Pyrrolo [1, 2-b] pyridazine derivatives

Abstract

PROVIDING A METHOD OF TREATING A DISEASE SOLUTION: Compounds of formula (I): (I), pharmaceutically acceptable salts thereof, deuterated analogs thereof, compositions thereof, and methods of treating diseases using the compounds (wherein variable substituents are disclosed herein). The compounds of the present disclosure have also been found to inhibit the production of the pro-inflammatory cytokines TNFα, IL-6, IL-1β, IL-8, IL-12, IL-23 and the type I interferons IFNα and IFNβ, all of which are mediators of inflammation and immune responses.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to novel compounds that are inhibitors of the kinase IRAK4. The disclosure also relates to methods for preparing those compounds and pharmaceutical compositions containing such compounds. [Background technology]

[0002] Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine-threonine kinase that acts as a mediator in the interleukin-1 / Toll-like receptor (IL-1 / TLR) signaling cascade. More specifically, IRAK4 is involved in the activation of the signaling cascade of the adaptor protein myeloid differentiation primary response gene 88 (MyD88) and is hypothesized to play a role in inflammatory and fibrotic disorders such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, viral myocarditis, acute and chronic tissue injury, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, and kidney diseases, including chronic kidney disease and diabetic kidney disease. Furthermore, IRAK4 is hypothesized to play a role in certain cancers and in inflammation associated with gastrointestinal infections, including C. difficile. Signaling through IL-1R / TLR leads to the activation of MyD88, which recruits IRAK4 and IRAK1 to form a signaling complex. This complex then interacts with a series of kinases, adaptor proteins, and ligases, ultimately leading to the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein-1 (AP1), cyclic AMP-responsive element-binding protein (CREB), and interferon regulatory factors (IRFs), including IRF5 and IRF7, inducing the production of proinflammatory cytokines and type I interferons.

[0003] Therefore, inhibitors of IRAK4 have potential therapeutic potential in the treatment of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, inflammation associated with gastrointestinal infections including C. difficile, viral myocarditis, acute and chronic tissue injury, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, and kidney diseases including chronic kidney disease and diabetic kidney disease (Joosten, L.A. et al., TOLL-LIKE RECEPTORS AND CHRONIC INFLAMMATION IN RHEUMATIC DISEASES: NEW DEVELOPMENTS, Nat. Rev. Rheumatol., 346 | JUNE 2016 12; 344-357 Published online 12 May 2016) (Valaperti, A. et al., INNATE IMMUNE INTERLEUKIN-1RECEPTOR-ASSOCIATED KINASE 4 EXACERBATES VIRAL MYOCARDITIS BY REDUCING CCR5 + CD11b + MONOCYTE MIGRATION AND IMPAIRING INTERFERON PRODUCTION, Circulation, 128 | SEPTEMBER 2013 14; 1542-1554), and type I interferonopathies (e.g., Aicardi-Goutières syndrome, familial lupus pernio, and retinal vasculopathy with cerebral leukodystrophy) (Lee-Kirsch et al., TYPE I INTERFERONOPATHIES—AN EXPANDING DISEASE SPECTRUM OF IMMUNODYSREGULATION, Semin. Immunopathol. (2015) 37:349-357), (Leaf, IA et al., PERICYTE MYD88 AND IRAK4 CONTROL INFLAMMATORY AND FIBROTIC RESPONSES TO TISSUE INJURY, The Journal of Clinical Investigation, 127 | JANUARY 2017 1; 321-334), (Seki, E. et al., TLR4 ENHANCES TGF-β SIGNALING AND HEPATIC FIBROSIS, Nature Medicine, 13 | NOVEMBER 2007 11; 1324-1332), (Garcia-Martinez, I. et al., HEPATOCYTE MITOCHONDRIAL DNA DRIVES NONALCHOLIC STEATOHEPATITIS BY ACTIVATION OF These compounds may be useful in treating inflammatory and fibrotic disorders, such as TLR9, The Journal of Clinical Investigation, 126 | MARCH 2016 3; 859-864.

[0004] Furthermore, certain cancers, including lymphomas, may contain one or more mutations in the MYD88 adaptor protein that result in a constitutively active signaling cascade that can promote tumor cell survival (Kelly et al., IRAK4 inhibitors for autoimmunity and lymphoma, J. Exp. Med. 2015 Vol. 212 No. 13 2189-2201).

[0005] Therefore, inhibitors of IRAK4 may be useful in the treatment of cancers, including lymphoma.

[0006] Currently, there are no approved pharmaceuticals that inhibit IRAK4. Therefore, it would be useful to provide IRAK4 inhibitor compounds with properties suitable for administration as pharmaceuticals to mammals, particularly humans. The considerations for selecting a pharmaceutical compound are multifactorial. Compound characteristics are often profiled, including precise potency, pharmacokinetics, pKa, solubility, stability (e.g., metabolic stability), and off-target burden (including potential cardiotoxicity), as well as potential drug-drug interactions.

[0007] Inhibition of the cardiac ion channel encoded by the human ether-a-go-go-related gene (hERG) can lead to arrhythmias, a major challenge in drug discovery and development. Automated electrophysiological patch clamp allows assessment of hERG channel activity early in drug development to support medicinal chemistry programs and has become routine for pharmaceutical companies. Early identification of hERG liability in drug discovery programs by automated patch clamp, Front Pharmaco. (2 Sept. 2014); 5: 203.

[0008] WO2016210034, WO2016210036, WO2015150995, WO2016127024 and WO2016210037 list compounds that are said to be useful as IRAK4 inhibitors. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2016 / 210034 [Patent Document 2] International Publication No. 2016 / 210036 [Patent Document 3] International Publication No. 2015 / 150995 [Patent Document 4] International Publication No. 2016 / 127024 [Patent Document 5] International Publication No. 2016 / 210037 [Non-patent literature]

[0010] [Non-Patent Document 1] Joosten, LAB et al., TOLL-LIKE RECEPTORS AND CHRONIC INFLAMMATION IN RHEUMATIC DISEASES: NEW DEVELOPMENTS, Nat. Rev. Rheumatol., 346 | JUNE 2016 12; 344-357 Published online 12 May 2016 [Non-patent document 2] Valaperti, A. et al., INNATE IMMUNE INTERLEUKIN-1RECEPTOR-ASSOCIATED KINASE 4 EXACERBATES VIRAL MYOCARDITIS BY REDUCING CCR5+CD11b+ MONOCYTE MIGRATION AND IMPAIRING INTERFERON PRODUCTION, Circulation, 128 | SEPTEMBER 2013 14; 1542-1554 [Non-patent document 3] Lee-Kirsch et al., TYPE I INTERFERONOPATHIES-AN EXPANDING DISEASE SPECTRUM OF IMMUNODYSREGULATION, Semin. Immunopathol. (2015) 37:349-357 [Non-patent document 4] Leaf, IA et al., PERICYTE MYD88 AND IRAK4 CONTROL INFLAMMATORY AND FIBROTIC RESPONSES TO TISSUE INJURY, The Journal of Clinical Investigation, 127 | JANUARY 2017 1; 321-334 [Non-patent document 5] Seki, E. et al., TLR4 ENHANCES TGF-β SIGNALING AND HEPATIC FIBROSIS, Nature Medicine, 13 | NOVEMBER 2007 11; 1324-1332 [Non-patent document 6] Garcia-Martinez, I. et al., HEPATOCYTE MITOCHONDRIAL DNA DRIVES NONALCHOLIC STEATOHEPATITIS BY ACTIVATION OF TLR9, The Journal of Clinical Investigation, 126 | MARCH 2016 3; 859-864 [Non-Patent Document 7] Kelly et al., IRAK4 inhibitors for autoimmunity and lymphoma,J.Exp.Med.2015 Vol.212 No.13 2189-2201 [Non-patent document 8] Early identification of hERG liability in drug discovery programs by automated patch clamp, Front Pharmaco. (2 Sept. 2014); 5: 203 Summary of the Invention [Means for solving the problem]

[0011] Provided herein are compounds and pharmaceutical compositions useful as IRAK4 inhibitors.Some compounds of the present disclosure can be used in pharmaceutical compositions with at least one pharmaceutically acceptable excipient to treat subjects in need thereof.All of the compounds of the present disclosure have also been found to inhibit the production of pro-inflammatory cytokines TNFα, IL-6, IL-1β, IL-8, IL-12, IL-23, and type I interferon IFNα and IFNβ, which are mediators of inflammation and immune response.The present disclosure also provides compositions including pharmaceutical compositions, kits including the present compounds, and methods for using and producing the present compounds.

[0012] In one embodiment of the present disclosure, a compound of formula (I): [ka] or a pharmaceutically acceptable salt or structural isomer thereof, wherein R 1 is H, deuterium or C 1~4 alkyl, wherein C 1~4 alkyl is optionally substituted with one or more halo; R 2 is H, deuterium or C 1~4 alky, said alkyl optionally substituted with one or more halo; or R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl; R 3 is C 0~4 alkyl-CN) is provided.

[0013] In embodiments, R 2 is H.

[0014] In embodiments, R 1 is methyl.

[0015] In embodiments, R 3 is -CN.

[0016] In another embodiment, the compound of formula II: [ka] or a pharmaceutically acceptable salt or structural isomer thereof, wherein R 1 is H, deuterium or C 1~4 alkyl, wherein C 1~4 Alkyl is one or more hydrogen atoms are optionally replaced by deuterium; R 2 is H, deuterium or C 1~4 alkyl, wherein C 1~4 Alkyl has one or more hydrogen atoms optionally replaced by deuterium; R 3 is C 0~4 alkyl-CN) is provided.

[0017] In embodiments of formula (II), R 2 is H.

[0018] In another embodiment, R 2 is deuterium.

[0019] In embodiments of formula (II), R 1 is methyl.

[0020] In embodiments of formula (II), R 1 is methyl, and one or more hydrogen atoms attached to said methyl are replaced with deuterium.

[0021] In embodiments, R 3 is -CN.

[0022] In another embodiment, the compound of formula (III): [ka] or a pharmaceutically acceptable salt or deuterated analog thereof, wherein R 1 is H, deuterium, or methyl, wherein one or more hydrogen atoms are optionally replaced by deuterium. is provided.

[0023] In embodiments, a compound having the structure [ka] or a pharmaceutically acceptable salt thereof is provided.

[0024] In embodiments, there is provided a pharmaceutical composition comprising a compound herein or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0025] Another embodiment of the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure together with a pharmaceutically acceptable carrier and optionally a diluent.

[0026] Another embodiment of the present disclosure provides a method of treating an inflammation-related disease or disorder in a patient in need thereof, the method comprising administering to said patient a compound of the present disclosure or a pharmaceutical composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0027] Detailed Description of the Invention definition The following description sets forth example methods, parameters, etc. However, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of example embodiments.

[0028] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes at the front or back of a chemical group are a matter of convenience; chemical groups may be represented with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0029] Prefix “C” u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. C0 indicates an absent carbon, or in other words, a bond to the next substituent.

[0030] Reference herein to "about" a value or parameter includes (and describes) embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Also, the term "about X" includes the description of "X". Also, the singular form "a" includes the description of "X". " and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "the compound" includes a plurality of such compounds, and a reference to "the assay" includes a reference to one or more assays and equivalents thereof known to those skilled in the art.

[0031] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1-20alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0032] "Cyano" refers to the group --CN.

[0033] "Halo" refers to -F, -Cl, -Br, and -I.

[0034] Certain alternative commonly used chemical names may also be used. For example, divalent groups, such as divalent "alkyl" groups, divalent "aryl" groups, etc., may also be referred to as "alkylene" or "alkylenyl" groups, "arylene" or "arylenyl" groups, respectively. Also, unless expressly indicated otherwise, when a combination of groups is referred to herein as one moiety, e.g., arylalkyl, the last-mentioned group includes the atom at which that moiety is attached to the remainder of the molecule.

[0035] The term "optionally" or "optionally" means that the 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. Also, the term "optionally substituted" refers to any one or more hydrogen atoms in the specified atom or group that may or may not be replaced by a non-hydrogen moiety. "Optionally substituted" can be from zero to the maximum possible number of substitutions, each occurrence being independent. When the term "substituted" is used, the substitution must be at a substitutable hydrogen atom of the indicated substituent. Optional substitutions may be the same as or different from (required) substitutions.

[0036] When a moiety is "optionally substituted," and when reference is made to a general term such as any "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl," the general term is inclusive of any of the preceding terms specifically recited (e.g., (C 1~3 alkyl), (C 4~6 alkyl), -O(C 1~4 alkyl), (C 3~10 cycloalkyl), O-(C 3~10 For example, "any aryl" includes both "aryl" and examples of aryl (e.g., phenyl or naphthyl). Similarly, the term "any heterocyclyl" includes heterocyclyl such as oxetanyl, tetrahydropyranyl, morpholino, piperidinyl, etc. Similarly, the term "any heteroaryl" includes Heteroaryls include pyridine, pyridazine, thiazole, thiadiazole, quinoline, and the like.

[0037] Some of the above compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, those compounds are understood by those skilled in the art to include both amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0038] Any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have a structure represented by the formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine (e.g., 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 15 O. 18 O. 31 P, 32 P, 35 S, 36 Cl and 125 I). Various isotopically labeled compounds of the present disclosure, such as, for example: 3 H, 13 C and 14 Compounds incorporating a radioactive isotope, such as C. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques (e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT) (including drug or substrate tissue distribution assays)), or radiation treatment of patients.

[0039] The present disclosure also includes "deuterated analogs" of compounds of Formula I in which one to n hydrogens bonded to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds are highly resistant to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0040] Therapeutic compounds of the present disclosure that are labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful for PET or SPECT studies.Isotopically labeled compounds of the present disclosure and their prodrugs can be prepared by carrying out the procedures disclosed in the schemes or examples and preparation methods described below, usually by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents.In this context, deuterium is considered as a substituent in the compound of formula I.

[0041] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to be any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position A position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of this disclosure, any atom explicitly designated as deuterium (D) is meant to be deuterium.

[0042] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0043] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in the preparation of pharmaceutical compositions suitable for pharmaceutical use in animals or humans.

[0044] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is biologically or otherwise desirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Furthermore, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include salts of primary, secondary, and tertiary amines (e.g., alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)). Suitable amines include, but are not limited to, N(substituted alkenyl)amines, tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)amines, mono-, di-, or tri-cycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)), mono-, di-, or tri-arylamines (i.e., NH(aryl), HN(aryl), N(aryl)), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0045] The term "substituted" refers to any one or more substituted groups at a specified atom or group. means that the hydrogen atoms in the group (a) and (b) are replaced with one or more substituents other than hydrogen, provided that the normal valence of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with an infinite number of additional substituents (e.g., substituted aryls with substituted alkyls, which themselves are substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended for inclusion herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituents on that group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the above substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted. Those skilled in the art will recognize that the substituents and other moieties of the compounds of the general formulas herein should be selected to provide a compound that is sufficiently stable to provide a pharmaceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. Compounds with such stability are intended to fall within the scope of the present invention. It should be understood by those skilled in the art that any combination of the definitions and substituents described above should not result in an infeasible species or compound.

[0046] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0047] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided. Use in combination

[0048] Patients treated by administration of the IRAK4 inhibitors of the present disclosure often exhibit diseases or conditions that would benefit from treatment with other therapeutic agents. These diseases or conditions include inflammation, The inflammation may be of a sexual nature or may be associated with cancer, metabolic disorders, gastrointestinal disorders, etc. Accordingly, one aspect of the present disclosure is a method of treating an inflammation-related disease or condition, or a metabolic disorder, gastrointestinal disorder, or cancer, etc., comprising administering a compound together with one or more compounds useful in treating such disease to a subject, particularly a human subject, in need thereof.

[0049] In some embodiments, the compounds of the present disclosure are co-formulated with one or more additional active ingredients. In some embodiments, the other active ingredients are administered approximately simultaneously in separate dosage forms. In some embodiments, the other active ingredients are administered sequentially and at different times relative to the compounds of the present disclosure. Combinations for Inflammatory Diseases and Conditions

[0050] For example, compounds of the disclosure may be one or more of 5-lipoxygenase inhibitors, acetylcholinesterase inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, ACTH receptor agonists, activin receptor antagonists, acyltransferase inhibitors, adrenocorticotropic hormone ligands, AKT1 gene inhibitors, alkaline phosphatase modulators, alkaline phosphatase stimulators, androgen receptor agonists, apolipoprotein C3 antagonists, ASK1 kinase inhibitors, bactericidal permeability protein stimulators, beta-adrenoceptor antagonists, beta-glucuronidase inhibitors, B-lymphocyte antigen CD20 inhibitors, bradykinin receptor modulators, BTK kinase inhibitors, calcineurin inhibitors, calcium channel inhibitors, cannabinoid CB1 receptor modulators, cannabinoid CB2 receptor modulators, cannabinoid CB3 receptor modulators, cannabinoid CB4 receptor modulators, cannabinoid CB5 receptor modulators, cannabinoid CB6 receptor modulators, cannabinoid CB7 receptor modulators, cannabinoid CB8 receptor modulators, cannabinoid CB9 receptor modulators, cannabinoid CB1 receptor modulators, cannabinoid CB1 receptor modulators, cannabinoid CB2 ... receptor modulators, cannabinoid receptor antagonists, cannabinoid receptor modulators, caspase inhibitors, cathepsin S inhibitors, CCN protein stimulators, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CCR9 chemokine antagonists, CD3 modulators, CD40 ligand inhibitors, CD40 ligand receptor antagonists, CD49b antagonists, CD49d antagonists, CD89 agonists, cell adhesion molecule inhibitors, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 agonists, CSF-1 antagonists, CXC10 chemokine ligand inhibitors, CXCR2 chemokine antagonists, cyclic GMP phosphodiesterase inhibitors, cyclooxygenase 2 inhibitors, cyclooxygenase inhibitors, cyclooxygenase stimulators, cytochrome P4503A4 inhibitors, cytotoxic T-lymphocyte protein-4 stimulators, dihydroceramide delta-4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, DNA polymerase inhibitors, DPP-4 inhibitors, EGFR family tyrosine kinase receptor modulators, eosinophil peroxidase inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, epidermal growth factor agonists, epidermal growth factor ligands, estrogen receptor beta agonists, factor XIII agonists, FGF-10 ligands, FGF2 receptor agonists, fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, FXR agonists, GATA3 transcription factor inhibitors, glucagon-like peptide 1 agonists, glucagon-like peptide 2 agonists, glucocorticoid agonists, GM-CSF receptor Agonists, G protein-coupled receptor 84 antagonists, guanylate cyclase receptor agonists, histamine H2 receptor antagonists, histone acetyltransferase inhibitors, histone deacetylase inhibitors, HLA class II antigen modulators, hydrolase inhibitors, HSD17β13 inhibitors, ICAM1 gene inhibitors, ICAM-1 inhibitors, IL1 gene inhibitors, IL-10 agonists, IL10 gene stimulators, IL-11 agonists, IL-12 antagonists, IL12 gene inhibitors, IL-13 antagonists, IL-17 antagonists, IL-2 antagonists, IL-2 receptor alpha subunit inhibitors, IL-21 antagonists, IL-23 antagonists, IL-6 antagonists, IL6 gene inhibitors, IL-6 receptor modulators, IL-7 antagonists, IL -8 antagonists, immunoglobulin G1 agonists, immunoglobulin G2 modulators, inosine monophosphate dehydrogenase inhibitors, insulin sensitizers, integrin alpha-4 / beta-1 antagonists, integrin alpha-4 / beta-7 antagonists, integrin alpha-E antagonists, integrin antagonists, integrin beta-7 antagonists, interferon beta ligands, interleukin-17E ligand inhibitors, interleukin ligand inhibitors, interleukin receptor 17A antagonists, interleukin receptor 17B antagonists, interleukin-1 beta ligands, interleukin-1 beta ligand modulators, interleukin-6 ligand inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, JAK2 gene inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, LanC-like protein 2 modulators, leukotriene BLT receptor antagonists, lipoxygenase modulators, L-selectin antagonists, MAdCAM inhibitors, matrix metalloproteinase inhibitors, matrix metalloproteinase modulators, melanocortin agonists, membrane copper amine oxidase inhibitors, metalloproteinase-2 inhibitors, metalloproteinase-9 inhibitors, MIP3 alpha ligand inhibitors, mitochondrial 10 kDa heat shock protein inhibitors Protein stimulators, monocyte differentiation antigen CD14 inhibitors, mTOR inhibitors, mucin stimulators, NAD-dependent deacetylase sirtuin-1 stimulators, natriuretic peptide receptor C agonists, neuregulin-4 ligands, nicotinic acetylcholine receptor agonists, nicotinic ACh receptor alpha 4 subunit modulators, nicotinic ACh receptor alpha 7 subunit stimulators, nicotinic ACh receptor beta 2 subunit modulators, NK1 receptor antagonists, NKG2 D-activated NK receptor antagonists, nuclear factor kappa B inhibitors, opioid growth factor receptor agonists, opioid receptor antagonists, opioid receptor delta antagonists, oxidoreductase inhibitors, P2X7 purinergic receptor agonists, p38 MAP kinase inhibitors, PARP inhibitors,PDE4 inhibitors, PDGF receptor agonists, phagocytosis-stimulating peptide modulators, phospho-MurNAc pentapeptide transferase inhibitors, phospholipase A2 inhibitors, platelet-activating factor receptor antagonists, potassium channel inhibitors, PPAR alpha agonists, PPAR delta agonists, PPAR gamma agonists, protein CYR61 stimulators, protein fimH inhibitors, protein kinase C alpha inhibitors, protein kinase C beta inhibitors, protein kinase C delta inhibitors, protein kinase C epsilon inhibitors , protein kinase C eta inhibitors, protein kinase C theta inhibitors, protein kinase G inhibitors, protein kinase inhibitors, P-selectin glycoprotein ligand-1 inhibitors, PurH purine biosynthesis protein inhibitors, retinoic acid receptor alpha agonists, retinoic acid receptor beta agonists, retinoid receptor agonists, RNA polymerase inhibitors, SMAD-7 inhibitors, sodium channel inhibitors, somatostatin receptor agonists, sphingosine 1 phosphate phosphatase 1 stimulators, sphingosine 1 phosphate Phosphatase modulators, sphingosine kinase 1 inhibitors, sphingosine kinase 2 inhibitors, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphate receptor-5 modulators, STAT3 gene inhibitors, STAT-3 inhibitors, STAT-4 inhibitors, stem cell antigen-1 inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, SYK kinase inhibitors, T cell surface glycoproteins CD28 inhibitors, TGF beta 1 ligand inhibitors, thymulin agonists, THR-beta agonists, TLR-2 antagonists, TLR-4 antagonists, TLR-9 agonists, TNF alpha ligand inhibitors, TNF alpha ligand modulators, TNF antagonists, TPL2 kinase inhibitors, trefoil factor modulators, tryptase inhibitors, tryptophan 5-hydroxylase inhibitors, tumor necrosis factor 14 ligand modulators, TYK2 kinase inhibitors, type I TNF receptor antagonists, type II TNF receptor modulators, Unspecified growth factor receptor modulators, vanilloid VR1 agonists, D3 receptor agonists, zonulin inhibitors, abatacept; acemannan; adalimumab; DCCT-10; apremilast; AST-120; balsalazide; balsalazide sodium; Basiliximab; beclomethasone dipropionate; budesonide; D-9421; budesonide MMX; catridecacog; certolizumab pegol; clostridium butyrate; etanercept; fingolimod; glatiramer acetate; golimumab; infliximab; infliximab biosimilar; infliximab successor biologics; interferon beta-1a; lenalidomide; mesalazine; GED-0001; AJG-501; met-enkephalin acetate combined with tridecactide acetate acetat; mycophenolate mofetil; naltrexone; natalizumab; nitazoxanide; olsalazine; oprelvekin; propionyl-L-carnitine; recombinant interferon beta-1a; remestemcel-L; rifaximin; rituximab; ropivacaine; rosiglitazone; sargramostim; secukinumab; SPD-480; tacrolimus; tamibarotene; teduglutide; thalidomide; tocilizumab; RO-4877533; tofacitinib; CP-690550; Trichuris suis eggs ova); ASP-1002; ustekinumab; valganciclovir; vedolizumab; zileuton; anti-CD3 imaging agent (antibody fragment, cancer / autoimmune disease), ImaginAb; AVX-470; cyclosporine; CXCR1 / 2 ligand mAb (immunology), Eli Lilly; FFP-102; GSK-3050002; INN-108; IR-777; SGM-1019; peg-ilodecakin; PF-06480605; PF-06651600; SER-287; Syn-1002; Thetanix; tolerogenic dendritic cell therapy TOP-1288; VBY-036; VBY-129; 946414-98-8; BMS-936557; 99mTc-annexin V-128; ABC-294640; abrilumab; Alequel; AMG-139; amiselimod; APD-334; ASP-3291; beclomethasone dipropionate; bertilimumab; cyclosporine;Clazakizumab; DLX-105; dolcanatide; E-6011; ETX-201; FFP-104; filgotinib; foralumab; GED-0507-34-Levo; givinostat; GLPG-0974; GLPG-1205; iberogast N (ulcerative colitis), Bayer r;BAY98-7410;INV-103;JNJ-40346527;K(D)PT;KAG-308;KHK-4083;KRP-203;Larazotide acetate;CB-01-05-MMX;LY-3074828;Mesalamine plus N-acetylcysteine;Midismase;Molgramostim successor biologic combination plus fosfomycin plus carbapenem,Reponex;Multipotent adult progenitor cells Cellular therapy (ischemia / cerebral palsy), Athersys / Healios; NN-8828; olokizumab; OvaSave; P-28-GST; PDA-002; PF-4236921; PF-547659; prednisolone; PUR-0110; QBECO; RBX-2660; repurposed naltrexone; JKB-122; SB-012; sotrastaurin; S TNM-01; TAK-114; tetomilast; Debio-0512; TRK-170; TRX-318; vatelizumab; VB-201; ZP-1848; zucapsaicin; ABT-494; alicaforsen; Ampion; BI-655066; briakinumab; cannabidiol; carotegast methyl; cobitolimod; dexamethasone sodium phosphate; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02; It may be used in combination with mesalazine; metronidazole mongersen; ocrelizumab; ozanimod; peficitinib; RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod; plecanatide; telotristat etiprate; infliximab biosimilar, Samsung Bioepis; AZD-058; and rifabutin in combination with clarithromycin, and even clofazimine.

[0051] The following non-exhaustive list of compound classes and compounds may also be used in combination with the compounds of the present disclosure: 5-lipoxygenase inhibitors (e.g., zileuton, etalocibm FPL-64170, E-3040, and BU-4601A); acetylcholinesterase inhibitors (e.g., BL-7040); ACTH receptor agonists (e.g., met-enkephalin acetate combined with tridecyl acetate, and FAR-404); activin receptor antagonists (e.g., follistatin); acyltransferase inhibitors (e.g., adrenocorticotropic hormone ligands (e.g., met-enkephalin acetate combined with tridecactide acetate, and FAR-404); AKT1 gene inhibitors (e.g., vidofludimus); alkaline phosphatase modulators (e.g., recombinant human alkaline phosphatase (oral, ulcerative colitis), AM-Pharma); alkaline phosphatase stimulators (e.g., bovine alkaline phosphatase); androgen receptor agonists (e.g., PB-005); apolipoprotein C3 antagonists antiseptics (e.g., AZD-0585); bactericidal permeability protein stimulators (e.g., opebacan); beta-adrenoceptor antagonists (e.g., NM-001); beta-glucuronidase inhibitors (e.g., KD-018); B-lymphocyte antigen CD20 inhibitors (e.g., ocrelizumab, rituximab); bradykinin receptor modulators (e.g., divinostat); calcineurin inhibitors (e.g., tacrolimus, cyclosporine); calcium channel inhibitors (e.g., clotrimazole); cannabinoids cannabinoid CB1 receptor modulators (e.g., GWP42003-P, cannabidiol); cannabinoid CB2 receptor modulators (e.g., GWP42003-P, cannabidiol); cannabinoid receptor antagonists (e.g., fingolimod); cannabinoid receptor modulators (e.g., GWP42003-P, cannabidiol); cathepsin S inhibitors (e.g., VBY-129, VBY-036); CCN protein stimulators (e.g., CSA-13); CCR3 chemokine antagonists (e.g., bertilimumab);CCR5 chemokine antagonists (e.g., HGS-1025); CCR9 chemokine antagonists (e.g., MLN-3126, vercirnon, CCX-025); CD3 modulators (e.g., visilizumab); CD40 ligand inhibitors (e.g., FFP-104); CD40 ligand receptor antagonists (e.g., FFP-104, FFP-102, tralizumab ... toralizumab); CD49b antagonists (e.g., batelizumab); CD49d antagonists (e.g., ELND-004); CD89 agonists (e.g., HF-1020); cell adhesion molecule inhibitors (e.g., natalizumab, alicaforsen (intravenous), ASP-2002, ISIS-2302); chemokine CXC ligand inhibitors (e.g., CXCR1 / 2 ligand mAb (immunology), Eli Lilly); CHST15 gene inhibitors (e.g., STNM-01); collagen regulators (e.g., Adipose-Derived Stem Cell Therapy (Celution System), Cytori, DCCT-10); CSF-1 agonists (e.g., sargramostim, molgramostim successor biologic combinations, fosfomycin combinations, carbapenems (in the small intestine, Crohn's disease), Reponex); CSF-1 antagonists (e.g., JNJ-40346527); CXC10 chemokine ligand inhibitors (e.g., 946414-98-8, BMS-936557); CXCR2 chemokine antagonists (e.g., elubrixin); cyclic GMP phosphodiesterase inhibitors (e.g., CEL-031); cyclooxygenase-2 inhibitors (e.g., P-54); Cyclooxygenase inhibitors (e.g., mesalazine, sodium 4-aminosalicylate, AJG-501, AGI-022); cyclooxygenase stimulators (e.g., nicotine polacrilex); cytochrome P450 3A4 inhibitors (e.g., KD-018); cytotoxic T-lymphocyte protein-4 stimulators (e.g., abatacept); dihydroceramide delta 4 desaturase inhibitors (e.g., ABC-294640); dihydroorotate dehydrogenase inhibitors (e.g., bidofludimus); DNA polymerase inhibitors (e.g., valganciclovir); EGFR family tyrosine kinase receptor modulators (e.g., neuregulin 4 (Crohn's disease / ulcerative colitis / necrotizing enterocolitis)), Avexegen Therapeutics / Children's Hospital of Los Angeles Angeles); eosinophil peroxidase inhibitors (e.g., AWEPOPD-01, AWEPO-003); eotaxin ligand inhibitors (e.g., bertilimumab); EP4 prostanoid receptor agonists (e.g., KAG-308); epidermal growth factor agonists (e.g., heparin-EGF-like factor, Scios Nova); epidermal growth factor ligands (e.g., Hebervis); estrogen receptor beta agonists (e.g., prinaberel); factor XIII agonists (e.g., catridecacog); FGF-10 ligands (e.g., repifermin); FGF2 receptor agonists (e.g., F2A); fractalkine ligand inhibitors (e.g., E-6011); free fatty acid receptor 2 antagonists (e.g., GLPG-0974); GATA3 Transcription factor inhibitors (e.g., SB-012); glucagon-like peptide 2 agonists (e.g., teduglutide, ZP-1848, NB-1002); glucocorticoid agonists (e.g., budesonide, beclomethasone dipropionate, dexamethasone sodium phosphate, AJG-511, DOR-201, D-9421-C); GM-CSF receptor agonists (e.g., sargramostim, molgramostim successor biologic combinations, fosfomycin combinations, carbapenems (in the small intestine, Crohn's disease), Reponex);G protein-coupled receptor 84 antagonists (e.g., GLPG-1205); guanylate cyclase receptor agonists (e.g., dolcatide, SP-333); histamine H2 receptor antagonists (e.g., bismuth, Medeva); histone acetyltransferase inhibitors (e.g., TIP60 inhibitors (ulcerative colitis / inflammatory bowel disease / autoimmune disease), University of Pennsylvania); histone deacetylase inhibitors (e.g., divinostat); HLA class II antigen modulators (e.g., HLA class II protein modulators (Crohn's disease), Nextera) AS); hydrolase inhibitors (e.g., SC-56938); ICAM1 gene inhibitors (e.g., alicaforsen); ICAM-1 inhibitors (e.g., alicaforsen (intravenous), ISIS-2302); IL1 gene inhibitors (e.g., PLR-14); IL-10 agonists (e.g., peg-ilodecaquin, AM-0010); IL10 gene stimulators, e.g., gene therapy (IL-10), Imperial College); IL-11 agonists (e.g., oprelvekin, YM-294); IL-12 antagonists (e.g., ustekinumab, briakinumab, apilimod); IL12 gene inhibitors (e.g., RDP-58); IL-13 antagonists (e.g., tralokinumab, anrukinzumab); IL-17 antagonists (e.g., secukinumab, bidofludimus); IL-2 antagonists (e.g., daclizumab); IL-2 receptor alpha subunit inhibitors (e.g., basiliximab, daclizumab, BSX-003, Ro-34-7375); IL-21 antagonists (e.g., NN-8828, ATR-107); IL-23 antagonists (e.g., tildrakizumab, ustekinumab, BI-655066, AMG-139, briakinumab, LY-3074828, apilimod); IL-6 antagonists (e.g., tocilizumab, clazakizumab, olokizumab, HMPL-004, AMG-220, FM-101); IL-6 gene inhibitors (e.g., YSIL6-T-PS); IL-6 receptor modulators (e.g., tocilizumab);IL-7 antagonists (e.g., interleukin-7 receptor modulators (ulcerative colitis / T-cell acute lymphoblastic leukemia)), Ef; fimune); IL-8 antagonists (e.g., elbrixine, clotrimazole); immunoglobulin G1 agonists (e.g., HF-1020); immunoglobulin G2 modulators (e.g., PF-547659); inosine monophosphate dehydrogenase inhibitors (e.g., mycophenolate mofetil); insulin sensitizers (e.g., elafibranor, rosiglitazone, HE-3286, EGS-21); integrin alpha-4 / beta-1 antagonists (e.g., natalizumab, TRK-170, filategrast); integrin alpha-4 / beta-7 antagonists (e.g., etrolizumab, vedolizumab, abrilumab, carotegrast methyl, TRK-170, filategrast); integrin alpha-E antagonists (e.g., etrolizumab); integrin antagonists (e.g., batelizumab, ASP-2002); integrin beta-7 antagonists (e.g., etrolizumab); interferon beta ligands (e.g., interferon beta-1a, recombinant interferon beta-1a, Serono); interleukin-17E ligand inhibitors (e.g., anti-IL-17BR humanized antibody (pulmonary fibrosis / asthma / ulcerative colitis)), Medical Research Council Technology); interleukin ligand inhibitors (e.g., HE-3286); interleukin receptor 17A antagonists (e.g., brodalumab); interleukin receptor 17B antagonists (e.g., anti-IL-17BR humanized antibodies (pulmonary fibrosis / asthma / ulcerative colitis)), Medical Research Council Technology); interleukin-1 beta ligands (e.g., K(D)PT, PUR-0110, HMPL-004); interleukin-1 beta ligand modulators (e.g., PUR-0110, HMPL-004); interleukin-6 ligand inhibitors (e.g., PF-4236921); JAK tyrosine kinase inhibitors (e.g., tofacitinib, peficitinib); Jak1 tyrosine kinase inhibitors (e.g., ABT-494, tofacitinib, filgotinib, peficitinib, GLPG-0555, solcitinib); JAK2 gene inhibitors (e.g., bidofludimus); Jak3 tyrosine kinase inhibitors (e.g., tofacitinib, peficitinib); Jun N-terminal kinase inhibitors (e.g., semapimod); LanC-like protein 2 modulators (e.g., BT-11); leukotriene BLT receptor antagonists (e.g., ONO-4057, etalocib, SC-53228, SC-52798); lipoxygenase modulators (e.g., mesalazine); L-selectin antagonists (e.g., BNP-001); MAdCAM inhibitors (e.g., vedolizumab, PF-547659); matrix metalloproteinase inhibitors (e.g., D-5410); matrix metalloproteinase modulators (e.g., D-5410); melanocortin agonists (e.g., ASP-3291); membrane copper amine oxidase inhibitors agents (e.g., bepalimomab); metalloproteinase-2 inhibitors (e.g., KD-018, RWJ-68354); metalloproteinase-9 inhibitors (e.g., GS-5745); MIP3 alpha ligand inhibitors (e.g., GSK-3050002); mitochondrial 10 kDa heat shock protein stimulators (e.g., INV-103); monocyte differentiation antigen CD14 inhibitors (e.g., CD14 anti-inflammatory drugs, Cornell); mTOR inhibitors (e.g., P-2281); mucin stimulators (e.g., rebamipide); NAD-dependent deacetylase sirtuin-1 stimulators (e.g., SRT-2104); natriuretic peptide receptor C agonists (e.g., plecanatide);Neuregulin-4 ligands (e.g., neuregulin 4 (Crohn's disease / ulcerative colitis / necrotizing enterocolitis), Avexegen Therapeutics / Children's Hospital of Los Angeles); nicotinic acetylcholine receptor agonists (e.g., TC-2403, nicotine polacrilex, nicotine); nicotinic ACh receptor alpha 4 subunit modulators (e.g., TC-2403); nicotinic ACh receptor alpha 7 subunit stimulators (e.g., GTS-21); nicotinic ACh receptor beta 2 subunit modulators (e.g., TC-2403); NK1 receptor antagonists (e.g., KD-018, norpitantium besylate (no; lpitantium besilate); NKG2 D-activating NK receptor antagonists (e.g., NNC-0142-002); nuclear factor kappa B inhibitors (e.g., KD-018, cobitolimod, CSA-13, HE-3286, HMPL-004, Avrina, N-acetylcysteine ​​with mesalamine, P-54); opioid growth factor receptor agonists (e.g., met-enkephalin acetate with tridecyl acetate, FAR-404); opioid receptor antagonists (e.g., naltrexone, IRT-103); opioid receptor delta antagonists (e.g., KD-018); oxidoreductase inhibitors (e.g., olsalazine); P2X7 purinergic receptor agonists (e.g., divinostat); p38 MAP kinase inhibitors (e.g., RDP-58, doramapimod, semapimod, RWJ-68354); PARP inhibitors (e.g., EB-47, INO-1003); PDE4 inhibitors (e.g., apremilast, tetomilast, CC-1088); PDGF receptor agonists (e.g., oprelvekin, YM-294); phagocytosis-stimulating peptide modulators (e.g., 99mTc-RP-128); phospho-MurNAc pentapeptide transferase inhibitors (e.g., SQ-641); phospholipase A2 inhibitors (e.g., varespladib methyl); platelet-activating factor receptor antagonists (e.g., delsalazine sodium); sodium channel inhibitors (e.g., clotrimazole); PPAR alpha agonists (e.g., elafibranor (GFT-1007)); PPAR delta agonists (e.g., elafibranor (GFT-1007)); PPAR gamma agonists (e.g., rosiglitazone, GED-0507-34-Levo, etalosib); protein CYR61 stimulators (e.g., CSA-13); protein fimH inhibitors (e.g., EB-8018); protein kinase C alpha inhibitors (e.g., sotrastaurin (AEB-071)); protein kinase C beta inhibitors (e.g., sotrastaurin (AEB-071)); protein kinase C delta inhibitors (e.g., sotrastaurin (AEB-071));Protein kinase C epsilon inhibitors (e.g., sotrastaurin (AEB-071)); protein kinase C eta inhibitors (e.g., sotrastaurin (AEB-071)); protein kinase C theta inhibitors (e.g., sotrastaurin (AEB-071)); protein kinases; G inhibitors (e.g., CEL-031); protein kinase inhibitors (e.g., TOP-1288); P-selectin glycoprotein ligand-1 inhibitors (e.g., SEL-K2); PurH purine biosynthesis protein inhibitors (e.g., mycophenolate mofetil); retinoic acid receptor alpha agonists (e.g., tamibarotene); retinoic acid receptor beta agonists (e.g., tamibarotene); retinoid receptor agonists (e.g., tamibarotene); RNA polymerase Sphingosine 1 phosphate phosphatase inhibitors (e.g., rifaximin); SMAD-7 inhibitors (e.g., mongelsen (GED-0301)); sodium channel inhibitors (e.g., ropivacaine); somatostatin receptor agonists (e.g., vapreotide); sphingosine 1 phosphate phosphatase 1 stimulators (e.g., APD-334); sphingosine 1 phosphate phosphatase modulators (e.g., S1P modulators (oral, multiple sclerosis / ulcerative colitis / rheumatoid arthritis), Akaal Pharma); sphingosine kinase 1 inhibitors (e.g., ABC-294640); sphingosine kinase 2 inhibitors (e.g., ABC-294640); sphingosine-1-phosphate receptor-1 agonists (e.g., ozanimod (RPC-1063), KRP-203); sphingosine-1-phosphate receptor-1 antagonists (e.g., amiselimod (MT-1303)); sphingosine-1-phosphate receptor-1 modulators (e.g., fingolimod (FTY-720), ozanimod (RPC-1063), amiselimod (MT-1303)); sphingosine-1-phosphate receptor-5 modulators (e.g., ozanimod); STAT3 gene inhibitors (e.g., bidofludimus); STAT-3 inhibitors (e.g., TAK-114); STAT-4 inhibitors (e.g., STAT-4 antisense oligonucleotides (Crohn's disease / colitis), NIAIDs); stem cell antigen-1 inhibitors antitumor agents (e.g., Ampion, DMI-9523); superoxide dismutase modulators (e.g., Midismase, LT-0011); superoxide dismutase stimulators (e.g., superoxide dismutase); T cell surface glycoprotein CD28 inhibitors (e.g., abatacept); TGF beta 1 ligand inhibitors (e.g., Mongelsen, GED-0301); thymulin agonists (e.g., Syn-1002); TLR-2 antagonists (e.g., VB-201); TLR-2 inhibitors (e.g., TLR-2 inhibitors); R-4 antagonists (e.g., JKB-122, VB-201); TLR-9 agonists (e.g., BL-7040, cobitolimod); TNF-alpha ligand inhibitors (e.g., adalimumab, certolizumab pegol, infliximab biosimilar, infliximab, golimumab, ISIS-104838, CSA-13, DLX-105, adalimumab biosimilar, delsalazine sodium, Debio-0512, HMPL-004, DLX-105, infliximab successor) drug products, AZD-9773, CYT-020-TNFQb, DOM-0200); TNF alpha ligand modulators (e.g., PUR-0110, CDP-571); TNF antagonists (e.g., etanercept, certolizumab pegol, AVX-470, onercept); trefoil factor modulators (e.g., AG-012); tryptase inhibitors (e.g., APC-2059); tryptophan 5-hydroxylase inhibitors (e.g., telotristat ethytidine); plate); tumor necrosis factor 14 ligand modulators (e.g., SAR-252067); type I TNF receptor antagonists (e.g., DOM-0100); type II TNF receptor modulators (e.g., etanercept); unspecified growth factor receptor modulators (e.g., AP-005); vanilloid VR1 agonists (e.g., zucapsaicin); vitamin D3 receptor agonists (e.g., calcitriol); and zonulin inhibitors (e.g., larazotide acetate, AT-1001).

[0052] The following non-exhaustive list of compound classes and compounds may also be used in combination with the compounds of the present disclosure: 14-3-3 protein eta inhibitors, 5-lipoxygenase inhibitors, Abl tyrosine kinase inhibitors, ACTH receptor agonists, adenosine A3 receptor agonists, adenosine deaminase inhibitors, ADP ribosyl cyclase-1 modulators, ADP ribosylation factor 6 inhibitors, adrenocorticotropic hormone ligands, aggrecanase-2 inhibitors, albumin modulators, AP1 transcription factors inhibitors, basigin inhibitors, Bcr protein inhibitors, B-lymphocyte antigen CD19 inhibitors, B-lymphocyte antigen CD20 inhibitors, B-lymphocyte antigen CD20 modulators, B-lymphocyte stimulator ligand inhibitors, bradykinin receptor modulators, BRAF gene inhibitors, branched amino acid aminotransferase 1 inhibitors, bromodomain-containing protein inhibitors, Btk tyrosine kinase inhibitors, cadherin-11 antagonists, calcineurin inhibitors, calcium Mu channel inhibitors, carbonic anhydrase inhibitors, cathepsin K inhibitors, cathepsin S inhibitors, CCR1 chemokine antagonists, CCR2 chemokine antagonists, CCR3 gene modulators, CCR5 chemokine antagonists, CD126 antagonists, CD29 modulators, CD3 modulators, CD39 agonists, CD4 agonists, CD4 antagonists, CD40 ligand inhibitors, CD40 ligand receptor antagonists, CD40 ligand receptor modulators, CD 52 antagonist, CD73 agonist, CD79b modulator, CD80 antagonist, CD86 antagonist, CD95 antagonist, cell adhesion molecule inhibitor, choline kinase inhibitor, clusterin stimulator, complement factor C5 inhibitor, complement factor stimulator, C-reactive protein inhibitor, CSF-1 antagonist, CXC10 chemokine ligand inhibitor, CXCR4 chemokine antagonist, cyclin-dependent kinase inhibitor 1 inhibitorinhibitors), cyclin-dependent kinase-2 inhibitors, cyclin-dependent kinase-4 inhibitors, cyclin-dependent kinase-5 inhibitors, cyclin-dependent kinase-6 inhibitors, cyclin-dependent kinase-7 inhibitors, cyclin-dependent kinase-9 inhibitors, cyclooxygenase-2 inhibitors, cyclooxygenase-2 modulators, cyclooxygenase inhibitors, cytosolic phospholipase A2 inhibitors agents, cytotoxic T-lymphocyte protein-4 modulators, cytotoxic T-lymphocyte protein-4 stimulators, DHFR inhibitors, diamine acetyltransferase inhibitors, dihydroorotate dehydrogenase inhibitors, elongation factor 2 inhibitors, eotaxin 2 ligand inhibitors, EP4 prostanoid receptor antagonists, erythropoietin receptor agonists, Fas ligand, FGF-2 ligand inhibitors, FK506 binding protein-12 modulators, folate antagonists, folate receptor agonists, folate receptor beta antagonists, folate receptor modulators, fractalkine ligand inhibitors, Fyn tyrosine kinase inhibitors, G protein-coupled receptor 15 antagonists, GABA A receptor modulators, glucocorticoid agonists, glucocorticoid antagonists, glucocorticoid-induced leucine zipper stimulators, GM-CSF ligand inhibitors, GM-CSF receptor antagonists, GM-CSF receptor modulators, growth regulatory protein alpha ligand inhibitors, Hwith Kwith ATPase inhibitors, histamine H4 receptor antagonists, histone deacetylase inhibitors, histone deacetylase-6 inhibitors, HIV-1gp120 protein inhibitor, HLA class II antigen DQ-2 alpha modulator, HLA class II antigen inhibitor, HLA class II antigen modulator, Hsp70 family inhibitor, hypoxia inducible factor-1 inhibitor, IFNB gene stimulator, I-kappa B kinase beta inhibitor, I-kappa B kinase inhibitor, IL-1 antagonist, IL-10 agonist, IL-11 agonist, IL-12 antagonist, IL-15 antagonist, IL-17 antagonist, IL-17 receptor modulator, I IL-2 agonist, IL-2 antagonist, IL-21 antagonist, IL-23 antagonist, IL-3 antagonist, IL-4 agonist, IL-6 antagonist, IL-6 receptor modulator, immunoglobulin antagonist, immunoglobulin G1 agonist, immunoglobulin G1 antagonist, immunoglobulin G1 modulator, immunoglobulin G2 antagonist, immunoglobulin G2 modulator, immunoglobulin gamma Fc receptor II modulator, immunoglobulin gamma Fc receptor -IIB antagonists, immunoglobulin kappa modulators, immunoglobulin M antagonists, inducible nitric oxide synthase inhibitors, inosine monophosphate dehydrogenase inhibitors, insulin sensitizers, integrin alpha-1 / beta-1 antagonists, integrin alpha-4 / beta-1 antagonists, integrin antagonists, interferon beta ligands, interferon gamma ligands, interleukin-17A ligand inhibitors, interleukin-17F ligand inhibitors, interleukin-23A inhibitors, interleukin ligands, interleukin receptor 17A antagonists, interleukin-1 beta ligand inhibitors, interleukin-10 ligands, interleukin-2 ligands, interleukin-4 ligands, interleukin-6 ligand inhibitors, Itk tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinase inhibitors, JAK3 gene inhibitors, Jak3 tyrosine kinase inhibitors, JunN-terminal kinase inhibitors, KCNA voltage-gated potassium channel-3 modulators, Kelch-like ECH-associated protein 1 modulators, Kit tyrosine kinase inhibitors, LanC-like protein 2 modulators, LITAF gene inhibitors, lymphocyte function antigen-3 receptor antagonists, Lyn tyrosine kinase inhibitors, macrophage mannose receptor 1 modulators, MAdCAM inhibitors, MAP kinase modulators, MAP3K2 gene inhibitors, MAPKAPK5 inhibitors, matrix metalloproteinase inhibitors, MCL1 gene inhibitors, MEK protein kinase inhibitors, MEK-1 protein kinase inhibitors, MEK-2 protein kinase inhibitors, membrane copper amine oxidase inhibitors, metalloproteinase-2 inhibitors, metalloproteinase-9 inhibitors, midkine ligand inhibitors, mitochondrial 10 kDa heat shock protein stimulators, mTOR complex 1 inhibitors, mTOR inhibitors, NAD ADP-ribosyltransferase stimulators, NAMPT gene inhibitors, NF-kappa B inhibitor stimulators, NFAT gene inhibitors, NFE2L2 gene stimulators, nicotinic acetylcholine receptor antagonists, NK cell receptor modulators, NKG2 AB-activating NK receptor antagonists, NKG2 D-activating NK receptor antagonists agonists, nuclear erythroid 2-related factor 2 stimulators, nuclear factor kappa B inhibitors, nuclear factor kappa B regulators, nuclear factor kappa B p105 inhibitors, opioid growth factor receptor agonists, opioid receptor delta antagonists, osteoclast differentiation factor antagonists, osteoclast differentiation factor ligand inhibitors, oxidoreductase inhibitors, P2X7 purinergic receptor agonists, p38 MAP kinase alpha inhibitors, p38 MAP kinase inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor agonists, PDGF receptor antagonists, PDGF-B ligand inhibitors, PERK gene inhibitors, phosphoinositide-3 kinase delta inhibitors, phosphoinositide-3 kinase gamma inhibitors, phospholipase A2 inhibitors, platelet-activating factor receptor antagonists, PPAR gamma agonists, programmed cell death protein 1 regulators, prostaglandin D synthase stimulators, protein arginine deiminase inhibitors, protein tyrosine kinase inhibitors, PurH purine biosynthesis protein inhibitors, Rho-associated protein kinase 2 inhibitors, seprase inhibitors, signal transduction modulators CD24, signal transduction inhibitors, sodium glucose transporter-2 inhibitors, sphingosine 1-phosphate phosphatase modulators, STAT3 gene inhibitors, superoxide dismutase stimulators, SYK family tyrosine kinase inhibitors, Syk tyrosine kinase inhibitors, syndecan-1 inhibitors, T cell receptor antagonists, T cell receptor modulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD28 stimulators, TAK1-binding protein modulators, talin modulators, T cell differentiation antigen CD6 inhibitors, T cell surface glycoprotein CD8 inhibitors, tenascin modulators, TGF beta agonists, thymulin agonists, TLR-2 antagonists, TLR-4 antagonists, TLR-9 antagonists, TNF alpha ligand inhibitors, TNF alpha ligand modulators, TNF antagonists, TNF gene inhibitors, TNF receptor modulators, TNFSF11 gene inhibitors, transcription factor p65 inhibitors, transcription factor RelB inhibitors, transferrin modulators, tumor necrosis factor 13C receptor antagonists, tumor necrosis factor 15 ligand inhibitors,Tumor necrosis factor ligand 13 inhibitors, tumor necrosis factor ligand inhibitors, type I IL-1 receptor antagonists, type I TNF receptor antagonists, type II TNF receptor modulators, unspecified GPCR agonists, VEGF receptor antagonists, VEGF-2 receptor antagonists, VEGF-2 receptor modulators, VEGF-B ligand inhibitors, X-linked inhibitor of apoptosis protein, Zap70 tyrosine kinase inhibitors, 99mTc-labeled annexin V-128, abatacept, abatacept biosimilars, A BBV-257, ABT-122, ABT-494, acalabrutinib, aceclofenac, Actarit, MS-392, adalimumab, adalimumab biosimilar, adalimumab successor biologic, AK-106, ALX-0061, aminopterin, anakinra, anakinra biosimilar, anakinra successor biologic, ARG-301, ASLAN-003, ASP-5094, AT-132, AZD-9567, baricitinib, BI-655064, bimekizumab, BiP (rheumatoid arthritis), King's College London, BLHP-006, blisibimod, BMS-986104, BMS-986142, ABBV-105, BTT-1023, canakinumab, Cartistem, CCX-354, CD24-IgFc, celecoxib, cerdulatinib, certolizumab pegol, CF-101, CFZ-533, CHR-5154, cibinetide, cyclosporine, clazakizumab, CNTO-6785, corticotropin, Mallinckrodt, CR-6086, Crea Vax-RA, CWG-92, CWG-940, Cx-611, DE-098, deflazacort, Rheumavax, denosumab, diacerein, diclofenac, E-6011, eicosapentaenoic acid monoglyceride, etanercept, etanercept biosimilar, etanercept successor biologic, etodolac, etoricoxib, filgotinib, fosdagrocorat, gerilimzumab, ginsenoside CK, divinostat, goat polyclonal antibody, golimumab,GS-5745, GS-9, 876, GSK-3196165, HM-71224, HMPL-523, Sodium hyaluronate, IB-RA (injection, rheumatoid arthritis), Innobioscience, IB -RA (oral, rheumatoid arthritis), Innobioscience, iguratimod, IMD-2560, imidazole salicylate, infliximab, infliximab biobetter, infliximab biosimilar, INSIX RA, interferon gamma successor biologic, interleukin-2 (injection), interleukin-2 successor biologic, INV-103, IR-501, itolizumab, JNJ-40346527, Ka Shu Ning, KD-025, omeprazole with ketoprofen, leflunomide, lenzilumab, LLDT-8, lumiracoxib, LY-3090106, masitinib, mavrilimumab, MBS-2320, MEDI-5117, meloxicam, methotrexate, MGD-010, misop Diclofenac combined with Rostoll, MM-A01-01, monalizumab, MORAb-022, MPC-300-IV, MRC-375, nabumetone, namilumab, esomeprazole combined with naproxen, esomeprazole strontium combined with naproxen, ocaratuzumab, ofatumumab, OHR-118, olokizumab, OM-89, once-daily naproxen (oral controlled-release, pain), Alvogen, ONO-4059, Oralgam, ozoralizumab, peficitinib, pelubiprofen, PF-06687234, piperidone hydrochloride, piroxicam, prednisolone, prednisone, Prosorba, PRT-2607, PRTX-100, PRX-167700, QBSAU, rabeximod, RCT-18, recombinant human CD22 monoclonal antibody (iv infusion), Lonn Ryonn Pharma / SinoMab Bioscience (Shenzhen), recombinant human interleukin-1 receptor antagonist (rheumatoid arthritis), Shanghai Fudan-Zhangjiang Bio-Pharmaceutical, recombinant human interleukin-2 recombinant TNF receptor 2-Fc fusion protein variant, RG-6125, RhuDex, rifabutin and clarithromycin combinations with clofazimine, rituximab, rituximab biosimilar, rituximab successor biologic, RPI-78, SAN-300, sarilumab, SBI-087, seliciclib, SHR-0302, sirukumab, spebrutinib, SSS-07, KDDF-201110-06, Syn-1002, T-5224, TAB-08, tacrolimus, TAK-020, TAK-079, tarenflurbil (transdermal spray gel, dermatological conditions / rheumatoid arthritis), MIKA Pharma / GALENpharma, technetium Tc99m tilmanocept, technetium methylenediphosphonate [99Tc], tenoxicam, Debio-0512, tocilizumab, tofacitinib, Trichuris suis eggs, umbilical cord-derived mesenchymal stem cells (iv, RA / liver disease), Alliancells / Zhongyuan Union, ustekinumab, VAY-736, VB-201, WF-10, XmAb-5871, YHB-1411-2; 14-3-3 protein eta inhibitors (e.g., anti-AGX-020 mAb (rheumatoid arthritis), Augurex);5-lipoxygenase inhibitors (e.g., tenoxicam, dalbufelone, tebufelone, licofelone, ZD-2138, etalosib, tenidap, tepoxalin, flobufen, SKF-86002, PGV-20229, L-708780, WY-28342, T-0 757, T-0799, ZM-216800, L-699333, BU-4601A, SKF-104351, CI-986); Abl tyrosine kinase inhibitors (e.g., imatinib); ACTH receptor agonists (e.g., FAR-404, met-enkephalin acetate combined with tridecyl acetate); adenosine A3 receptor agonists (e.g., CF-101; adenosine deaminase inhibitors (e.g., cladribine, pentostatin, FR-221647); ADP-ribosyl cyclase-1 modulators (e.g., indatuximab, ravtansine); ADP-ribosylation factor 6 inhibitors (e.g., NAV-2729); adrenocorticotropic hormone ligands (e.g., corticotropin, Mallinckrodt, FAR-404, met-enkephalin acetate combined with trideceth-1 acetate); aggrecanase-2 inhibitors (e.g., GI BH-R-001-2); albumin regulators (e.g., ALX-0061, ONS-1210); AP1 transcription factor inhibitors (e.g., T-5224, tarenflurvir, SP-10030); basigin inhibitors (e.g., ERG-240); Bcr protein inhibitors (e.g., imatinib); B-lymphocyte antigen CD19 inhibitors (e.g., XmAb-5871, MDX-1342); B-lymphocyte antigen CD20 inhibitors (e.g., ocrelizumab, ofatumumab, rituximab, rituximab biosimilars) , veltuzumab, rituximab successor biologics, ocaratu- zumab, BLX-301, IDEC-102, ABP-798, GP-2013, MK-8808, HLX-01, CT-P10, TL-011, PF-05280586, IBPM-001RX, IBI-301, AME-133v, BCD-020, BT-D004, SAIT-101); B-lymphocyte antigen CD20 modulators (e.g., rituximab biosimilars, SBI-087, TRU-015, DXL-625); B-lymphocyte Stimulatory ligand inhibitors (e.g., belimumab, RCT-18, blissibimod, tabalumab, atacicept, briobacept); bradykinin receptor modulators (e.g., divinostat); BRAF gene inhibitors (e.g., binimetinib); branched-chain amino acid aminotransferase 1 inhibitors (e.g., ERG-240); bromodomain-containing protein inhibitors (e.g., RVX-297, ZEN-003694);BTK tyrosine kinase inhibitors (e.g., acalabrutinib, HM-71224, spebrutinib, BTK inhibitors (rheumatoid arthritis), Humanwell Healthcare / Wuxi AppTech, BMS-986142, TAK-020, ONO-4059, TAS-5315, ABBV-105, AC-0025, RN-486, CG-026806, GDC-0834); cadherin-11 antagonists (e.g., RG-6125); calcineurin inhibitors (e.g., HS-378, cyclosporine); calcium channel inhibitors (e.g., RP-3128); carbonic anhydrase inhibitors (e.g., polmacoxib); cathepsin K inhibitors (e.g., C RA-013783, T-5224, AM-3876, VEL-0230, NPI-2019); cathepsin S inhibitors (e.g., MIV-247, AM-3876, RWJ-445380, NPI-2019); CCR1 chemokine antagonists (e.g., BX-471, BMS-817399, BI-638683, CCX-354, MLN-3701, MLN-3897, CP-481715, PS-375179); CCR2 chemokine antagonists (e.g., MK-0812, AZD-69 42); CCR3 gene modulators (e.g., CM-102); CCR5 chemokine antagonists (e.g., maraviroc, OHR-118, NIBR-6465, AZD-5672, AZD-8566); CD126 antagonists (e.g., sarilumab); CD29 modulators (e.g., PF-06687234); CD3 modulators (e.g., otelixizumab); CD39 agonists (e.g., AAV5-CD39 / CD73 (rheumatoid arthritis) Arthrogens; CD4 agonists (e.g., maraviroc); CD4 antagonists (e.g., tregalizumab, zanolimumab, MTRX-1011A, BW-4162W94, EP-1645, clenoliximab); CD40 ligand inhibitors (e.g., dapirolizumab pegol); CD40 ligand receptor antagonists (e.g., BI-655064, anti-CD40-XTEN, teneliximab);CD40 ligand receptor modulators (e.g., CFZ-533); CD52 antagonists (e.g., alemtuzumab); CD73 agonists (e.g., A; AV5-CD39 / CD73 (rheumatoid arthritis), Arthrogen); CD79b modulators (e.g., MGD-010); CD80 antagonists (e.g., RhuDex, XENP-9523, ASP-2408, abatacept biobetter); CD86 antagonists (e.g., ES-210, abatacept biosuperior, ASP-2408, XENP-9523); CD95 antagonists (e.g., DE-098, CS-9507); cell adhesion molecule inhibitors (e.g., natalizumab, alicaforsen, NPC-17923, TK-280, PD-144795); choline kinase inhibitors (e.g., choline kinase inhibitor (rheumatoid arthritis), UC San Diego); clusterin stimulators (e.g., alemtuzumab); complement factor C5 inhibitors (e.g., eculizumab, antisense oligonucleotides (rheumatoid arthritis)), Leiden University Medical Center); complement factor stimulators (e.g., CM-101); C-reactive protein inhibitors (e.g., IB-RA (oral, rheumatoid arthritis), Innobioscience, ISIS-353512); CSF-1 antagonists (e.g., masitinib, FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578, PD-360324, JNJ-28312141); CXC10 chemokine ligand inhibitors (e.g., 946414-98-8, BMS-936557); CXCR4 chemokine antagonists (e.g., plerixafor); cyclin-dependent kinase inhibitor 1 inhibitors (e.g., CDK-1 / 2 / 5 / 7 / 9 inhibitors (cancer / tumor formation / rheumatoid arthritis), BioPatterns); cyclin-dependent kinase-2 inhibitors (e.g., seliciclib, BP-14); cyclin-dependent kinase-4 inhibitors (e.g., CDK-4 / 6 inhibitors (rheumatoid arthritis), Teijin); cyclin-dependent kinase-5 inhibitors (e.g., BP-14); cyclin-dependent kinase-6 inhibitors (e.g., CDK-4 / 6 inhibitors (rheumatoid arthritis), Teijin); cyclin-dependent kinase-7 inhibitors (e.g., BP-14, seliciclib); cyclin-dependent kinase-9 inhibitors (e.g., BP-14, seliciclib);Cyclooxygenase 2 inhibitors (e.g., celecoxib, etoricoxib, pormacoxib, laflunimus, etodolac, meloxicam, IB-RA (injection, rheumatoid arthritis), Innobioscience, IB-RA (oral, rheumatoid arthritis), Innobioscience, SKLB-023, meloxicam, lumiracoxib); cyclooxygenase 2 modulators (e.g., DRGT-46); cyclooxygenase inhibitors (e.g., aceclofenac, diclofenac, imidazole salicylate, naproxen, naproxen; Mesyl, diclofenac with misoprostol, nabumetone, esomeprazole with naproxen, esomeprazole strontium with naproxen, once-daily naproxen (oral controlled-release, pain), Alvogen, perbiprofen, LY-210073, tenoxicam, licofelone, NS-398, bromfenac, L-746483, LY-255283, tenidap, tepoxalin, flobufen, ibuprofen, flurbiprofen, SKF-86002, SC-57666, WY-28342, CI-986, bermoprofen; Cytosolic phospholipase A2 inhibitors (e.g., AVX-002); cytotoxic T-lymphocyte protein-4 modulators (e.g., belatacept, ES-210); cytotoxic T-lymphocyte protein-4 stimulators (e.g., abatacept, abatacept biosimilar, BMS-188667); DHFR inhibitors (e.g., methotrexate, MPI-2505, MBP-Y003); diamine acetyltransferase inhibitors (e.g., diminazene aceturate); dihydroorotate dehydrogenase inhibitors (e.g., DHODH inhibitors (rheumatoid arthritis / autoimmune diseases)), East China University of Science and Technology, ASLAN-003, raflunimus, leflunomide, HWA-486, ABR-224050); elongation factor 2 inhibitors (e.g., denileukin diftitox); eotaxin 2 ligand inhibitors (e.g., CM-102); EP4 prostanoid receptor receptor antagonists (e.g., CR-6086); erythropoietin receptor agonists (e.g., sibinetide); Fas ligand (e.g., AP-300); FGF-2 ligand inhibitors (e.g., RBM-007); FK506 binding protein-12 modulators (e.g., temsirolimus); folate antagonists (e.g., methotrexate, MBP-Y003); folate receptor agonists (e.g., folate receptor modulators (chimeric proteins, cancer / rheumatoid arthritis), Proda Biotech; folate receptor modulators (e.g., technetium (99mTc) etarfolatide); fractalkine ligand inhibitors (e.g., E-6011); Fyn tyrosine kinase inhibitors (e.g., masitinib, raflunimus); G protein-coupled receptor 15 antagonists (e.g., GPR15 antagonists (rheumatoid arthritis / HIV-mediated enteropathy), Omeros); GABA A receptor modulators (e.g., raffinim); glucocorticoid agonists (e.g., prednisolone, fosdaglobulin); glucocorticoid antagonists (e.g., REC-200); glucocorticoid-induced leucine zipper stimulators (e.g., ART-GO1); GM-CSF ligand inhibitors (e.g., namilumab, MORAb-022, lenzilumab); GM-CSF receptor antagonists (e.g., mavrilimumab); GM-CSF receptor modulators (e.g., GSK-3196165); growth regulatory protein alpha ligand inhibitors (e.g., T-5224); ATPase inhibitors (e.g., esomeprazole with naproxen, esomeprazole strontium with naproxen, omeprazole with ketoprofen, KEO-25001, HC-1004, PN-40020); histamine H4 receptor antagonists (e.g., toreforant, GD-48); histone deacetylase inhibitors (e.g., divinostat, CHR-5154); histone deacetylase-6 inhibitors (e.g., CKD-506); HIV-1 gp120 protein inhibitors (e.g., maraviroc); HLA class II antigen DQ-2 alpha modulators (e.g., NexVax2);HLA class II antigen inhibitors (e.g., HLA-DR1 / DR4 inhibitors (rheumatoid arthritis), Provid); HLA class II antigen modulators (e.g., ARG-301, recombinant T-cell receptor ligands (rheumatoid arthritis), Artielle); Hsp70 family inhibitors (e.g., gusperimus trihydrochloride); hypoxia-inducible factor-1 inhibitors (e.g., 2-methoxyestradiol); IFNB gene stimulators (e.g., ART-102); I-kappa B kinase beta inhibitors (e.g., IMD-2560, IMD-0560); I-kappa B kinase inhibitors (e.g., bardoxolone methyl); IL-1 antagonists (e.g., rilonacept, IBPB-007-IL, antisense oligonucleotides (rheumatoid arthritis), Leiden University Medical Center; recombinant human interleukin-1 receptor antagonists (rheumatoid arthritis), Shanghai Fudan-Zhangjiang Bio-Pharmaceutical; IL-10 agonists (e.g., peg-ilodecaquin); IL-11 agonists (e.g., oprelvekin); IL-12 antagonists (e.g., ustekinumab, briakinumab, ddRNAi therapy (rheumatoid arthritis), Medistem / Benitec); IL-15 antagonists (e.g., AMG-714, BNZ-132-2); IL-17 antagonists (e.g., ixekizumab, secukinumab, KD-025); IL-17 receptor modulators (e.g., CNTO-67 85); IL-2 agonists (e.g., interleukin-2 successor biologics); IL-2 antagonists (e.g., IB-RA (injection, rheumatoid arthritis), Innobioscience, IB-RA (oral, rheumatoid arthritis), Innobioscience, BNZ-132-2); IL-21 antagonists (e.g., NN-8828, BNZ-132-2); IL-23 antagonists (e.g., ustekinumab, briakinumab); IL-3 antagonists (e.g., anti-IL-3 mAb (rheumatoid arthritis), University of Regensburg); IL-4 agonists (e.g., SER-130-AMI);IL-6 antagonists (e.g., olokizumab, clazakizumab, sirukumab, SA-237, tocilizumab, ALX-0061, FB-704A, OP-R; 003, peptide IL-6 antagonists, MEDI-5117, T-5224, humanized anti-IL-6 mAb, tocilizumab biosimilar, IL-6 neutralizing human antibody, anti-IL6 antibody, RN-486, BLX-1002, AMG-220, FM-101, K-832, BLX-1025, esonarimod, TA-383); IL-6 receptor modulators (e.g., tocilizumab, tocilizumab biosimilar, RO-4877533); immunoglobulin antagonists (e.g., iguratimod); immunoglobulin G1 agonists (e.g., canakinumab, Infliximab biobetter, infliximab biosimilar, BX-2922, STI-002, HF-1020); immunoglobulin G1 antagonists (e.g., YHB-1411-2); immunoglobulin G1 modulators (e.g., CFZ-533, lenzilumab); immunoglobulin G2 antagonists (e.g., denosumab); immunoglobulin G2 modulators (e.g., PF-547659); immunoglobulin gamma Fc receptor II modulators (e.g., MGD-010); immunoglobulin gamma Fc receptor IIB antagonists (e.g., for example, XmAb-5871); immunoglobulin kappa modulators (e.g., lenzilumab); immunoglobulin M antagonists (e.g., IB-RA (injection, rheumatoid arthritis), Innobioscience, IB-RA (oral, rheumatoid arthritis), Innobioscience); inducible nitric oxide synthase inhibitors (e.g., SKLB-023); inosine monophosphate dehydrogenase inhibitors (e.g., mycophenolate mofetil); insulin sensitizers (e.g., rosiglitazone, THR-0921, HE-3286, BLX-1002); Integrin alpha-1 / beta-1 antagonists (e.g., SAN-300); integrin alpha-4 / beta-1 antagonists (e.g., natalizumab); integrin antagonists (e.g., PEG-HM-3, CY-9652); interferon beta ligands (e.g., recombinant interferon beta-1a, TA-383); interferon gamma ligands (e.g., interferon gamma successor biologics); interleukin-17A ligand inhibitors (e.g., ABT-122, bimekizumab, ABBV-257);Interleukin-17F ligand inhibitors (e.g., bimekizumab); interleukin-23A inhibitors (e.g., guselkumab); interleukin ligands (e.g., IBPB-007-IL); interleukin receptor 17A antagonists (e.g., brodalumab); interleukin-1 beta ligand inhibitors (e.g., canakinumab, rilonacept, T-5224, gevokizumab, BLX-1002, LY-2189102, PMI-001, K-832, C DP-484); interleukin-10 ligands (e.g., PF-06687234); interleukin-2 ligands (e.g., denileukin diftitox, recombinant interleukin-2, interleukin-2 successor biologics, recombinant human interleukin-2, interleukin-2 (injection)); interleukin-4 ligands (e.g., Tetravil); interleukin-6 ligand inhibitors (e.g., Gelilimuzumab, PF-4236921); Itk tyrosine kinase inhibitors (e.g., ARN-4079); JAK tyrosine kinase inhibitors (e.g., tofacitinib, SHR-0302, celduratinib, peficitinib, deuterated tofacitinib analogs, SD-900, CVXL-0074); Jak1 tyrosine kinase inhibitors (e.g., ABT-494, baricitinib, ruxolitinib, filgotinib, tofacitinib, itacitinib, peficitinib, NIP-585, CS-944) X, YJC-50018, GLPG-0555, MRK-12); Jak2 tyrosine kinase inhibitors (e.g., baricitinib, ruxolitinib, CT-1578); JAK3 gene inhibitors (e.g., GBL-5b); Jak3 tyrosine kinase inhibitors (e.g., decernotinib, tofacitinib, peficitinib, AC-0025, CS-944X, DNX-04042, MTF-003, ARN-4079, PS-020613); Jun N-terminal kinase inhibitors (e.g., IQ-1S); KCNA voltage-gated potassium channel-3 modulators (e.g., MRAD-P1); Kelch-like ECH-associated protein 1 modulators (e.g., dimethyl fumarate); Kit tyrosine kinase inhibitors (e.g., imatinib, masitinib);LanC-like protein 2 regulators (e.g., BT-11); LITAF gene inhibitors (e.g., lymphocyte function antigen-3 receptor antagonists (e.g., alefacept); Lyn tyrosine kinase inhibitors (e.g., masitinib); macrophage mannose receptor 1 modulators (e.g., technetium Tc99m tilmanocept); MAdCAM inhibitors (e.g., PF-547659); MAP kinase modulators (e.g., SKLB-023); MAP3K2 gene inhibitors (e.g., GBL-5b); MAPKAPK5 inhibitors (e.g., matrix metalloproteinase inhibitors (e.g., GLPG-0259); MCL1 gene inhibitors (e.g., seliciclib); MEK protein kinase inhibitors (e.g., binimetinib, AD-GL0001); MEK-1 protein kinase inhibitors (e.g., binimetinib); MEK-2 protein kinase inhibitors (e.g., binimetinib); membrane copper amine oxidase inhibitors (e.g., BTT-1023, PRX-167700, beparimomab); metalloproteinase inhibitors ase-2 inhibitors (e.g., ERG-240); metalloproteinase-9 inhibitors (e.g., GS-5745, ERG-240); midkine ligand inhibitors (e.g., CAB-102); mitochondrial 10 kDa heat shock protein stimulators (e.g., INV-103); mTOR complex 1 inhibitors (e.g., everolimus); mTOR inhibitors (e.g., everolimus, temsirolimus); NAD ADP-ribosyltransferase stimulators (e.g., denileukin diftitox); NAMPT gene inhibitors (e.g., ART-D01); NF-kappa B inhibitor stimulators (e.g., denosumab); NFAT gene inhibitors (e.g., T-5224); NFE2L2 gene stimulators (e.g., bardoxolone methyl); nicotinic acetylcholine receptor antagonists (e.g., RPI-78, RPI-MN); NK cell receptor modulators (e.g., masitinib); NKG2 AB-activating NK receptor antagonists (e.g., monalizumab); NKG2 D-activating NK receptor antagonists (e.g., NNC-0142-002); nuclear erythroid 2-related factor 2 stimulators (e.g., dimethyl fumarate); nuclear factor kappa B inhibitors (e.g., bardoxolone methyl, IB-RA (injection, rheumatoid arthritis), Innobioscience, dehydroxymethylepoxyquinomicin, HE-3286, IMD-0560, MP-42, tarenflurvir, VGX-1027, SKLB-023, SP-650003, MG-132, SIM-916, VGX-350, VGX-300, GIT-027, SP-100030, MLN-1145, NVP-IKK-005); nuclear factor kappa B regulators (e.g., REM-1086); nuclear factor kappa B p105 inhibitors (e.g., REM-1086); opioid growth factor receptor agonists (e.g., met-enkephalin acetate combined with tridecactide acetate, FAR-404); opioid receptor delta antagonists (e.g., HS-378); osteoclast differentiation factor antagonists (e.g., denosumab, cyclic peptidomimetics (rheumatoid arthritis / osteoporosis)), University of Osteoclast differentiation factor ligand inhibitors (e.g., denosumab); oxidoreductase inhibitors (e.g., etodolac, imidazole salicylate); P2X7 purinergic receptor agonists (e.g., divinostat); p38 MAP kinase alpha inhibitors (e.g., VX-745, BMS-582949 prodrug, BMS-751324); p38 MAP kinase inhibitors (e.g., BCT-197, losmapimod, ARRY-797); PDE4 inhibitors (e.g., apremilast); PDE5 inhibitors (e.g., PDE5 inhibitors (rheumatoid arthritis), University of Michigan) Rochester); PDGF receptor agonists (e.g., oprelvekin); PDGF receptor antagonists (e.g., imatinib, masitinib); PDGF-B ligand inhibitors (e.g., SL-1026); PERK gene inhibitors (e.g., binimetinib); phosphoinositide-3 kinase delta inhibitors (e.g., duvelisib, RP-6503, CT-732, INK-007, GNE-293); phosphoinositide-3 kinase phospholipase A2 inhibitors (e.g., AVX-002, human secretory phospholipase A2 type IIA-integrin binding inhibitor peptide (rheumatoid arthritis / asthma / Alzheimer's disease / cancer), University of California, Davis, AK-106, varespladib methyl, Ro-31-4493, BM-162353, Ro-23-9358, YM-26734); platelet-activating factor receptor antagonists (e.g., piperidone hydrochloride); PPAR gamma agonists (e.g., rosiglitazone, THR-0921, rosiglitazone XR, etalosib); programmed cell death protein 1 modulators (e.g., INSIX RA); prostaglandin D synthase stimulators (e.g., HF-0220); protein arginine deiminase inhibitors (e.g., PAD inhibitors (rheumatoid arthritis), Leiden University Medical Center / LURIS); protein tyrosine kinase inhibitors (e.g., leflunomide); PurH purine biosynthesis protein inhibitors (e.g., mycophenolate mofetil); Rho-associated protein kinase 2 inhibitors (e.g., KD-025); seprase inhibitors (e.g., anti-fibroblast activation protein (FAP) antibody radiotracer (rheumatoid arthritis), Hoffmann-La Roche / Radboud University); signal transduction substances CD24 modulators (e.g., CD24-IgFc); signal transduction inhibitors (e.g., imatinib); sodium glucose transporter-2 inhibitors (e.g., THR-0921); sphingosine 1-phosphate phosphatase modulators (e.g., S1P modulators (oral, multiple sclerosis / ulcerative colitis / rheumatoid arthritis), Akaal Pharma); STAT3 gene inhibitors (e.g., bardoxolone methyl, bidofludimus); superoxide dismutase stimulators (e.g., imisopasem, manganese); SYK family tyrosine kinase inhibitors (e.g., MK-8457);Syk tyrosine kinase inhibitors (e.g., fostamatinib, entospletinib, KDDF-201110-06, HMPL-523, celduratinib, AB-8779, GS-9876, PRT-2607, CVXL-0074, CG-103065, and CG-026806); syndecan-1 inhibitors (e.g., indatuximab ravtansine); T cell receptor antagonists (e.g., TCR inhibitors, SCHOOL peptides (systemic / topical, rheumatoid arthritis / dermatitis / scleroderma), SignaBlok, CII modified peptides (rheumatoid arthritis), Peking University); T cell receptor modulators (e.g., ARG-301); T cell surface glycoprotein CD28 inhibitors (e.g., abatacept, belatacept, abatacept biosimilar, RhuDex, BMS-188667); T cell surface glycoprotein CD28 stimulators (e.g., TAB-08); TAK1 binding protein modulators (e.g., epigallocatechin-3-gallate); talin modulators (e.g., short talin regulator (rheumatoid arthritis), KayteeBio) ; T cell differentiation antigen CD6 inhibitors (e.g., Itolizumab); T cell surface glycoprotein CD8 inhibitors (e.g., Tregalizumab); Tenascin modulators (e.g., Tetravil); TGF beta agonists (e.g., Tregalizumab); Thymulin agonists (e.g., Syn-1002); TLR-2 antagonists (e.g., VB-201, P-13); TLR-4 antagonists (e.g., VB-201, P-13); TLR-9 antagonists (e.g., P-13);TNF-alpha ligand inhibitors (e.g., adalimumab biosimilar YHB-1411-2, adalimumab, infliximab, infliximab biosimilar, recombinant humanized anti-TNF-alpha monoclonal antibody, certolizumab pegol, golimumab, ozoralizumab, AT-132, etanercept biosimilar, ISIS-104838, ISU-202, CT-P17, MB-612, Debio-05) 12, anti-TNF alpha human monoclonal antibody, infliximab biobetter, UB-721, KN-002, DA-3113, BX-2922, R-TPR-015, BOW-050, PF-06410293, CKD-760, CHS-1420, GS-071, ABP-710, STI-002, BOW-015, FKB-327, BAX-2200, HLX-03, BI-695501, CNTO-148; MYL-1401AABP-501, HOT-3010, BAX-2923, SCH-215596, ABT-D2E7, BAT-1406, XPro-1595, Atsttrin, SSS-07, golimumab biosimilar, TA-101, adalimumab successor biologic, BLX-1002, ABX-0401, TAQ-588, golimumab biosimilar, TeHL-1, placulumab, PMI-001, tgAAV-TNFR:Fc, K-832, CYT-007-TNFQb, SSR-150106, PassTNF, Verigen, DO M-0200, DOM-0215, AME-527, anti-TNF-alpha mAb, GENZ-38167, BLX-1028, CYT-020-TNFQb, CC-1080, CC-1069); TNF-alpha ligand modulators (e.g., MM-A01-01, CDP-571, camobucol); TNF antagonists (e.g., etanercept, certolizumab pegol, etanercept successor biologics, etanercept biosimilars, DNX-114, TNF antagonist combined with IL-12 antagonist (rheumatoid arthritis)), University of Oxford, BN-006, SCB-131, pegsunercept, GBL-5b, ACE-772, onercept, DE-096, PN-0615, lenercept, ITF-1779, MDL-201112, BAX-2200, SCB-808, DA-3853, HD-203); TNF gene inhibitors (e.g., GIBH-R-001-2); TNF receptor modulators (e.g., recombinant TNF receptor 2-Fc fusion protein mutant, T-0001, tgAAV-TNFR :Fc); TNFSF11 gene inhibitors (e.g., denosumab); transcription factor p65 inhibitors (e.g., REM-1086); transcription factor RelB inhibitors (e.g., REM-1086); transferrin regulators (e.g., methotrexate, MBP-Y003); tumor necrosis factor 13C receptor antagonists (e.g., VAY-736); tumor necrosis factor 15 ligand inhibitors (e.g., anti-TL1A antibody (rheumatoid arthritis / inflammatory bowel disease), NIAMS); tumor necrosis factor ligand 13 inhibitors (e.g., atacicept);Tumor necrosis factor ligand inhibitors (e.g., ABBV-257, etanercept biosimilars, ABT-122); type I IL-1 receptor antagonists (e.g., anakinra, anakinra biosimilars, anakinra successor biologics, AXXO); type I TNF receptor antagonists (e.g., NM-9405); type II TNF receptor modulators (e.g., etanercept, SCB-131, etanercept biosimilars, etanercept successor biologics, BAX-2200, SC) B-808, LBEC-0101, DMB-3853, DWP-422, BT-D001, DA-3853); unspecified GPCR agonists (e.g., NCP-70X); VEGF receptor antagonists (e.g., 2-methoxyestradiol and NSC-650853, SL-1026); VEGF-2 receptor antagonists (e.g., CG-026806); VEGF-2 receptor modulators (e.g., VEGFR2 neutralizing antibodies (rheumatoid arthritis), University of Rochester); VEGF-B ligand inhibitors (e.g., CSL-346); X-linked inhibitors of apoptosis protein (e.g., IAP inhibitors (oral), Pharmascience); and Zap70 tyrosine kinase inhibitors (e.g., MK-8457, CT-5332). Combinations for metabolic diseases or conditions

[0053] Examples of metabolic disorders include, but are not limited to, diabetes (including type I and type II diabetes), metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, high serum cholesterol, and high triglycerides. Examples of therapeutic agents used to treat metabolic disorders include antihypertensives and hypolipidemics. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas such as thiazolidinediones (e.g., pioglitazone), peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, biguanides, alpha-glucosidase inhibitors, vitamin E, and incretin mimetics. Thus, one embodiment of the present disclosure is a method for treating metabolic disease, comprising administering to a subject in need thereof, particularly a human subject, a compound of the present disclosure. in combination with one or more compounds useful in the treatment of metabolic diseases. Pharmaceutical Compositions

[0054] While it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations (compositions). Formulations of the present invention, intended for both veterinary and human use, comprise at least one active ingredient as defined above, together with one or more acceptable carriers therefor and, optionally, other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient.

[0055] Formulations include those suitable for the aforementioned routes of administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with inert ingredients (e.g., carriers, pharmaceutical excipients, etc.), which constitute one or more accessory ingredients. Generally, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0056] In certain embodiments, formulations suitable for oral administration are presented as discrete units (eg, capsules, cachets or tablets) each containing a predetermined amount of the active ingredient.

[0057] In certain embodiments, pharmaceutical preparations comprise one or more compounds of the present invention, together with one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents. Pharmaceutical preparations comprising active ingredients can be in any form suitable for the intended method of administration. For oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more active agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets comprising the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients can be, for example, inert diluents (e.g., calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate); granulating and disintegrating agents (e.g., corn starch or alginic acid); binders (e.g., cellulose, microcrystalline cellulose, starch, gelatin, or acacia); and lubricants (e.g., magnesium stearate, stearic acid, or talc). Tablets can be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material (e.g., glyceryl monostearate or glyceryl distearate) alone or with a wax can be used.

[0058] The amount of active ingredient combined with inactive ingredients to produce a dosage form will vary depending on the host treated and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans will contain approximately 1 to 1000 mg of active ingredient, formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, In embodiments, the carrier material ranges from about 5 to about 95% (weight:weight) of the total composition. In some embodiments, the pharmaceutical compositions described herein contain about 1-800 mg, 1-600 mg, 1-400 mg, 1-200 mg, 1-100 mg, or 1-50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein contain about 400 mg or less of a compound of Formula I. In some embodiments, the pharmaceutical compositions described herein contain about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0059] It should be understood that in addition to the ingredients particularly mentioned above, the formulations disclosed herein may also include other agents conventional in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

[0060] There is further provided a veterinary composition comprising at least one active ingredient as defined above together with a veterinary carrier.

[0061] Veterinary carriers are materials useful for the purpose of administering the compositions and can be solid, liquid, or gaseous materials that are inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

[0062] The effective dose of the active ingredient will depend, at least, on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (low doses), method of delivery and pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. Route of administration

[0063] One or more compounds of Formula I (herein referred to as the active ingredients), or pharmaceutically acceptable salts thereof, are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). The preferred route may include. It is understood that preferred route may vary, for example, depending on the condition of recipient. The advantage of the compounds of the present invention is that they are orally bioavailable and can be orally administered.Therefore, in one embodiment, the pharmaceutical compositions described herein are oral dosage forms.In certain embodiments, the pharmaceutical compositions described herein are oral solid dosage forms. Formulation Example 1 Hard gelatin capsules are prepared containing the following ingredients: amount Ingredients (mg / capsule) Active ingredients 30.0 Starch 305.0 Magnesium stearate 5.0

[0064] The above ingredients are mixed and loaded into a hard gelatin capsule. Formulation Example 2 A tablet formula is prepared using the following ingredients: amount Ingredients (mg / tablet) Active ingredients 25.0 Microcrystalline cellulose 200.0 Colloidal silicon dioxide 10.0 Stearic Acid 5.0

[0065] These ingredients are blended and compressed to form a tablet. Formulation Example 3 A formulation for a dry powder inhaler is prepared containing the following components: Ingredients Weight% Active ingredients 5 Lactose 95

[0066] The active ingredient is mixed with lactose and the mixture is added to a dry powder inhaler device. Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: amount Ingredients (mg / tablet) Active ingredient 30.0mg Starch 45.0mg Microcrystalline cellulose 35.0mg Polyvinylpyrrolidone (as a 10% solution in sterile water) 4.0 mg Sodium carboxymethyl starch 4.5mg Magnesium stearate 0.5mg Talc 1.0mg Total 120mg

[0067] The active ingredient, starch, and cellulose are passed through a No. 20 mesh US sieve and thoroughly mixed. The resulting powder is mixed with the polyvinylpyrrolidone solution, which is then passed through a 16 mesh US sieve. The granules so produced are dried at 50°C to 60°C and passed through a 16 mesh US sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh US sieve, are then added to the granules, mixed, and compressed on a tablet machine to yield tablets each weighing 120 mg. Formulation Example 5 Suppositories, each containing 25 mg of active ingredient, are made as follows: Ingredients Quantity Active ingredient 25mg Saturated fatty acid glycerides up to 2,000 mg

[0068] The active ingredient is passed through a No. 60 mesh US sieve and suspended in pre-melted saturated fatty acid glycerides using minimal heat. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Formulation Example 6 Suspensions containing 50 mg of active ingredient per 5.0 mL dose are made as follows: Ingredients Quantity Active ingredient 50.0mg Xanthan gum 4.0mg Sodium carboxymethylcellulose (11%) Microcrystalline cellulose (89%) 50.0mg 1.75g ​​sucrose Sodium benzoate 10.0mg Flavorings and Colorings qv Diluted with purified water until it reaches 5.0 mL

[0069] The active ingredient, sucrose, and xanthan gum are blended and passed through a No. 10 mesh US sieve, then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose. The sodium benzoate, flavor, and color are diluted with some water and added with stirring. Sufficient water is then added to obtain the required volume. Formulation Example 7 A subcutaneous formulation may be prepared as follows: Ingredients Quantity Active ingredient 5.0mg 1.0mL corn oil Formulation Example 8 An injectable preparation is prepared having the following composition: Ingredients Quantity Active ingredient 2.0mg / mL Mannitol, USP 50 mg / mL Gluconic acid, USP qs (pH 5-6) Water (sterile distilled water) up to 1.0 mL Nitrogen gas, NF qs Formulation Example 9 A topical preparation is prepared having the following composition: Ingredients grams Active ingredient 0.2~10 Span60 2.0 Tween60 2.0 Mineral oil 5.0 Petrolatum 0.10 Methylparaben 0.15 Propylparaben 0.05 BHA (butylhydroxyanisole) 0.01 Water 100 qs

[0070] All of the above ingredients, except water, are combined and heated, with stirring, to 60° C. A sufficient quantity of water at 60° C. is then added with vigorous stirring to emulsify the ingredients, and water then added qs 100 g. Formulation Example 10 sustained release composition Ingredients Weight Range % Active ingredient 50~95 Microcrystalline cellulose (filler) 1-35 Methacrylic acid copolymer 1~35 Sodium hydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5~5.0 Magnesium stearate 0.5~5.0

[0071] The sustained release formulations of the present disclosure can be prepared as follows: the compound and pH-dependent binder and any optional excipients are intimately mixed (dry blended). The dry blended mixture is then granulated in the presence of an aqueous solution of a strong base, which is sprayed onto the blended powder. The granules are dried, sieved, mixed with an optional lubricant (e.g., talc or magnesium stearate), and compressed into tablets. A preferred aqueous solution of a strong base is an aqueous solution of an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide, preferably sodium hydroxide), optionally containing up to 25% of a water-miscible solvent such as a lower alcohol.

[0072] The resulting tablets may be coated with an optional film-forming agent for identification, taste-masking purposes, and to improve swallowing ease. The film-forming agent is typically present in an amount ranging from 2% to 4% of the tablet weight. Suitable film-forming agents are well known in the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate / methyl-butyl methacrylate copolymers—Eudragit® E-Roehm.Pharma), and the like. These film-forming agents may optionally contain colorants, plasticizers, and other auxiliary ingredients.

[0073] The compressed tablets preferably have a hardness sufficient to withstand 8 Kp compression. Tablet size depends primarily on the amount of compound in the tablet. Tablets contain 300-1100 mg of compound free base. Preferably, tablets contain amounts of compound free base in the ranges of 400-600 mg, 650-850 mg, and 900-1100 mg.

[0074] The time during which the powder containing the compound is wet-mixed is controlled to affect the dissolution rate. Preferably, the total powder mixing time, i.e., the time during which the powder is exposed to the sodium hydroxide solution, is in the range of 1 to 10 minutes, preferably 2 to 5 minutes. After granulation, the particles are removed from the granulator and placed in a fluidized bed dryer at approximately 60°C for drying. Formulation Example 11 A tablet formulation is prepared using the following ingredients: amount Ingredients (mg / tablet) Active ingredients 300.0 Microcrystalline cellulose 100.0 Colloidal silicon dioxide 10.0 Stearic Acid 5.0

[0075] The above ingredients are blended and compressed to form a tablet. [Example]

[0076] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the examples that follow are well-functioning techniques in the practice of the present disclosure, and that they can therefore be considered to constitute specific modes for its practice. However, those skilled in the art should understand in light of the present disclosure that many changes can be made in those specific embodiments that are disclosed, and that these changes will still achieve the same or similar results without departing from the spirit and scope of the present disclosure. List of Abbreviations and Acronyms Abbreviation Meaning ℃ Celsius temperature Ac Acetyl aq. water-based ATP adenosine triphosphate B2Pin2 Bis(pinacolato)diboron BOC tert-butoxycarbonyl Br Broad BSA Bovine serum albumin d double line DCM dichloromethane dd double line double line ddd double line double line double line DIPEA N,N-Diisopropylethylamine (Hunig's base) DMA Dimethylacetamide DME 1,2-dimethoxyethane DMF Dimethylformamide DMSO dimethyl sulfoxide dt double line-triple line DTT Dithiothreitol (Cleland Reagent) EC 50 Median effective concentration EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDTA Ethylenediaminetetraacetic acid EGFR epidermal growth factor receptor Eq equivalent ES / MS electrospray mass spectrometry Et Ethyl EtOAc ethyl acetate EtOH Ethanol (Ethyl Alcohol) FBS Fetal Bovine Serum g grams HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HCl Hydrochloric acid HPLC High Pressure Liquid Chromatography Hrs time HTRF® Homogeneous Time-Resolved Fluorescence, a registered trademark of Cisbio Bioassays (Parc Marcel Boiteux 30200 Codolet, France) Hz Hertz IBD inflammatory bowel disease I C 50 Half maximal inhibitory concentration i-pr isopropyl J coupling constant (MHz) K3PO4 Tripotassium Phosphate KOtBu Potassium tert-butoxide KOAc Potassium Acetate LCMS Liquid Chromatography-Mass Spectrometry LiHMDS Lithium bis(trimethylsilyl)amide LiOH Lithium hydroxide LiI Lithium iodide LPS lipopolysaccharide M molar concentration m multiplet M+ mass peak M+H+ mass peak + hydrogen Me methyl MeCN acetonitrile MeOH Methanol (methyl alcohol) MeLi Methyllithium MeMgX Methylmagnesium halide (Grignard reagent) (X is fluoro, chloro, bromo, or iodo) Me6Sn2Hexamethyldistannane (hexamethylditin) mg milligram MgSO4 Magnesium Sulfate MHz Megahertz Min ml / mL milliliter mM millimolar concentration mmol millimole MS mass spectrometry MsCl Mesyl chloride NBS N-Bromosuccinimide n-normal nBu / Bu n-butyl (normal butyl) n-BuLi n-butyllithium NaH sodium hydride NaHCO3 Sodium bicarbonate NaN3 Sodium Azide Na3PO4 Trisodium Phosphate Na2SO4 Sodium Sulfate nL nanoliter nm nanometer NMP 1-methylpyrrolidin-2-one NMR nuclear magnetic resonance NP-40 Nonylphenoxypolyethoxyethanol Pd-PEPPSI TM -IPent [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride Pen-Strep penicillin-streptomycin (0.85% saline solution containing 5,000 units of penicillin G sodium salt and 5,000 μg of streptomycin sulfate) Ph Phenyl q quartet qs A quantity sufficient to achieve the stated function RP reverse phase RPMI Roswell Park Memorial Institute Medium Rt room temperature s Single line sat. saturation Selectfluor® 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis (registered trademark of Air Products and Chemicals) SFC Supercritical Fluid Chromatography SiliaMetS® Thiol silica-based palladium scavenger, a registered trademark of Silicycle T triple line THF tetrahydrofuran TFA trifluoroacetic acid XPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0077] 1. Comparative example A Comparative Example A is shown as Example 193 in International Patent Application PCT / US2016 / 038861, published as WO2016 / 210036(A1). The structure of Comparative Example A is as follows: [ka] 2. Synthesis of intermediates Preparation of intermediate I-1: [ka] 3,3-Diethoxy-2-formylpropionitrile potassium salt (I-1C):

[0078] To a stirred solution of 3,3-diethoxypropane-nitrile (I-1A, 283.80 g, 1.98 mol) and methyl formate (I-1B, 148.80 g, 2.48 mol) in anhydrous THF (1.1 L) at 10°C was added 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2 mol). The temperature was maintained between 10°C and 15°C over the 45 minute addition. After the addition, the resulting slurry was stirred at ambient temperature for 2 hours. Hexane (400 mL) was then added, and stirring was continued for an additional 20 minutes. The slurry was filtered, the cake washed with 1 / 1 hexane / THF, and dried in a vacuum oven at 60°C overnight to give I-1C. 1 H-NMR (CD3OD) was consistent with the desired structure. . Pyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1E):

[0079] A stirred suspension of 3,3-diethoxy-2-formylpropionitrile potassium salt (I-1C, 5.10 g, 24.36 mmol) was cooled to 0 °C, and concentrated HCl (7.11 mL, 85.26 mmol) was added dropwise at a rate such that the internal temperature of the reaction did not rise above 20 °C. After the dropwise addition was complete, the reaction was stirred at room temperature for 20 minutes. To this reaction mixture was added a solution of 1-aminopyrrole (I-1D, 1.00 g, 12.18 mmol) in methanol (4.0 mL). After the addition, the reaction mixture was refluxed at 90 °C for 2 hours. Upon completion of heating, the reaction was cooled to room temperature and concentrated to approximately half of its original volume. Saturated aqueous sodium bicarbonate solution was carefully added to the resulting residue until effervescence ceased. The solution was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo, and the resulting residue was purified by silica gel chromatography (eluent: EtOAc / hexanes) to afford I-1E. 1H NMR (400 MHz, Chloroform-d) δ 8.16 - 8.03 (m, 2H), 7.93 (ddd, J= 2.6,1.4,0.6 Hz, 1H), 7.04 (dd, J = 4.5, 2.7 Hz, 1H), 6.84 (dd, J = 4.6, 1.4Hz, 1H). 7-Bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1F):

[0080] To a solution of pyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1E, 840.0 mg, 5.9 mmol) in MeCN (30 mL) at room temperature was added N-bromosuccinimide in one portion. The reaction was stirred at room temperature for 30 minutes and then poured into saturated aqueous sodium bicarbonate. The solution was concentrated in vacuo to remove acetonitrile. The resulting aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (eluent: EtOAc / hexanes) to give I-1F. 1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 2.1 Hz, 1H), 8.10 (d,J =2.1Hz,1H), 7.12 (d, J = 4.8 Hz, 1H), 6.93 (d, J = 4.8 Hz, 1H). 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1):

[0081] A microwave vial was charged with 7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1F, 416.5 mg, 1.9 mmol), bis(pinacolato)diboron (762.1 mg, 3.0 mmol), potassium acetate (552.3 mg, 5.6 mmol), and bis(triphenylphosphine)palladium(II) dichloride (65.8 mg, 0.094 mmol). Dioxane (8.0 mL) and DMF (4.0 mL) were added, and the reaction mixture was degassed by bubbling argon through for 2 minutes. The vial was sealed, and the reaction was heated at 120 °C in a microwave reactor for 60 minutes. After cooling, the reaction mixture was filtered and concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with a second portion of EtOAc, and the combined organic layers were dried over sodium sulfate, filtered through a plug of Celite, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluent: EtOAc / hexanes) to give I-1. H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 4.6 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 1.41 (s, 12H). Preparation of intermediate I-2: [ka]

[0082] 6-Bromo-4-chloronicotinic acid. To a solution of methyl 6-bromo-4-chloronicotinate (15 g, 59.89 mmol) in methanol (240 mL) was added water (68 mL) containing lithium hydroxide (2.93 g, 119.77 mmol). The solution was heated to 43° C. overnight and then cooled to room temperature. Aqueous hydrochloric acid (1 M, 120 mL) was added and the volatiles were removed in vacuo. The resulting slurry was filtered and washed with HO to give 6-bromo-4-chloronicotinic acid. ES / MS: 238.0 (M+H + ). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.03 (s, 1H).

[0083] (R)-6-Bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide. To a solution of 6-bromo-4-chloronicotinic acid (3 g, 12.69 mmol) in DMF (42 mL) was added HATU (6.27 g, 16.49 mmol), (R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride (2.4 g, 15.23 mmol), and N,N-diisopropylethylamine (5.62 mL, 32.26 mmol). The resulting solution was stirred overnight at room temperature and then diluted with ethyl acetate. The organic solution was washed with saturated aqueous lithium chloride (3 times), then dried over Na2SO4, and then concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give (R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide. ES / MS: 341.1 (M+H + ). 1H NMR (400 MHz, DMSO-d6) δ 8.88 (t, J = 5.5 Hz,1H), 8.41(s,1H),8.01 (s, 1H), 4.82 (s, 1H), 4.28 (ddd, J = 49.3, 9.4,2.0 Hz, 1H), 3.84 - 3.63(m, 1H), 3.40-3.22 (m, 1H), 1.13 (d, J = 7.0Hz, 6H).

[0084] (R)-4-Chloro-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (I-5). To a solution of (R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (0.2 g, 0.59 mmol) in DME (3.9 mL) was added 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.24 g, 0.9 mmol), XPhos Pd G3 (0.05 g, 0.06 mmol), and aqueous potassium phosphate trihydrate (2 M, 0.59 mL, 1.18 mmol). The resulting solution was degassed with argon and heated in a microwave reactor for 12 minutes at 120° C. The crude reaction mixture was purified by silica gel chromatography (eluent: EtOAc / hexanes) to give (R)-4-chloro-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide. ES / MS: 402.2 (M+H + ). 3. Example Procedures and Example Compounds Procedure 1: Example 1: (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide [ka]

[0085] Methyl 6-chloro-4-(methylamino)nicotinate: To a solution of methyl 4,6-dichloronicotinate (0.5 g, 2.43 mmol) and methylamine hydrochloride (0.82 g, 12.16 mmol) in acetonitrile (10 mL) and water (0.3 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (1.8 mL, 12.04 mmol). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated to dryness in vacuo and diluted with ethyl acetate. The resulting solution was washed with water and aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting material was purified by normal phase SiO2 chromatography (eluent: ethyl acetate / hexane) to give the desired product. ES / MS: 201.180 (M+H + ).

[0086] 6-Chloro-4-(methylamino)nicotinic acid: To a solution of methyl 6-chloro-4-(methylamino)nicotinate (0.38 g, 1.92 mmol) in MeOH (10 mL), THF (5 mL), and water (5 mL) was added lithium hydroxide (0.12 g, 5.01 mmol). The solution was stirred at room temperature for 18 hours, neutralized with HCl (1N, 5 mL), concentrated in vacuo, and dried. The crude material obtained was used in the subsequent step. ES / MS: 187.070 (M+H + ).

[0087] (R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide: To a solution of 6-chloro-4-(methylamino)nicotinic acid (0.36 g, 1.92 mmol) and (R)-4-amino-3-fluoro-2-methylbutan-2-ol (0.31 g, 2.56 mmol) in DMF (10 mL) was added HATU (0.97 g, 2.55 mmol) and N,N-diisopropylethylamine (1.5 ml, 8.61 mmol) was added. The resulting solution was stirred at room temperature for 1 hour and diluted with ethyl acetate. This solution was washed with 5% aqueous lithium chloride (3x), dried over sodium sulfate, and concentrated in vacuo. The resulting material was purified by normal phase SiO2 chromatography (eluent: ethyl acetate / hexanes) to give the desired product. ES / MS: 290.472 (M+H + ).

[0088] (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide: To a solution of (R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide (30 mg, 0.10 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (39 mg, 0.15 mmol), and Xphos Pd G3 (9 mg, 0.011 mmol) in DME (1 mL) was added aqueous potassium phosphate (2 M, 0.10 mL, 0.20 mmol). The resulting solution was degassed with argon for 2 min and heated at 120 °C under microwave conditions for 20 min. The reaction mixture was filtered and the resulting solid was washed with DMF. The filtrate was then concentrated in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN * 0.1% TFA) to give the product as the trifluoroacetate salt. ES / MS: 397.283 (M+H + ). 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz,1H),8.51(s,1H), 8.02 (d, J = 5.1 Hz, 1H), 7.76 (s, 1H), 7.21 (d, J = 5.1 Hz,1H),4.42(ddd,J = 49.0, 9.3, 2.1 Hz, 1H), 3.93 (ddd, J = 36.4, 14.5, 2.2 Hz,1H),3.48(ddd, J =16.2, 14.5, 9.4 Hz, 1H), 3.19 (s, 3H), 1.28 (d, J = 1.7 Hz, 6H) Step 2 Example 2 (R)-4-((cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide [ka]

[0089] (R)-6-chloro-4-((cyanomethyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide: To a slurry of (R)-4,6-dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (100 mg, 0.34 mmol) and aminoacetonitrile hydrochloride (47.03 mg, 0.51 mmol) in DMA (1 mL) was added N,N-diisopropylethylamine (0.2 mL, 1.12 mmol). The resulting solution was then heated under microwave conditions at 150 °C for 3 min. The resulting mixture was heated for 10 minutes. Additional aminoacetonitrile hydrochloride (47.03 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.12 mmol) were added, and the reaction was heated at 130° C. under thermal conditions for 16 hours. The solution was cooled to room temperature and diluted with ethyl acetate. The resulting slurry was filtered, and the solid was washed with EtOAc. The combined filtrate was washed with aqueous ammonium chloride. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting material was purified by normal phase SiO chromatography (eluent: ethyl acetate / hexanes) to give the desired product. ES / MS: 315.159 (M+H + ).

[0090] (R)-4-((cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide: To a solution of (R)-6-chloro-4-((cyanomethyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (53 mg, 0.17 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (68 mg, 0.25 mmol), and Xphos Pd G3 (16 mg, 0.019 mmol) in DME (2 mL) was added aqueous potassium phosphate (2 M, 0.17 mL, 0.34 mmol). The resulting solution was degassed with argon for 2 min and heated at 120° C. for 20 min under microwave conditions. The reaction mixture was filtered and the resulting solid was washed with DMF and MeOH. The filtrate was then concentrated in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN). * Purification by HCl (0.1% TFA) gave the product as the trifluoroacetic acid salt. This material was further purified by normal phase SiO chromatography (eluent: methanol / dichloromethane) and lyophilized from acetonitrile and water (0.1% trifluoroacetic acid) to give the desired product. ES / MS: 422.250 (M+H + ). 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J =2.0Hz,2H), 8.10(d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H),4.73(s,2H), 4.46(ddd, J = 49.1, 9.4, 2.2 Hz, 1H), 3.98 (ddd, J = 36.6, 14.5,2.2Hz,1H), 3.60- 3.41 (m, 1H), 1.31 (d, J = 1.7 Hz, 6H). Step 3: Example 3: 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide [ka]

[0091] 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide: To a slurry of (R)-4,6-dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (200 mg, 0.68 mmol) and (R)-2-aminopropanamide hydrochloride (172 mg, 1.38 mmol) in DMA (3 mL) was added N,N-diisopropylethylamine (0.6 mL, 3.37 mmol). The resulting solution was then heated at 150° C. for 60 min under microwave conditions. The resulting material was purified by RP-HPLC (eluent: water / MeCN). * 0.1% TFA) to give the product as the trifluoroacetate salt. ES / MS: 347.521 (M+H + ). [Table 1] [Table 2-1] [Table 2-2]

[0092] Biological assays Biological assays were performed to measure activity against TNFα and IRAK4. As summarized in Table 3, the test compounds are inhibitors of IRAK4. IRAK4 Monocyte TNFα Cell-Based Assay Procedure:

[0093] Cryopreserved human monocytes (Stem Cell Technologies) were thawed and incubated in GlutaMAX 1000-mL PBS containing 10% FBS. TM (Gibco® 200 mM L-alanine 0.125 × 10 cells / ml in RPMI medium (10 mM HEPES, 1X Pen-Strep, 55 μM β-mercaptoethanol, 1 mM sodium pyruvate) supplemented with 100 μL of lysed leucine (L-glutamine). 6 The cells were diluted to 5,000 cells / ml and allowed to recover for 2 hours at 37°C. The cell suspension was then plated into black 384-well Greiner clear-bottom plates at a density of 5,000 cells / well. The plates were pre-spotted with test compounds, serially diluted in DMSO. The cells were dispensed into an Echo 550 acoustic liquid dispenser (Labcyte®) at a final DMSO concentration of 0.1%. )) was used to deliver 40 nL / well. Plated cells were treated with compound for 1 hour at 37°C. Cells were then stimulated with 50 pg / ml LPS (Sigma), except for the outer rows of the plate, which were used for unstimulated cell control wells. Cells were incubated for an additional 4 hours at 37°C. Cells were then centrifuged from the medium, and 5 μl samples were taken and analyzed for total TNFα content using the TR-FRET human TNFα detection system (CisBio). This system uses two labeled antibodies (cryptate and XL665) that bind to two different epitopes on the TNFα molecule and generate a FRET signal proportional to the TNFα concentration in the sample. The detection antibodies were mixed 50:50, and 5 μL was dispensed into each well. The plate was covered with a clear seal and incubated overnight at room temperature. The next morning, plates were read using an Envision2103 Multilabeled reader (PerkinElmer) with excitation / emission / FRET emission at 340 nm / 615 nm / 665 nm, respectively. Fluorescence intensities at 615 nm and 665 nm emission wavelengths were expressed as a ratio (665 nm / 615 nm). Percentages of control were calculated as follows: % Control = 100 × (ratio サンプル -ratio 0%刺激 ) / (ratio 100%刺激 -ratio 0%刺激 ) Here, unstimulated cells (0% stimulation) served as a negative control, and stimulated cells (100% stimulation) served as a positive control. IRAK4 biochemical assay procedure:

[0094] The activity of the IRAK4 enzyme (Carna Biosciences, Chuo-ku, Kobe, Japan) was measured by detecting the formation of phosphorylated peptide substrates using antibodies against the substrate. This is a time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay based on the STK1 KinEASE Assay (Cisbio, Bedford, Massachusetts). The assay was designed as a simple two-step endpoint assay (5 μl enzyme reaction solution followed by 5 μl stop / detection solution) performed in a ProxiPlate-384 Plus plate (Perkin Elmer, Waltham, Massachusetts). Staurosporine, a nonselective kinase inhibitor, was used as a positive control. Compounds diluted in DMSO were spotted onto a 384-well plate using a Labcyte® Echo 550 Liquid Handling System, followed by the addition of the IRAK4 enzyme and peptide substrate. The reaction mixture was delivered using a Multi-Flo (Bio-Tek Instruments). The enzyme and peptide solutions were incubated with the compounds for 15 minutes at room temperature, after which the reaction was initiated by the addition of ATP. A standard 5 μl reaction mixture contained 500 μM ATP, 2 μM peptide (STK1 peptide), and 0.75 nM IRAK4 in reaction buffer (50 mM HEPES, pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 5 mM MgCl2, 0.025% NP-40, 1 mM DTT). After 120 minutes of incubation at room temperature, 5 μl of stop and detection solution (1:100 cryptate-labeled anti-phosphopeptide antibody solution and 125 nM tracer in 50 mM HEPES pH 7.0 detection buffer containing sufficient EDTA) was added. The plate was then incubated for an additional 60 minutes at room temperature and assayed for Enviromental Imaging using excitation, emission, and FRET emission at 340 nm, 615 nm, and 665 nm, respectively. The readings were taken on a Ssion 2103 Multilabeled reader (PerkinElmer). The fluorescence intensities at 615 nm and 665 nm emission wavelengths were expressed as the ratio (665 nm / 615 nm). The percentage of inhibition was calculated as follows: % Inhibition = 100 × (ratio サンプル -ratio 0%阻害 ) / (ratio 100%阻害 -ratio 0%阻害 )

[0095] The 0% inhibition value comes from a control well lacking inhibitor. The 100% inhibition value comes from a control well containing saturating amounts of the known inhibitor staurosporine. Liver stability:

[0096] Metabolic stability in cryopreserved hepatocytes: Complete HT medium is a novel method for the treatment of hepatic leukemia. TM Supplemented KHB medium was prepared by adding 1 mL of Torpedo Antibiotic Mix to 45 mL of HT medium. The supplemented KHB medium consisted of Krebs-Henseleit buffer containing amikacin (84 μg / mL), calcium chloride (1 mM), gentamicin (84 μg / mL), HEPES (20 mM), heptanoic acid (4.2 μM), and sodium bicarbonate (28.5 mM). The pH was adjusted to 7.4 at 37°C using 1 M NaOH or 1 M HCl. Human cryopreserved hepatocytes were pooled from 10 adult donors (Celsis, lot: HBZ).

[0097] The vial containing the cryopreserved hepatocytes was removed from liquid nitrogen and immediately immersed in a 37°C water bath. The vial was gently shaken until its contents thawed, then immediately transferred to 48 mL of pre-warmed complete HT medium in a 50 mL conical tube. The remaining cells in the vial were resuspended in 1.0 mL of pre-warmed complete HT medium and added to the conical tube. The tube was capped and then gently inverted several times to resuspend the hepatocytes. The cell suspension was centrifuged at 50 × g for 5 minutes at room temperature, and the supernatant was discarded. The cell pellet was broken up by gently swirling the centrifuge tube, and supplemented KHB medium was added to the tube to reach a target density of 2 × 10 cells. 6 Cells / mL were obtained. Total cell counts and percentage of viable cells were determined by trypan blue exclusion using a hemocytometer.

[0098] For incubation, an aliquot of hepatocyte suspension (250 μL containing 500,000 cells) was added to 250 μL of 2 μM test compound or metabolic stability control in duplicate wells of a 24-well plate in supplemented KHB. The final incubation concentration was 1×10 6 The concentrations of cells / mL and test compound were 1 μM. 7-Hydroxycoumarin and testosterone, compounds known to be efficiently metabolized by hepatocytes, were used as positive controls in parallel incubations (final concentration of 2 μM each). Incubations were performed at 37°C in a humidified atmosphere of 95% air / 5% CO2 (v / v) with gentle shaking. Aliquots (50 μL) were removed at 0, 1, 3, and 6 hours and added to 100 μL of IS / Q quenching solution. Upon completion, 150 μL of water was added, the plate was centrifuged at 3000 × g for 10 minutes, and an aliquot of the supernatant was analyzed on a Micromass Quattro Premier mass spectrometer connected to an Agilent 1200 Series HPLC system equipped with a Leap Technologies HTC PAL autosampler, as described below.

[0099] Liquid chromatography-mass spectrometry: Quantitation of test compounds and metabolic stability control was performed by analyte / internal standard peak area ratio (PAR) measured on a Micromass Quattro Premier XL tandem triple quadrupole mass spectrometer connected to an Agilent 1200 Series HPLC system equipped with a Leap Technologies HTC PAL autosampler. The column used was a Phenomenex® MercuryMS. TM The column was a Synergi Max-RP (100 Å pore size, 2.5 μm particle size, 20 × 2.0 mm). Mobile phase A consisted of 0.2% (v / v) formic acid in 99% water / 1% acetonitrile (v / v). Mobile phase B consisted of 0.2% (v / v) formic acid in 5% water / 95% acetonitrile (v / v). Elution was performed with the following linear gradient set: initial condition 0% B, held for 30 seconds, then increased to 100% B over 90 seconds, then returned to initial conditions over 1 second. The system allowed a minimum of 60 seconds of re-equilibration between injections. Sample injection volume was 10 μL. LTP Plasma Protein Binding:

[0100] Stock solutions of test compounds in dimethyl sulfoxide (DMSO) with a final concentration of 10 mM were prepared and used in all experiments.

[0101] Commercially available chemicals were obtained from Sigma-Aldrich (St. Louis, MO) and VWR (West Chester, PA). Cell culture medium (CCM) was Gibco Dulbecco's modified Eagle's medium (DMEM) containing 10% (v / v) fetal bovine serum.

[0102] Equilibrium dialysis assay: Pooled plasma (at least three males and three females) was derived from humans, beagle dogs, Sprague-Dawley rats, cynomolgus monkeys, and rhesus monkeys. Sodium EDTA was used as an anticoagulant.

[0103] Competitive equilibrium dialysis was performed at 37°C using human plasma against CCM containing 10% FBS, with both sides of the matrix spiked with sample to a final concentration of 2 μM. Prior to the study, the dialysis membrane was soaked in 0.133 M phosphate buffer, pH 7.4, for approximately 1 h. Spiked plasma (1 mL) and CCM (1 mL) were placed on opposite sides of the assembled dialysis cell. For recovery assessment, after a 24-h equilibration period in a 37°C water bath, plasma samples were poured into pre-weighed polypropylene tubes containing 1 mL of CCM (no compound), and CCM samples were poured into pre-weighed tubes containing 1 mL of the relevant blank plasma. The weights of the post-dialysis plasma and CCM were measured and recorded for calculations. Liquid chromatography-mass spectrometry:

[0104] Quantitation of test compounds was performed by analyte / internal standard peak area ratio (PAR) measured on a Q-Exactive mass spectrometer connected to an Agilent 1260 Series HPLC system equipped with a Leap Technologies HTS PAL autosampler. Mobile phase A consisted of 0.2% (v / v) formic acid in 99% water / 1% acetonitrile (v / v). Mobile phase B consisted of 0.2% (v / v) formic acid in 5% water / 95% acetonitrile (v / v). Sample injection volume was 10 μL. pK a Decision:

[0105] Sample preparation: Stock solutions of test compounds in dimethyl sulfoxide (DMSO) with a final concentration of 10 mM were prepared and used in all experiments. The DMSO stock solutions were thawed, swirled, and sonicated in a 40°C water bath to facilitate dissolution.

[0106] pK aAnalysis: The 10 mM DMSO stock solution was diluted 100-fold with 10 mM HCl to a final compound concentration of 100 μM and 1% DMSO. The compound was then transferred to 24 consecutive wells of a 96-well PCR plate for analysis using the aqueous solution method. For compounds that did not produce high-quality data using the aqueous solution method, the 10 mM DMSO stock solution was diluted 100-fold with 2 mM HCl and methanol to a final methanol concentration of 60%, compound concentration of 100 μM, and DMSO concentration of 1%. For analysis using the cosolvent method, the compound was transferred to 24 consecutive wells of a 96-well plate.

[0107] Analysis: All data were analyzed using a pKa PRO analyzer (AATI, Ames, IA). For the aqueous method, electrophoretic separations were performed in parallel over 24 different pH values, providing a direct measure of total compound charge versus pH. Compounds were detected by UV at 228 nm. The average pH interval between buffer points was 0.4 pH units, spanning a typical pH range of 1.7 to 11.2.

[0108] The cosolvent method is suitable for the analysis of compounds with low aqueous solubility (typically with a predicted intrinsic solubility <10 μg / ml). The average pH interval between buffer points is 0.4 pH units, spanning a pH range of 1.7 to 11.2. For each compound, four consecutive CE runs are performed, starting with 60% cosolvent buffer and decreasing to 30% cosolvent buffer.

[0109] Norfloxacin is used as the daily performance index standard.

[0110] Calculation of Results: A total number of pKa values ​​are predicted by relating mobility to the molecular weight of the compound using pKa Estimator® software (AATI, Ames, IA). Automated hERG Assay (formerly Chantest) at Charles River-Cleveland

[0111] The FASTPatch® assay (Charles River) was used to test the in vitro effects of various compounds on cloned hERG potassium channels encoded by the KCNH2 gene and stably expressed in HEK293T cells. Vehicle, test, and control formulations were prepared by diluting DMSO stock solutions in HB-PS (HEPES-buffered saline solution) and delivered to cells using a QPatch robotic pipette system to a final concentration of 0.3% DMSO. Test compounds were applied to cells at final concentrations of 0.3, 1, 3, 10, and 30 μM in ascending order (n≧3, n=cells / concentration) at intervals of at least 3 minutes separated by solution changes. The positive control, 50 nM cisparide, was applied in the same manner. Cell membrane Currents were recorded at room temperature using up to 48 parallel patch-clamp amplifiers in a QPatch HT® or QPatch HTX® system. Only cells with validated whole-cell recordings (seal resistance ≥ 200 MΩ and leak current ≤ 25% channel current) were used. hERG current onset and block were measured using a stimulus voltage pattern consisting of a 500 ms prepulse to -40 mV, a 2 s activation pulse to +40 mV, and then a 2 s test pulse to -40 mV. The pulse pattern was repeated consecutively with 10 s intervals from a holding potential of -80 mV. TurboSol analysis of test compound solubility was performed for each concentration tested using a Nephelostar reader measuring light scattering from a 635 nm laser source. Based on validation experiments, light scattering greater than four times the background level was considered an indication of the presence of particles in the suspension.

[0112] Table 3 below presents the results from the in vitro assay. [Table 3]

[0113] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Compounds of formula (II): [ka] or a pharmaceutically acceptable salt or structural isomer thereof, wherein: R 1 is H, D or methyl, and R 2 is H, D or methyl, or R 1 and R 2 together with the carbon atom to which they are attached form cyclopropyl, A compound or a pharmaceutically acceptable salt or structural isomer thereof. (Section 2) R 1 The compound according to item 1, wherein is H. (Section 3) R 1 Item 1. The compound according to item 1, wherein is methyl. (Section 4) Compounds of Formula III: [ka] or a pharmaceutically acceptable salt, deuterated analog thereof, wherein: R 1 is H, D or methyl, R 2 is H, D or methyl; The compound or a pharmaceutically acceptable salt thereof, a deuterated analog thereof. (Section 5) compound [ka] or a pharmaceutically acceptable salt thereof. (Section 6) A pharmaceutical composition comprising the compound according to any one of items 1 to 5 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. (Section 7) A method for treating an inflammatory condition in a patient in need thereof, the method comprising administering to the patient a compound according to any one of items 1 to 5 above, or a composition according to item 6 above. (Section 8) 8. The method according to item 7, wherein the inflammatory condition is selected from IBD, SLE, psoriasis, or rheumatoid arthritis.

Claims

1. A composition for treating cancer, comprising a compound of formula (II): 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, wherein R 1 is H, D or methyl and R 2 is H, D or methyl; or R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl; composition.

2. The composition of claim 1, wherein R 1 is H.

3. The composition of claim 1, wherein R 1 is methyl.

4. A composition for treating cancer, comprising a compound of formula III: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, including a deuterated analog, wherein: R 1 is H, D or methyl, and R 2 is H, D or methyl; composition.

5. A composition for treating cancer, comprising the compound 【Chemistry 13】 or a pharmaceutically acceptable salt thereof.

6. A composition described in any one of claims 1 to 5, wherein the cancer is lymphoma.

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