compositions, the choice of excipients will depend on the route of administration, the agent being delivered, the time course of delivery of the agent, etc., and may be administered to humans and / or animals orally, rectally, parenterally, intracisternally, intravaginally, intranasally, intraperitoneally, topically (such as by powder, cream, ointment, or drops), bucally, or as an oral or nasal spray. In some embodiments, the active compounds disclosed herein are administered topically.

[0110] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and the like, and combinations thereof.

[0111] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus juice pomace, agar, bentonite, cellulose and wood products, sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (croscarmellose), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and the like, and combinations thereof.

[0112] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and veegum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol monostearate, propylene ... glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxyethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and the like, and / or combinations thereof. Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and the like, and / or combinations thereof.

[0113] Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0114] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0115] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0116] Exemplary fungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0117] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0118] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0119] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tricalcium phosphate, calcium phosphate hydroxide, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and the like, and combinations thereof.

[0120] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and the like, and combinations thereof.

[0121] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, blackcurrant seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, linseed, geraniol, loofah, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cucumber, macadamia. Exemplary synthetic oils include macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0122] Furthermore, the composition may further comprise a polymer. Exemplary polymers contemplated herein include cellulose polymers and copolymers, such as cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethylcellulose (CMC) and various salts thereof, including, for example, sodium salts, hydroxyethylcarboxymethylcellulose (HECMC) and various salts thereof, carboxymethylhydroxyethylcellulose (CMHEC) and various salts thereof, starch, dextran, dextran derivatives, chitosan, and other polysaccharides and polysaccharide derivatives, such as alginic acid and various salts thereof, various gums, including carrageenan, xanthan gum, guar gum, gum arabic, karaya gum, ghatti gum, konjac, and tragacanth gum, glycosaminoglycans and proteoglycans, such as hyaluronic acid and salts thereof, proteins, such as gelatin, collagen, albumin, and fibrin, Other polymers, such as polyhydroxy acids such as polylactide, polyglycolide, poly(lactide-co-glycolide) and poly(epsilon-caprolactone-co-glycolide), carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, polyacrylic acid / acrylamide copolymers, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxide-propylene oxide), and Pluronics. (Pluronic) polymers, polyethylene glycol (PEG) polymers such as polyoxyethylene (polyethylene glycol), polyanhydrides, polyvinyl alcohol, polyethyleneamines and polypyridines, and PEGylated lipids (e.g., PEG-stearate, l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-1000], l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000], and l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000]), copolymers and salts thereof, but are not limited to these.

[0123] In addition, the composition may further comprise an emulsifier. Exemplary emulsifiers include polyethylene glycol (PEG), polypropylene glycol, polyvinyl alcohol, poly-N-vinylpyrrolidone and its copolymers, poloxamer nonionic surfactants, natural water-soluble polysaccharides (e.g., dextran, ficoll, cellulose), non-cationic poly(meth)acrylates, non-cationic polyacrylates such as poly(meth)acrylic acid and its ester amides and hydroxyalkyl amides, natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [ magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxyethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or combinations thereof. In certain embodiments, the emulsifier is cholesterol.

[0124] Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid composition may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0125] Injectable compositions, for example, injectable aqueous or oily suspensions, can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that can be used include water, Ringer's solution, and USP saline. In addition, sterile, solidified oils are conventionally used as solvents or suspending media. Any brand of solidified oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in injectable formulations. In certain embodiments, particles are suspended in a carrier fluid containing 1% (w / v) sodium carboxymethylcellulose and 0.1% (v / v) Tween 80. Injectable compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0126] Compositions for rectal or vaginal administration may be in the form of suppositories, which can be prepared by mixing the particles with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the particles.

[0127] Solid compositions include capsules, tablets, pills, powders, and granules. In such solid compositions, particles are mixed with at least one excipient and / or a) filler such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binder such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) wetting agent such as glycerol; d) disintegrating agent such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardant such as paraffin; f) absorption accelerator such as quaternary ammonium compound; g) wetting agent such as cetyl alcohol and glycerol monostearate; h) absorbent such as kaolin and bentonite clay; i) lubricant such as talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering materials. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0128] Tablets, capsules, pills, and granules can be prepared with coatings such as enteric coatings, as well as shells and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0129] Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is mixed with an excipient and any needed preservatives or buffers as required.

[0130] The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0131] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can also contain conventional propellants such as chlorofluorohydrocarbons.

[0132] Transdermal patches have the added advantage of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispersing nanoparticles in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the particles in a polymer matrix or gel.

[0133] The active ingredient may be administered in such amounts, for such times, and by such routes as are deemed necessary to achieve the desired results. The precise amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular active ingredient, its mode of administration, its mode of activity, and the like. The active ingredient, whether it is the active compound itself or the active compound is combined with a drug, is preferably formulated in unit dosage form for ease of administration and uniformity of dosage. However, it will be understood that the total daily amount of the active ingredient will be determined by the attending physician within the scope of sound medical judgment. A certain therapeutically effective dose level for any particular subject will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the active ingredient used; the particular composition used; the patient's age, weight, general health, sex, and diet; the time, route of administration, and excretion rate of the particular active ingredient used; the duration of treatment; drugs used in combination or concurrently with the particular active ingredient used; and similar factors well known in the medical field.

[0134] The active ingredient may be administered by any route. In some embodiments, the active ingredient is administered via various routes, including oral, intravenous, intramuscular, intraarterial, intraspinal, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, vaginal, intraperitoneal, topical (as powder, ointment, cream, and / or liquid drops), mucosal, intranasal, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as oral spray, nasal spray, and / or aerosol. Generally, the most appropriate route of administration will depend on various factors, including the properties of the active ingredient (e.g., its stability in the gastrointestinal environment), the condition of the subject (e.g., whether the subject can tolerate oral administration), etc.

[0135] The exact amount of active ingredient required to obtain a therapeutically or prophylactically effective amount will vary from subject to subject, depending on the species, age, and general health of the subject, the severity of the side effect or disorder, the identity of the particular compound, the mode of administration, etc. For example, the amount to be administered to a child or adolescent can be determined by a medical professional or skilled artisan, or may be lower than or similar to the amount administered to an adult.

[0136] Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art.

[0137] The dosage range for administering the compositions is a dosage large enough to produce the desired effect in which the symptom or disorder is affected, based on their in vitro activity and in vivo activity range. The dosage should not be so large as to cause side effects such as undesirable cross-reactions, anaphylactic-type reactions, etc. Generally, the dosage will vary depending on the patient's age, condition, sex, and degree of disease, and can be determined by one skilled in the art. The dosage can be adjusted by an individual physician in the event of any contraindications. The dosage can be varied and can be administered in one or more doses daily for one or several days.

[0138] Although several embodiments of the present disclosure have been described, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0139] By way of non-limiting illustration, examples of specific embodiments of the present disclosure are given below. [Example]

[0140] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the present disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers, but some errors and deviations should be accounted for.

[0141] Example 1: Inhibition of IL1b-induced NF-κB activation in ST2 cells using Compound 1 UR241-2, which has the following chemical structure: [ka] was administered to ST2 cells.

[0142] Procedure: For drug treatment, 1x10 cells per well 4 THP-1 NF-κB-luciferase reporter cells were seeded in RPMI / 0.5% FBS medium in a 96-well white plate. Small molecule compounds were serially diluted in RPMI / 0.5% FBS medium and pre-incubated with the cells for 30 minutes at 37°C. Human IL-1β was added to the wells to a final concentration of 10 ng / mL, and the plate was incubated for an additional 6 hours at 37°C. Luciferase assays were performed using the ONE-Glo Luciferase Assay System (Promega) according to the manufacturer's protocol. Briefly, 100 μL of ONE-Glo reagent was added per well (1:1) and allowed to stand for at least 3 minutes to allow complete cell lysis. Luminescence was measured using a Synergy2 microplate reader (BioTek).

[0143] Synthetic Method: Commercially available acids were coupled with substituted anilines using DCC in anhydrous DMF. Briefly, equimolar DCC was added to a solution of the substituted pyridine carboxylic acid and stirred at ice temperature for 20 minutes. Then, equimolar substituted aniline was added, and the reaction mixture was stirred overnight. DMF was removed under reduced pressure using a Buchi rotary evaporator. The reaction mixture was triturated with ice. The crude solid separated was filtered. A small portion of the crude product was purified using a preparative TLC plate. The pure compound band was extracted from the preparative TLC plate. The compound was stripped from the silica gel using MeOH / DCM (90:10). The solvent was evaporated, and the compound was stored at -20 °C for further study. The structure of the compound was confirmed using high-resolution mass spectrometry (HRMS).

[0144] According to the above synthetic procedures, representative compounds UR241-1 and UR241-2 were prepared: [ka]

[0145] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein; they are intended as illustrations of some aspects of the claims; any compositions and methods that are functionally equivalent are intended to be within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to be within the scope of the appended claims. Furthermore, while only certain representative compositions and method steps disclosed herein are specifically recited, other combinations of compositions and method steps, even if not specifically recited, are also intended to be within the scope of the appended claims. Thus, although combinations of steps, elements, components, or ingredients may be explicitly referred to herein or hereinafter, other combinations of steps, elements, components, or ingredients are included, even if not explicitly recited.

[0146] Other than in the examples, or unless otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims should be understood to be construed in light of the number of significant digits and ordinary rounding approaches, at least as an attempt to limit the application of the doctrine of equivalents to the scope of the claims. The present invention includes the following aspects. [1] A compound of formula I [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof, During the ceremony, X 1 is NR a , O, or S; X 2 are N, CH, and CR 1 is selected from X 3 and X 4 are independently N, CH, and CR 2 is selected from X 5 , O, NR a , S, and CR b R c is selected from X 6 is NR a , -CR d R e -, S, and O; X 7 is a bond or NR a and R a is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 selected from cycloalkyl, 4-10 membered monocyclic or bicyclic heterocycle, 5-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted, valence permitting, with one or more Y groups; R b and R c is independently, at each occurrence, hydrogen, halo, nitro, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, 4-10 membered monocyclic or bicyclic heterocycle, 5-10 membered monocyclic or bicyclic aryl, C(O)R z , -S(O)R z , and -S(O) 2 R z each of which may be optionally substituted, valence permitting, with one or more Y groups; R 1 、R 2 , and R 3 is independently, in each occurrence, halo, nitro, cyano, azido, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 cycloalkyl, (4-10 membered monocyclic or bicyclic heterocycle)-(C 0 -C 6 alkyl), (5-10 membered monocyclic or bicyclic aryl)-(C 0 -C 6 alkyl), (5-10 membered monocyclic or bicyclic heteroaryl)-(C 0 -C 6 alkyl), -OR x , -SR x , -NR x R y , -C(O)R z , -S(O)R z , and -S(O) 2 R z each of which may be optionally substituted, valence permitting, with one or more Y groups; m is 0, 1, or 2; n is 0, 1, or 2; o is 0, 1, 2, 3, or 4; R 4 teeth,

change

change

change

[10] X 3 The compound according to any one of the above [1] to [9], or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

[11] X 3 The compound according to any one of the above [1] to [9], or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is CH.

[12] X 4 The compound according to any one of the above [1] to

[11] , wherein is N, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[13] X 4 The compound according to any one of the above [1] to

[11] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

[14]

change

[15]

change

[16] X 5 The compound according to any one of the above [1] to

[15] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

[17] X 6 The compound according to any one of the above [1] to

[16] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is NH.

[18]

change

[15] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from:

[19]

change

[18] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from:

[20] X 7 The compound according to any one of the above [1] to

[19] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is a bond.

[21] X 7 The compound according to any one of the above [1] to

[19] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein is NH.

[22] R 4 but

change

[21] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

[23] X 8 The compound according to

[22] above, wherein is N, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[24] X 9 The compound according to

[22] or

[23] above, wherein is S(O), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[25] X 9 is S(O) 2 The compound according to

[22] or

[23] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

[26]

change

[22] above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from:

[27]

change

[22] above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from:

[28] R 4 but

change

[21] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

[29] X 10 The compound according to

[28] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

[30] X 11 -(CR d R e ) 2 The compound according to

[28] or

[29] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

[31] R6 -S(O) 2 R z The compound according to any one of the above

[28] to

[30] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

[32] R 6 -S(O) 2 (C 1 -C 6 The compound according to any one of the above

[28] to

[30] , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is 1 or 2;

[33]

change

[28] above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from:

[34] The compound,

change

[35] The compound,

change

change

[36] The compound,

change

change

[37] The compound,

change

change

[38] A pharmaceutical composition comprising the compound according to any one of [1] to

[37] above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[39] The pharmaceutical composition according to

[38] above, further comprising a second therapeutic agent.

[40] A method for treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of [1] to

[37] above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or the pharmaceutical composition according to

[38] above.

[41] The method of

[40] , wherein the autoimmune disorder is selected from the group consisting of rheumatoid arthritis, lupus, diabetes, systemic sclerosis, vasculitis, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), giant cell arteritis (GCA), autoimmune encephalitis, autoimmune uveitis, autoimmune hepatitis, hemolytic anemia, inflammatory bowel disease, clonal hematopoiesis, anemia or chronic disease, and inflammatory eye disease.

[42] A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of [1] to

[37] above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or the pharmaceutical composition according to

[38] above.

[43] The method according to

[42] above, wherein the cancer is a solid tumor.

[44] The method according to

[43] , wherein the solid tumor is selected from the group consisting of pancreatic cancer, lung cancer, ovarian cancer, colorectal cancer, breast cancer, endometrial cancer, head and neck cancer, and renal cancer.

[45] The method according to

[42] , wherein the cancer comprises blood cancer.

[46] The method according to

[45] , wherein the blood cancer includes leukemia.

[47] The method according to

[45] , wherein the blood cancer comprises myeloma.

[48] ​​A method for treating a pain disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to any one of [1] to

[37] above, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition according to

[38] above.

[49] The method according to

[48] , wherein the pain disorder comprises neuropathic pain or nociceptive pain.

[50] The method of

[48] , wherein the pain disorder comprises inflammatory pain, postoperative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, or phantom limb pain.

[51] The method according to any one of

[40] to

[50] above, wherein the compound is administered in combination with or alternating with one or more additional therapeutic agents.

[52] The method of

[51] , wherein the one or more additional therapeutic agents include an NLRP3 inhibitor.

[53] The method of

[51] , wherein the one or more additional therapeutic agents include a chemotherapeutic agent.

[54] The method of

[51] , wherein the one or more additional therapeutic agents comprise a therapeutic antibody.

Claims

【Request Item 1】 【Chemistry 1】 【change】 or a pharmaceutically acceptable salt or solvate thereof.

2. 10. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

3. 3. The pharmaceutical composition of claim 2, further comprising a second therapeutic agent.

4. 10. A pharmaceutical composition for treating an autoimmune disorder in a subject in need thereof, comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

5. 5. The pharmaceutical composition of claim 4, wherein the autoimmune disorder is selected from the group consisting of rheumatoid arthritis, lupus, diabetes, systemic sclerosis, vasculitis, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), giant cell arteritis (GCA), autoimmune encephalitis, autoimmune uveitis, autoimmune hepatitis, hemolytic anemia, inflammatory bowel disease, clonal hematopoiesis, anemia or chronic disease, and inflammatory eye disease.

6. 10. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

7. The pharmaceutical composition of claim 6, wherein the cancer is a solid tumor.

8. 8. The pharmaceutical composition of claim 7, wherein the solid tumor is selected from the group consisting of pancreatic cancer, lung cancer, ovarian cancer, colorectal cancer, breast cancer, endometrial cancer, head and neck cancer, and renal cancer.

9. The pharmaceutical composition of claim 6 , wherein the cancer comprises a hematological cancer.

10. 10. The pharmaceutical composition of claim 9, wherein the hematological cancer comprises leukemia or myeloma.

11. 10. A pharmaceutical composition for treating a pain disorder in a subject in need thereof, comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

12. 12. The pharmaceutical composition of claim 11, wherein the pain disorder comprises neuropathic pain or nociceptive pain.

13. 12. The pharmaceutical composition of claim 11, wherein the pain disorder comprises inflammatory pain, post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, or phantom limb pain.

14. The pharmaceutical composition of any one of claims 4 to 13, wherein the compound is administered in combination or alternation with one or more additional therapeutic agents.

15. 15. The pharmaceutical composition of claim 14, wherein the one or more additional therapeutic agents comprise an NLRP3 inhibitor, a chemotherapeutic agent, or a therapeutic antibody.

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