EA045296B1 - DERIVATIVES OF PYRROLO[1,2-b]PYRIDAZINE - Google Patents

Description

Field of technology

The present disclosure relates to novel compounds that are IRAK4 kinase inhibitors. The present description also relates to methods for preparing the compounds and pharmaceutical compositions containing such compounds.

State of the art

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 cascades. In particular, IRAK4 is involved in the activation of the myeloid differentiation adapter protein primary response gene 88 (MyD88) signaling cascades and is proposed to play a role in inflammatory and fibrotic diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, viral myocarditis, acute and chronic tissue damage, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis and kidney disease, including chronic kidney disease and diabetic kidney disease. In addition, IRAK4 plays a role in some cancers and is thought to play a role in inflammation associated with gastrointestinal infections, including C. difficile. Signaling through IL-1R/TLR leads to activation of MyD88, which recruits IRAK4 and IRAKI to form a signaling complex. This complex then interacts with a number of kinases, adapter proteins and ligases, which ultimately leads to the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-κB), activator protein-1 (AP1), binding protein cyclic AMP response element (CREB) and interferon regulatory factors (IRFs), including IRF5 and IRF7, inducing the production of proinflammatory cytokines and type I interferons.

Therefore, IRAK4 inhibitors may be suitable for the treatment of inflammatory and fibrotic diseases such as 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, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis and kidney disease, including chronic kidney disease and diabetic kidney disease (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 May 12, 2016; Valaperti, A. et al. , INNATE IMMUNE INTERLEUKIN1RECEPTOR-ASSOCIATED KINASE 4 EXACERBATES VIRAL MYOCARDITIS BY REDUCING CCR5+CD11b ⁺ MONOCYTE MIGRATION AND IMPAIRING INTERFERON PRODUCTION, Circulation, 128 | SEPTEMBER, 2013, 14, 1542-1554), as well as type I interferonopathies, such as Aicardi-Goutières syndrome, hereditary lupus pernio, and retinal vasculopathy with cerebral leukodystrophy (Lee-Kirsch et al., TYPE I INTERFERONOPATHIES-AN EXPANDING DISEASE SPECTRUM OF IMMUNODYSR EGULATION Semin. Immunopathol. (2015), 37:349-357; Leaf, LA 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 TLR9, The Journal of Clinical Investigation, 126 | MARCH 2016 3, 859-864).

In addition, some cancers, including lymphomas, may contain one or more mutations in the adapter protein MYD88, resulting in a constitutively active signaling cascade that may promote tumor cell survival (Kelly et al., IRAK4 inhibitors for autoimmunity and lymphoma, J. Exp Med., 2015, vol. 212, no. 13, 2189-2201).

Therefore, an IRAK4 inhibitor may be suitable for the treatment of cancer, including lymphomas.

There are currently no approved drugs that inhibit IRAK4. Therefore, it would be useful to provide an IRAK4 inhibitory compound with properties suitable for administration as a pharmaceutical agent to a mammal, in particular a human. The criteria for selecting a pharmaceutical compound are multifactorial. Compound characteristics are often described, including target activity, pharmacokinetics, _pKa , solubility, stability (eg, metabolic stability) and off-target properties (including potential cardiac toxicity), as well as possible drug-drug interactions.

Inhibition of the cardiac ion channel encoded by the human potassium channel alpha subunit gene (hERG) can lead to cardiac arrhythmia, which is a major concern in drug discovery and development. Automated electrophysiological patch clamp allows the assessment of effects on hERG channels in early drug development to aid medicinal chemistry programs and has become commonplace in pharmaceutical companies (Early identification of hERG liability in drug discovery programs by automated patch clamp, Front Pharmaco (2 Sept . 2014), 5:203).

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WO 2016210034, WO 2016210036, WO 2015150995, WO 2016127024 and WO 2016210037 list compounds that are considered useful as IRAK4 inhibitors.

Brief description of the invention

Provided herein are compounds and pharmaceutical compositions suitable as IRAK4 inhibitors. Certain compounds according to the present description may find use in pharmaceutical compositions in conjunction with at least one pharmaceutically acceptable excipient for the treatment of a subject in need thereof. The compounds of the present invention have also been found to inhibit the production of the pro-inflammatory cytokines TNFa, IL-6, ΓΕ-1β, IL-8, IL-12, IL-23 and type I interferons IFNa and IFNe, all of which are mediators of inflammation and immune function. answer. Also provided herein are compositions, including pharmaceutical compositions, kits that include the compounds, and methods for using and preparing the compounds.

One embodiment of the present disclosure provides a compound of formula (I)

or a pharmaceutically acceptable salt or structural isomer thereof, wherein R ¹ is selected from H, deuterium or C ₁ _ ₄ alkyl and said C ₁ _ ₄ alkyl is optionally substituted with one or more halogen;

R ² is selected from H, deuterium or C ₁ - ₄ alkyl and said alkyl is optionally substituted with one or more halogen; or

R ¹ and R ² together with the carbon atoms to which they are attached form C ₃ -C ₆ cycloalkyl; And

R ³ represents C ₀ _ ₄ alkyl-CN.

In one embodiment ^{, R2} is H.

In one embodiment, R ¹ is methyl.

In one embodiment, R ³ is -CN.

In another embodiment, provided herein is a compound of formula (II)

or a pharmaceutically acceptable salt or structural isomer thereof, wherein R ¹ is selected from H, deuterium or C ₁ _ ₄ alkyl and said C ₁ _ ₄ alkyl contains one or more hydrogen atoms, optionally substituted with deuterium;

R ² _is selected from H, deuterium or C _{1_4} alkyl and said C _{1_4} alkyl contains one or more hydrogen atoms, _optionally substituted with deuterium; And

R ³ represents C ₀ _ ₄ alkyl-CN.

In one embodiment of formula (II), R ² is H.

In another embodiment, R ² is deuterium.

In one embodiment of Formula (II), R ¹ is methyl.

In one embodiment of Formula (II), R ¹ is methyl with one or more hydrogen atoms attached to the methyl substituted with deuterium.

In one embodiment, R ³ is -CN.

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In another embodiment, provided herein is a compound of formula (III)

or a pharmaceutically acceptable salt thereof or a deuterated analogue thereof, wherein R ¹ is H or methyl, said methyl containing one or more hydrogen atoms, optionally replaced by deuterium.

In one embodiment, provided herein is a compound having the structure

or a pharmaceutically acceptable salt thereof.

In one embodiment, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

In another embodiment, a pharmaceutical composition is provided comprising a compound as described herein together with a pharmaceutically acceptable carrier and optionally a diluent.

In another embodiment, the present disclosure provides a method of treating a disease or disorder associated with inflammation in a patient in need thereof, comprising administering to said patient a compound of the present disclosure or a pharmaceutical composition thereof.

Detailed Description of the Invention

Definitions.

The following description sets forth exemplary methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of the disclosure, but rather is a description of exemplary embodiments of the invention.

A dash (-) that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached via a carbon atom. A dash at the beginning or end of a chemical group represents a matter of convenience; chemical groups may be shown with or without one or more dashes without losing their normal meaning. A wavy line drawn through a line in the structure indicates the point at which the group is attached. Unless necessary from a chemical or structural point of view, the order in which a chemical group is written or named does not indicate or imply any direction.

The prefix Cu-v indicates that the following group has from u to v carbon atoms. For example, C _1-6 alkyl indicates that the alkyl group has 1 to 6 carbon atoms. C ₀ indicates the absence of carbon atoms or, in other words, a bond with the next substituent.

Reference to an exemplary value or parameter herein includes (and describes) implementations that relate to that value or parameter per se. In some embodiments, the term approximately includes the indicated amount ±10%. In other embodiments, the term approximately includes the indicated amount ±5%. In some other embodiments, the term approximately includes the indicated amount ±1%. Also, the term about X includes a description of X. In addition, the singular and definite articles include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to a compound includes a plurality of such compounds and a reference to an assay includes a reference to one or more assays and their equivalents known to those skilled in the art.

Alkyl refers to a straight or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to _{20 carbon atoms (i.e., C 1_20 alkyl} ), 1 to 8 carbon atoms

- 3 045296 (ie _C1-8 alkyl), from 1 to 6 carbon atoms (ie C _1-6 alkyl) or 1 to 4 carbon atoms (ie C _1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl moiety having a certain number of carbon atoms is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms may be covered; thus, for example, butyl includes n-butyl (i.e. -(CH ₂ ) ₃ CH ₃ ), sec-butyl (i.e. -CH(CH ₃ )CH ₂ CH ₃ ), isobutyl (i.e. -CH ₂ CH(CH ₃ ) ₂ ) and tert-butyl (i.e. -C(CH ₃ ) ₃ ); and propyl includes n-propyl (ie -(CH2)CH3) and isopropyl (ie -CH( _CH3 ) ₂ ).

Cyano belongs to the -CN group. Halogen refers to -F, -Cl, -Br, -I.

Some commonly used alternative chemical names may be used. For example, a divalent group such as a divalent alkyl group, a divalent aryl group, etc. may also be referred to as an alkylene group or alkylenyl group, an arylene group or an arylenyl group, respectively. Also, unless explicitly stated otherwise, when combinations of groups are referred to herein as a single moiety, such as arylalkyl, the last group mentioned contains the atom by which the moiety is attached to the rest of the molecule.

The terms optional or optional mean that the event or circumstance described below may or may not occur and that the description includes cases in which the specified event or circumstance occurs and cases in which it does not occur. In addition, the term optionally substituted refers to any one or more hydrogen atoms on the specified atom or group, which may or may not be replaced by a moiety other than hydrogen. Optionally substituted can contain from zero to a maximum number of possible substitutions, and each occurrence is independent. When the term substituted is used, it is necessary that such substitution be made at the replaced hydrogen atom of the specified substituent. An optional replacement may be the same or different from a (mandatory) replacement.

When a moiety is optionally substituted and reference is made to a general term such as any alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl or heteroaryl, the general term may refer to any preceding specifically specified term, for example (C ₁ . ₃ alkyl), ( C ₄ - ₆ alkyl), -O(C ₁ . ₄ alkyl), (C ₃ . ₁₀ cycloalkyl), O-(C ₃ . ₁₀ cycloalkyl), etc. For example, any aryl includes both aryl and examples of aryl such as phenyl or naphthyl and the like. Also, the term any heterocyclyl includes heterocyclyls such as oxetanyl, tetrahydropyranyl, morpholino, piperidinyl and the like. Likewise, the term any heteroaryl includes heteroaryls such as pyridine, pyridazine, thiazole, thiadiazole, quinoline and the like.

Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imido acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between tautomers, those of ordinary skill in the art understand that the compounds include both amide and imido acid tautomers. Thus, amide-containing compounds are intended to include their imido acid tautomers. Likewise, compounds containing imido acid include their amide tautomers.

Any formula or structure given herein is also intended to represent the unlabeled forms as well as the isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures depicted by the formulas provided herein, except that one or more atoms are replaced by an atom having the selected atomic mass or mass number. Examples of isotopes that may be included in the compounds herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2H (deuterium, D), ^3H (tritium), ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, 18 F, ¹⁵ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. Included are various isotopically labeled compounds of the present invention, such as those that include radioactive isotopes such as 3H, ^13C and ^14C . Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) , including analyzes of the distribution of drugs or substrates in tissues, or when treating patients with radioactive drugs.

The present description also includes deuterated analogs of compounds of formula I in which 1 to n hydrogen atoms attached to the carbon atom are/are replaced by deuterium, in which n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and are thus suitable for increasing the half-life of any compound of formula I when administered to a mammal, especially a human. See, for example, Foster, Deuterium Isotope Effects in Studies of Drug Metabolism, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, using starting materials in which one or more hydrogen atoms are replaced by deuterium.

Deuterium-labeled or substituted therapeutic compounds according to the present description may have improved DMPK properties (drug metabolism and pharmacokinetics),

- 4 045296 related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and/or improved therapeutic index. The ¹⁸ F labeled compound can be used for PET or SPECT studies. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by following the procedures described in the Schemes or in the Examples and Drugs described below by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent. It should be understood that deuterium is considered in this context as a substituent in the compound of formula I.

The concentration of such a heavier isotope, in particular deuterium, can be determined by the isotope enrichment factor. In the compounds herein, any atom not specifically designated as a particular isotope means any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as H or hydrogen, the position is understood to contain hydrogen in its natural isotopic composition. Accordingly, in the compounds herein, any atom specifically designated deuterium (D) is deuterium.

In many cases, the compounds described herein are capable of forming acid and/or basic salts due to the presence of amino and/or carboxyl groups or the like.

Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs and prodrugs of the compounds described herein. Pharmaceutically acceptable or physiologically acceptable refers to compounds, salts, compositions, dosage forms and other materials that can be used to prepare a pharmaceutical composition suitable for veterinary or human pharmaceutical use.

The term pharmaceutically acceptable salt of a present compound refers to salts which retain the biological effectiveness and properties of the present compound and which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts or physiologically acceptable salts include, for example, inorganic acid salts and organic acid salts. In addition, if the compounds described herein are prepared as an acid addition salt, the free base can be prepared by making the acid salt solution alkaline. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from basic compounds. Various synthetic methodologies are known to those skilled in the art that can 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. Likewise, 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, but are not limited to, salts of primary, secondary and tertiary amines such as alkylamines (i.e. NH ₂ (alkyl)), dialkylamines (i.e. NH (alkyl) ₂ ), trialkylamines (i.e. N(alkyl) ₃ ), substituted alkylamines (i.e. NH ₂ (substituted alkyl)), di(substituted alkyl) amines (i.e. HN(substituted alkyl) ₂ ), tri(substituted alkyl)amines (i.e. ^substituted alkyl) ₃ ), alkenyl amines (i.e. NH ₂ (alkenyl)), dialkenyl amines (i.e. NH (alkenyl) ₂ ), trialkenyl amines (i.e. N (alkenyl) ) ₃ ), substituted alkenyl amines (i.e. NH ₂ (substituted alkenyl)), di(substituted alkenyl) amines (i.e. NH (substituted alkenyl) ₂ ), tri(substituted alkenyl) amines (i.e. ^ substituted alkenyl) ₃ , mono-, di- or tricycloalkylamines (i.e. NH ₂ (cycloalkyl), NH(cycloalkyl) ₂ , N(cycloalkyl) ₃ ), mono-, di- or tri-arylamines (e.g. NH ₂ (aryl), NH(aryl) ₂ , N(aryl) ₃ ) 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. .

The term substituted means that any one or more hydrogen atoms in the specified atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylic acid ester, cyano, guanidino, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl,

- 5 045296 sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione or combinations thereof. Polymers or similar undefined structures obtained by defining substituents with additional substituents attached ad infinitum (e.g., a substituted aryl having a substituted alkyl that is itself substituted by a substituted aryl group that is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion in this document. Unless otherwise noted, the maximum number of consecutive substitutions in the compounds described herein is three. For example, sequential substitutions of substituted aryl groups by two other substituted aryl groups are limited to ((substituted aryl)substituted aryl)substituted aryl. Likewise, the above definitions are not intended to include unacceptable substitution schemes (eg, methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen atoms on the ring). Such unacceptable 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 as defined herein. Unless otherwise indicated, when a group is described as optionally substituted, any substituents on the 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, halogen, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more substituents may be further substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted. One skilled in the art will appreciate that substituents and other moieties of compounds of the general formula described herein must be selected to provide a compound that is sufficiently stable to provide a pharmaceutically acceptable compound that can be included in a pharmaceutical composition with acceptable stability . Compounds that exhibit such stability are considered to fall within the scope of the present invention. One skilled in the art will appreciate that any combination of terms and substituents described above should not result in a non-functional species or compound.

As used herein, the terms pharmaceutically acceptable carrier or pharmaceutically acceptable excipient include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional vehicle or agent is incompatible with the active ingredient, it is intended for use in therapeutic compositions. Additional active ingredients may also be included in the compositions.

The solvate is formed by the interaction of a solvent and a compound. Also provided are solvates of salts of the compounds described herein. Hydrates of the compounds described herein are also provided.

Combinations.

Patients treated by administration of IRAK4 inhibitors according to the present description often have diseases or conditions that benefit from treatment with other therapeutic agents. These diseases or conditions may be inflammatory in nature or may be associated with cancer, metabolic disorders, gastrointestinal disorders, and the like. Thus, one aspect of the present disclosure is a method of treating a disease or condition associated with inflammation, or a metabolic disorder, gastrointestinal disorder or cancer, or the like, comprising administering a compound in combination with one or more compounds suitable for treating such diseases, the subject, especially the person in need.

In some embodiments, a compound described herein is formulated in conjunction with one or more additional active ingredients. In some embodiments, another active ingredient is administered at approximately the same time in a separate dosage form. In some embodiments, the other active ingredient is administered sequentially and may be administered at different times relative to the compound described herein.

Combinations for the treatment of inflammatory diseases or conditions.

For example, a compound of the present invention may be combined with one or more 5-lipoxygenase inhibitors, acetylcholinesterase inhibitors, acetyl-CoAcarboxylase (ACC) inhibitors, ACTH receptor agonists, activin receptor antagonists, acyltransferase inhibitors, adrenocorticotropic hormone ligands, AKT1 gene inhibitors, alkaline phosphatase, alkaline phosphatase stimulators, androgen receptor agonists, apolipoprotein C3 antagonists, ASK1 kinase inhibitors, bactericidal protein permeability stimulators, beta-adrenergic receptor antagonists, beta-glucuronidase inhibitors, CD20 B-lymphocyte antigen inhibitors, bradykinin receptor modulators, kinase inhibitors

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BTK, calcineurin inhibitors, calcium channel inhibitors, CB1 cannabinoid receptor modulators, CB2 cannabinoid receptor modulators, cannabinoid receptor antagonists, cannabinoid receptor modulators, caspase inhibitors, cathepsin S inhibitors, CCN protein stimulators, CCR3 chemokine antagonists, CCR5 chemokine antagonists, antagonists of CCR9 chemokines, CD3 modulators, CD40 ligand inhibitors, CD40 ligand receptor antagonists, CD49b antagonists, CD49d antagonists, CD89 agonists, cell adhesion molecule inhibitors, CXC chemokine ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 agonists, CSF-1 antagonists, ligand inhibitors CXC10 chemokine, CXCR2 chemokine antagonists, cyclic GMP phosphodiesterase inhibitors, cyclooxygenase 2 inhibitors, cyclooxygenase inhibitors, cyclooxygenase stimulators, cytochrome P450 3A4 inhibitors, cytotoxic T-lymphocyte protein-4 stimulators, dihydroceramide delta-4 desaturase inhibitors, dihydro orotate dehydrogenase, DNA polymerase inhibitors , DPP-4 inhibitors, EGFR family tyrosine kinase receptor modulators, eosinophil peroxidases 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, GATA transcription factor 3 inhibitors, glucagon-like peptide 1 agonists, glucagon-like peptide 2 agonists, glucocorticoid agonists, GM-CSF receptor agonists, 84 receptor antagonists associated with G -protein, guanylate cyclase receptor agonists, histamine H2 receptor antagonists, histone acetyltransferase inhibitors, histone deacetylase inhibitors, HLA class II antigen modulators, hydrolase inhibitors, HSD17e13 inhibitors, ICAM1 gene inhibitors, ICAM-1 inhibitors, IL1 gene inhibitors, IL-10 agonists, gene stimulators IL10, 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, alpha4/beta-1 integrin antagonists, alpha integrin antagonists -4/beta-7, integrin alpha-E antagonists, integrin antagonists, integrin beta-7 antagonists, interferon beta ligands, interleukin 17E ligand inhibitors, interleukin ligand inhibitors, interleukin 17A receptor antagonists, interleukin 17B receptor antagonists, interleukin beta ligands- 1, 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, BLT leukotriene receptor antagonists , lipoxygenase modulators, L-selectin antagonists, MAdCAM inhibitors, matrix metalloprotease inhibitors, matrix metalloprotease modulators, melanocortin agonists, membrane copper amine oxidase inhibitors, metalloprotease-2 inhibitors, metalloprotease-9 inhibitors, MIP 3 alpha ligand inhibitors, mitochondrial heat shock protein stimulators 10 kDa, CD14 monocyte differentiation antigen inhibitors, mTOR inhibitors, mucin stimulators, NAD-dependent sirtuin-1 deacetylase stimulators, natriuretic peptide receptor C agonists, neuregulin-4 ligands, nicotinic acetylcholine receptor agonists, alpha-4 subunit nicotinic ACh receptor modulators a , nicotinic ACh receptor alpha 7 subunit stimulators, nicotinic ACh receptor beta 2 subunit modulators, NK1 receptor antagonists, NK receptor antagonists activating NKG2 D, nuclear factor kappa B inhibitors, opioid growth factor receptor agonists, opioid receptor antagonists, antagonists opioid delta receptors, oxidoreductase inhibitors, P2X7 purinergic receptor agonists, p38 MAP kinase inhibitors, PARP inhibitors, PDE 4 inhibitors, PDGF receptor agonists, peptide modulators that stimulate phagocytosis, phospho-N-acetylmuramoyl-pentapeptide transferase inhibitors, phospholipase A2 inhibitors, antagonists platelet activating factor receptors, potassium channel inhibitors, PPAR alpha agonists, PPAR delta agonists, PPAR gamma agonists, CYR61 protein stimulators, fimH protein inhibitors, protein kinase C alpha inhibitors, protein kinase C beta inhibitors, protein kinase C delta inhibitors, protein kinase C epsilon inhibitors, inhibitors protein kinase C eta, protein kinase C theta inhibitors, protein kinase G inhibitors, protein kinase inhibitors, glycoprotein ligand-1 P-selectin inhibitors, purine biosynthesis protein PurH inhibitors, retinoic acid receptor alpha agonists, retinoic acid receptor beta agonists, retinoid receptor agonists, inhibitors RNA polymerase, 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 agonists receptors 1, antagonists of sphingosine-1-phosphate receptors 1, modulators of sphingosine-1-phosphate receptors 1,

- 7 045296 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 glycoprotein inhibitors CD28, TGF beta 1 ligand inhibitors, thymulin agonists, THR-β 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 ligand 14 modulators, TYK2 kinase inhibitors, TNF type I receptor antagonists, TNF type II receptor modulators, nonspecific growth factor receptor modulators, vanilloid VR1 agonists, vitamin receptor agonists D3, zonulin inhibitors, abatacept; acemannan; adalimumab; DCCT-10; apremilast; AST-120; balsalazide; sodium balsalazide; basiliximab; beclomethasone dipropionate; budesonide; D-9421; budesonide MMX; catridekakogom; certolizumab pegol; Clostridium butyricum; etanercept; fingolimod; glatiramer acetate; golimumab; infliximab; biosimilar to infliximab; a generic biosimilar of infliximab; interferon beta-1a; lenalidomide; mesalazine; GED-0001; AJG-501; metenkephalin acetate with tridecactide acetate, mycophenolate mofetil; naltrexone; natalizumab; nitazoxanide; olsalazine; oprelvequin; propionyl-b-carnitine; recombinant interferon beta-1a; remestemwhole-L; rifaximin; rituximab; ropivacaine; rosiglitazone; sargramostim; secukinumab; SPD-480; tacrolimus; tamibarotene; teduglutide; thalidomide; tocilizumab; RO-4877533; tofacitinib; SR-690550; pig whipworm eggs (Trichuris suis ova); ASP-1002; ustekinumab; valganciclovir; vedolizumab; zileuton; anti-CD3 imaging agent (antibody fragment, cancer/autoimmune disease), ImaginAb; AVX-470; cyclosporine; mAb to CXCR1/2 ligands (immunology), Eli Lilly; FFP-102; GSK-3050002; INN-108; IR-777; SGM-1019; pegilodecakin; PF-06480605; PF-06651600; SER-287; Syn-1002; Thetanix; therapy with tolerogenic dendritic cells TOP-1288; VBY-036; VBY-129; 946414-98-8; BMS-936557; 99mTc-annexin V-128; ABC294640; abrilumab; Alekvelem; 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; BAY98-7410; INV-103; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate; SV-01-05-MMH; LY-3074828; mesalamine with N-acetylcysteine; midismase; molgramostim followed by taking the biologic drug fosfomycin with carbapenem, Reponex; multipotent adult progenitor cell therapy (ischemia/cerebral palsy), Athersys/Healios; NN-8828; olokizumab; OvaSave; P-28-GST; PDA-002; PF-4236921; PF-547659; prednisone; PUR-0110; QBECO; RBX-2660; repurposed naltrexone; JKB-122; SB-012; sotrastaurin; STNM-01; TAK-114; tetomilast; Debio-0512; TRK-170; TRX-318; vatelizumab; VB201; ZP-1848; tsucapsaicin; AVT-494; alicaforsen; Ampion; BI-655066; briakinumab; cannabidiol; carotegast methyl; cobitolimod; dexamethasone sodium phosphate; elafibranor; etrolizumab; GS-5745; FDVIPL-004; LP-02; mesalazine; metronidazole, mongersen; ocrelizumab; ozanimod; peficitinib; RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod; plecanatide; telotristat etiprate; biosimilar infliximab, Samsung Bioepis; AZD-058 and rifabutin with clarithromycin and then clofazimine.

In addition, the following non-exhaustive list of classes of compounds and compounds may be combined with a compound of the present invention: 5-lipoxygenase inhibitors such as zileuton, etalocybe FPL-64170, E-3040 and BU-4601A; acetylcholinesterase inhibitors such as BL-7040; ACTH receptor agonists such as metenkephalin acetate with tridecactide acetate and FAR-404; activin receptor antagonists such as follistatin; acyltransferase inhibitors such as AZD-0585; adrenocorticotropic hormone ligands such as metenkephalin acetate with tridecactide acetate and FAR-404; AKT1 gene inhibitors such as vidofludimus; alkaline phosphatase modulators such as recombinant human alkaline phosphatase (oral, ulcerative colitis), AM-Pharma; alkaline phosphatase stimulants such as bovine alkaline phosphatase; androgen receptor agonists such as RV-005; apolipoprotein C3 antagonists such as AZD-0585; bactericidal protein permeation stimulators such as opabacan; beta-adrenergic antagonists such as NM-001; beta-glucuronidase inhibitors such as KD-018; inhibitors of B-lymphocyte antigens CD20, such as ocrelizumab, rituximab; bradykinin receptor modulators such as givinostat; calcineurin inhibitors such as tacrolimus, cyclosporine; calcium channel inhibitors such as clotrimazole; CB1 cannabinoid receptor modulators such as GWP42003-P, cannabidiol; CB2 cannabinoid receptor modulators such as GWP42003-P, cannabidiol; cannabinoid receptor antagonists such as fingolimod; cannabinoid receptor modulators such as GWP42003-P, cannabidiol; cathepsin S inhibitors such as VBY-129, VBY-036; CCN protein stimulators such as CSA-13; CCR3 chemokine antagonists such as bertilimumab; CCR5 chemokine antagonists such as HGS-1025; CCR9 chemokine antagonists such as MLN-3126, vercirnon, CCX-025; CD3 modulators such as visilizumab; CD40 ligand inhibitors such as FFP-104; receptor antagonists

- 8 045296 CD40 ligand, such as FFP-104, FFP-102, toralizumab; CD49b antagonists such as vatelizumab; CD49d antagonists such as ELND-004; CD89 agonists such as HF-1020; cell adhesion molecule inhibitors such as natalizumab, alicaforsen (intravenous), ASP-2002, ISIS-2302; CXC chemokine ligand inhibitors, such as CXCR1/2 ligand mAbs (immunology), Eli Lilly; CHST15 gene inhibitors such as STNM-01; collagen modulators such as adipose tissue stem cell therapy (Celution System), Cytori, DCCT-10; CSF-1 agonists such as sargramostim, a generic biosimilar of molgramostim with fosfomycin with carbapenem (intraintestinal, Crohn's disease), Reponex; CSF-1 antagonists such as JNJ-40346527; CXC10 chemokine ligand inhibitors such as 946414-98-8, BMS-936557; CXCR2 chemokine antagonists such as elubrixin; cyclic GMP phosphodiesterase inhibitors such as CEL-031; cyclooxygenase 2 inhibitors such as P-54; cyclooxygenase inhibitors such as mesalazine, sodium 4-aminosalicylate, AJG-501, AGI-022; cyclooxygenase stimulants such as nicotine polacrilex; cytochrome P450 3A4 inhibitors such as KD-018; cytotoxic T-lymphocyte protein-4 stimulants such as abatacept; dihydroceramide delta-4 desaturase inhibitors such as ABC-294640; dihydroorotate dehydrogenase inhibitors such as vidofludimus; DNA polymerase inhibitors such as valganciclovir; EGFR family tyrosine kinase receptor modulators such as neuregulin 4 (Crohn's disease/ulcerative colitis/necrotizing enterocolitis), Avexegen Therapeutics/Children's Hospital Los Angeles; eosinophil peroxidase inhibitors such as AWEPOPD-01, AWEPO-003; eotaxin ligand inhibitors such as bertilimumab; EP4 prostanoid receptor agonists such as KAG-308; epidermal growth factor agonists such as heparin-EGF-like factor, Scios Nova; epidermal growth factor ligands such as Hebervis; estrogen receptor beta agonists such as gain; factor XIII agonists such as catridecacog; FGF-10 ligands such as repifermin; FGF2 receptor agonists such as F2A; fractalkine ligand inhibitors such as E-6011; free fatty acid receptor 2 antagonists such as GLPG-0974; GATA 3 transcription factor inhibitors such as SB-012; glucagon-like peptide 2 agonists such as teduglutide, ZP-1848, NB-1002; glucocorticoid agonists such as budesonide, beclomethasone dipropionate, dexamethasone sodium phosphate, AJG-511, DOR-201, D-9421-C; GM-CSF receptor agonists such as sargramostim, a generic biosimilar of molgramostim with fosfomycin with carbapenem (intraintestinal, Crohn's disease), Reponex; G protein-coupled receptor 84 antagonists such as GLPG-1205; guanylate cyclase receptor agonists such as dolcanatide, SP-333; histamine H2 receptor antagonists such as bismuth, Medeva; histone acetyltransferase inhibitors such as TIP60 inhibitors (ulcerative colitis/inflammatory bowel disease/autoimmune diseases), University of Pennsylvania; histone deacetylase inhibitors such as givinostat; HLA class II antigen modulators, such as HLA class II protein modulators (Crohn's disease), Nextera AS; hydrolase inhibitors such as SC-56938; ICAM1 gene inhibitors such as alicaforsen; ICAM-1 inhibitors such as alicaforsen (intravenous), ISIS-2302; IL1 gene inhibitors such as PLR-14; IL-10 agonists such as pegilodecakin, AM-0010; IL10 gene stimulators such as gene therapy (IL-10), Imperial College; IL-11 agonists such as oprelvekin, YM-294; IL-12 antagonists such as ustekinumab, briakinumab, apilimod; IL12 gene inhibitors such as RDP-58; IL-13 antagonists such as tralokinumab, anrukinzumab; IL-17 antagonists such as secukinumab, vidofludimus; IL-2 antagonists such as daclizumab; IL-2 receptor alpha subunit inhibitors such as basiliximab, daclizumab, BSX-003, Ro-34-7375; IL-21 antagonists such as NN-8828, ATR-107; IL-23 antagonists such as tildrakizumab, ustekinumab, BI-655066, AMG-139, briakinumab, LY-3074828, apilimod; IL-6 antagonists such as tocilizumab, clazakizumab, olokizumab, HMPL-004, AMG-220, FM-101; IL6 gene inhibitors such as YSIL6-T-PS; IL-6 receptor modulators such as tocilizumab; IL-7 antagonists such as interleukin-7 receptor modulators (ulcerative colitis/acute T-cell lymphoblastic leukemia), Effimune; IL-8 antagonists such as elubrixin, clotrimazole; immunoglobulin G1 agonists such as HF-1020; immunoglobulin G2 modulators such as PF-547659; inosine monophosphate dehydrogenase inhibitors such as mycophenolate mofetil; insulin sensitizers such as elafibranor, rosiglitazone, HE-3286, EGS-21; alpha-4/beta-1 integrin antagonists such as natalizumab, TRK-170, firategrast; alpha-4/beta-7 integrin antagonists such as etrolizumab, vedolizumab, abrilumab, carotegast methyl, TRK-170, firategrast; alpha-E integrin antagonists such as etrolizumab; integrin antagonists such as vatelizumab, ASP-2002; beta-7 integrin antagonists such as etrolizumab; interferon beta ligands such as interferon beta-1a, recombinant interferon beta-1a, Serono; interleukin 17E ligand inhibitors such as anti-IL-17BR humanized antibody (pulmonary fibrosis/asthma/ulcerative colitis), Medical Research Council Technology; interleukin ligand inhibitors such as HE-3286; interleukin 17A receptor antagonists such as brodalumab; interleukin 17B receptor antagonists such as anti-IL-17BR humanized antibody (pulmonary fibrosis/asthma/ulcerative colitis), Medical Research Council Technology; interleukin-1 beta ligands such as K(D)PT, PUR-0110, HMPL-004; interleukin-1 beta ligand modulators such as PUR-0110, HMPL-004; interleukin-6 ligand inhibitors such as PF-4236921; JAK tyrosine kinase inhibitors such as tofacitinib, peficitinib; JAK1 tyrosine kinase inhibitors such as ABT-494, tofacitinib, filgotinib, peficitinib, GLPG-0555, solcitinib; JAK2 gene inhibitors,

- 9 045296 such as vidofludimus; JAK3 tyrosine kinase inhibitors such as tofacitinib, peficitinib; Jun N-terminal kinase inhibitors such as semapimod; LanC-like protein 2 modulators such as BT-11; leukotriene receptor BLT antagonists such as ONO-4057, etalocyb, SC-53228, SC-52798; lipoxygenase modulators such as mesalazine; L-selectin antagonists such as BNP-001; MAdCAM inhibitors such as vedolizumab, PF-547659; matrix metalloprotease inhibitors such as D-5410; matrix metalloprotease modulators such as D-5410; melanocortin agonists such as ASP-3291; membrane copper amine oxidase inhibitors such as vepalimomab; metalloprotease-2 inhibitors such as KD-018, RWJ-68354; metalloprotease-9 inhibitors such as GS-5745; MIP 3 alpha ligand inhibitors such as GSK-3050002; stimulators of mitochondrial heat shock proteins 10 kDa, such as INV-103; inhibitors of monocyte differentiation antigen CD14, such as anti-inflammatory CD14, Cornell; mTOR inhibitors such as P-2281; mucin stimulants such as rebamipide; NAD-dependent sirtuin-1 deacetylase stimulators, such as SRT-2104; natriuretic peptide C receptor agonists such as plecanatide; neuregulin-4 ligands such as neuregulin 4 (Crohn's disease/ulcerative colitis/necrotizing enterocolitis), Avexegen Therapeutics/Children's Hospital Los Angeles; nicotinic acetylcholine receptor agonists such as TC-2403, nicotine polacrilex, nicotine; nicotinic ACh receptor alpha 4 subunit modulators such as TC-2403; nicotinic ACh receptor alpha 7 subunit stimulators such as GTS-21; nicotinic ACh receptor beta 2 subunit modulators such as TC-2403; NK1 receptor antagonists such as KD-018, nolpitanium besylate; NK receptor activating NKG2 D antagonists such as NNC-0142-002; nuclear factor kappa B inhibitors such as KD-018, cobitolimod, CSA-13, HE-3286, HMPL-004, Avrina, mesalamine with N-acetylcysteine, P-54; opioid growth factor receptor agonists such as metenkephalin acetate with tridecactide acetate, FAR-404; opioid receptor antagonists such as naltrexone, IRT-103; delta opioid receptor antagonists such as KD-018; oxidoreductase inhibitors such as olsalazine; P2X7 purinergic receptor agonists such as givinostat; p38 MAP kinase inhibitors such as RDP-58, doramapimod, semapimod, RWJ-68354; PARP inhibitors such as EB-47, INO-1003; PDE 4 inhibitors such as apremilast, tetomilast, CC-1088; PDGF receptor agonists such as oprelvekin, YM-294; peptide modulators that stimulate phagocytosis, such as 99mTc-RP-128; phospho-H-acetylmuramoylpentapeptide transferase inhibitors such as SQ-641; phospholipase A2 inhibitors such as varespladib methyl; platelet activating factor receptor antagonists such as dersalazine sodium; potassium channel inhibitors such as clotrimazole; PPAR alpha agonists such as elafibranor (GFT-1007); PPAR delta agonists such as elafibranor (GFT-1007); PPAR gamma agonists such as rosiglitazone, GED-0507-34-Levo, etalocyb; CYR61 protein stimulators such as CSA-13; fimH protein inhibitors such as EB-8018; protein kinase C alpha inhibitors such as sotrastaurin (AEB-071); protein kinase C beta inhibitors such as sotrastaurin (AEB-071); protein kinase C delta inhibitors such as sotrastaurin (AEB-071); protein kinase C epsilon inhibitors such as sotrastaurin (AEB071); protein kinase C eta inhibitors such as sotrastaurin (AEB-071); protein kinase C theta inhibitors such as sotrastaurin (AEB-071); protein kinase G inhibitors such as CEL-031; protein kinase inhibitors such as TOP-1288; P-selectin glycoprotein ligand-1 inhibitors such as SEL-K2; purine biosynthesis protein inhibitors PurH, such as mycophenolate mofetil; retinoic acid receptor alpha agonists such as tamibarotene; retinoic acid receptor beta-agonists such as tamibarotene; retinoid receptor agonists such as tamibarotene; RNA polymerase inhibitors such as rifaximin; SMAD-7 inhibitors such as Mongersen (GED-0301); sodium channel inhibitors such as ropivacaine; somatostatin receptor agonists such as vapreotide; sphingosine-1-phosphate phosphatase 1 stimulators such as APD-334; sphingosine-1-phosphate phosphatase modulators such as S1P modulators (oral, multiple sclerosis/ulcerative colitis/rheumatoid arthritis), Akaal Pharma; sphingosine kinase 1 inhibitors such as ABC-294640; sphingosine kinase 2 inhibitors such as ABC-294640; sphingosine-1-phosphate receptor 1 agonists such as ozanimod (RPC-1063), KRP-203; sphingosine-1-phosphate receptor 1 antagonists such as amiselimod (MT-1303); sphingosine-1-phosphate receptor 1 modulators such as fingolimod (FTY-720), ozanimod (RPC-1063), amiselimod (MT-1303); sphingosine-1-phosphate receptor-5 modulators such as ozanimod; STAT3 gene inhibitors such as vidofludimus; STAT-3 inhibitors such as TAK-114; STAT-4 inhibitors such as STAT-4 antisense oligonucleotide (Crohn's disease/colitis), NIAID; stem cell antigen-1 inhibitors such as Ampion, DMI-9523; superoxide dismutase modulators such as midismase, LT-0011; superoxide dismutase stimulants such as superoxide dismutase; CD28 T cell surface glycoprotein inhibitors such as abatacept; TGF beta 1 ligand inhibitors such as Mongersen, GED-0301; thymulin agonists such as Syn-1002; TLR-2 antagonists such as VB-201; TLR-4 antagonists such as JKB-122, VB-201; TLR-9 agonists such as BL-7040, cobitolimod; TNF alpha ligand inhibitors such as adalimumab, certolizumab pegol, infliximab biosimilar, infliximab, golimumab, ISIS-104838, CSA-13, DLX-105, adalimumab biosimilar, dersalazine sodium, Debio-0512, HMPL-004, DLX-105, generic infliximab biosimilar, AZD-9773, CYT-020-TNFQb, DOM-0200; TNF alpha ligand modulators such as PUR-0110,

- 10 045296

CDP-571; TNF antagonists such as etanercept, certolizumab pegol, AVX-470, onercept; trefoil factor modulators such as AG-012; tryptase inhibitors such as APC-2059; tryptophan 5-hydroxylase inhibitors such as telotristat etiprate; tumor necrosis factor ligand 14 modulators such as SAR-252067; TNF type I receptor antagonists such as DOM-0100; TNF type II receptor modulators such as etanercept; nonspecific growth factor receptor modulators such as AP-005; vanilloid VR1 agonists such as zucapsaicin; vitamin D3 receptor agonists such as calcitriol; and zonulin inhibitors such as larazotide acetate, AT-1001.

In addition, the following non-exhaustive list of classes of compounds and compounds may be combined with a compound of the present disclosure: 14-3-3 eta protein inhibitors, 5-lipoxygenase inhibitors, Abl tyrosine kinase inhibitors, ACTH receptor agonists, adenosine A3 receptor agonists, adenosine deaminase inhibitors, modulators ADP-ribosyl cyclase-1, ADP-ribosylation factor 6 inhibitors, adrenocorticotropic hormone ligands, aggrecanase-2 inhibitors, albumin modulators, AP1 transcription factor inhibitors, basigin inhibitors, Bcr protein inhibitors, CD19 B-lymphocyte antigen inhibitors, CD20 B-lymphocyte antigen inhibitors, CD20 B-lymphocyte antigen modulators, B-lymphocyte stimulatory ligand inhibitors, bradykinin receptor modulators, BRAF gene inhibitors, branched chain amino acid aminotransferase 1 inhibitors, bromodomain containing protein inhibitors, Btk tyrosine kinase inhibitors, cadherin-11 antagonists, calcineurin inhibitors, calcium 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, antagonist ists CD40 ligand receptor, CD40 ligand receptor modulators, CD52 antagonists, CD73 agonists, CD79b modulators, CD80 antagonists, CD86 antagonists, CD95 antagonists, cell adhesion molecule inhibitors, choline kinase inhibitors, clusterin stimulators, complement factor C5 inhibitors, complement factor stimulators, C-inhibitors reactive protein, CSF-1 antagonists, CXC10 chemokine ligand inhibitors, CXCR4 chemokine antagonists, cyclin-dependent kinase 1 inhibitors, cyclin-dependent kinase inhibitors-2, cyclin-dependent kinase inhibitors4, cyclin-dependent kinase inhibitors-5, cyclin-dependent kinase inhibitors kinases-6, cyclin-dependent kinase inhibitors-7, cyclin-dependent kinase inhibitors-9, cyclooxygenase 2 inhibitors, cyclooxygenase 2 modulators, cyclooxygenase inhibitors, cytosolic phospholipase A2 inhibitors, cytotoxic T-lymphocyte protein-4 modulators, cytotoxic T-lymphocyte protein stimulators- 4, DHFR inhibitors, diaminacetylinetransferase inhibitors, dihydroorotatexyrogenase inhibitors, elongation factor inhibitors 2, liganda inhibitors Eotaxin 2, agonoids of prostacular EP4, erythropoetin receptor, fas liganda, liganda fgf50, FK50 liganda inhibitors, FK50 liganders 6-binding protein-12, folic acid antagonists , folate receptor agonists, folate beta receptor 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, leucine zipper stimulants glucocorticoid-induced, 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, protein inhibitors gp120 HIV-1, HLA class II antigen modulators DQ-2 alpha, HLA class II antigen inhibitors, HLA class II antigen modulators, Hsp 70 family inhibitors, hypoxia-inducible factor-1 inhibitors, IFNB gene stimulators, I-kappa beta kinase inhibitors B, I-kappa B kinase inhibitors, IL-1 antagonists, IL-10 agonists, IL-11 agonists, IL-12 antagonists, IL-15 antagonists, IL-17 antagonists, IL-17 receptor modulators, IL-2 agonists, IL-2 antagonists, IL-21 antagonists, IL-23 antagonists, IL-3 antagonists, IL-4 agonists, IL-6 antagonists, IL-6 receptor modulators, immunoglobulin antagonists, immunoglobulin G1 agonists, immunoglobulin G1 antagonists, immunoglobulin G1 modulators , immunoglobulin G2 antagonists, immunoglobulin G2 modulators, immunoglobulin gamma Fc receptor II modulators, immunoglobulin gamma Fc receptor IIB antagonists, immunoglobulin kappa modulators, immunoglobulin M antagonists, inducible nitric oxide synthase inhibitors, inosine monophosphate dehydrogenase inhibitors, insulin sensitizers, alpha1 integrin antagonists /beta -1, alpha-4/beta-1 integrin antagonists, integrin antagonists, interferon beta ligands, interferon gamma ligands, interleukin 17A ligand inhibitors, interleukin 17F ligand inhibitors, interleukin 23A inhibitors, interleukin ligands, interleukin 17A receptor antagonists, interleukin ligand inhibitors- 1 beta, 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, N-con inhibitors ring kinase Jun , voltage-gated potassium channel-3 KCNA modulators, Kelch-like ECH-associated protein 1 modulators, Kit tyrosine kinase inhibitors, LanC-like protein 2 modulators, LITAF gene inhibitors, antago

- 11 045296 antigen receptor-3 lymphocyte function nists, Lyn tyrosine kinase inhibitors, macrophage mannose receptor 1 modulators, MAdCAM inhibitors, MAP kinase modulators, MAPZK2 gene inhibitors, MAPKAPK5 inhibitors, matrix metalloprotease inhibitors, MCL1 gene inhibitors, MEK protein kinase inhibitors, protein kinase inhibitors MEK-1, MEK-2 protein kinase inhibitors, membrane copper amine oxidase inhibitors, metalloprotease-2 inhibitors, metalloprotease-9 inhibitors, midkine ligand inhibitors, mitochondrial heat shock protein 10 kDa 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, NK receptor antagonists activating NKG2 A B, NK receptor antagonists activating NKG2 D, nuclear factor 2 stimulators, erythroid 2-related, nuclear factor kappa B inhibitors, nuclear factor kappa B modulators, 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, agonists P2X7 purinergic receptors, p38 MAP alpha kinase inhibitors, p38 MAP kinase inhibitors, PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor agonists, PDGF receptor antagonists, PDGF-B ligand inhibitors, PERK gene inhibitors, delta phosphoinositide 3-kinase inhibitors, inhibitors phosphoinositide-3 kinase gamma, phospholipase A2 inhibitors, platelet activating factor receptor antagonists, PPAR gamma agonists, programmed cell death protein 1 modulators, prostaglandin D synthase stimulators, protein arginine deiminase inhibitors, protein tyrosine kinase inhibitors, purine biosynthetic protein inhibitors PurH, Rho inhibitors -associated protein kinase 2, seprase inhibitors, CD24 signal transducer modulators, signal transduction inhibitors, glucose-sodium transporter-2 inhibitors, sphingosine 1 phosphate phosphatase modulators, STAT3 gene inhibitors, superoxide dismutase stimulators, SYK family tyrosine kinase inhibitors, Syk tyrosine kinase inhibitors, syndecan inhibitors- 1, T-cell receptor antagonists, T-cell receptor modulators, CD28 T-cell surface glycoprotein inhibitors, CD28 T-cell surface glycoprotein stimulators, TAK1 binding protein modulators, talin modulators, CD6 T-cell differentiation antigen inhibitors, T-cell differentiation antigen inhibitors CD8 cell surface glycoprotein, 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, p65 transcription factor inhibitors, RelB transcription factor inhibitors, transferrin modulators, tumor necrosis factor 13C receptor antagonists, tumor necrosis factor ligand 15 inhibitors, tumor necrosis factor ligand 13 inhibitors, tumor necrosis factor ligand inhibitors, receptor antagonists IL-1 type I, TNF receptor antagonists type I, TNF receptor modulators type II, unspecified GPCR agonists, VEGF receptor antagonists, VEGF-2 receptor antagonists, VEGF-2 receptor modulators, VEGF-B ligand inhibitors, X-linked protein inhibitor inhibitors apoptosis, Zap70 tyrosine kinase inhibitors, 99mTc-labeled annexin V-128, abatacept, abatacept biosimilar, ABBV-257, ABT-122, ABT-494, acalabrutinib, aceclofenac, actarit, MS-392, adalimumab, adalimumab biosimilar, generic adali biosimilar mumaba, AK-106, ALX-0061, aminopterin, anakinra, anakinra biosimilar, generic anakinra biosimilar, ARG-301, ASLAN-003, ASP-5094, AT-132, AZD-9567, baricitinib, BI-655064, bimekizumab, BiP (rheumatoid arthritis), Kings 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, CreaVax-RA, CWG-92, CWG-940, Cx-611, DE-098, deflazacort, Rheumavax, denosumab, diacerein, diclofenac, E-6011, eicosapentaenoic acid monoglycerides, etanercept, etanercept biosimilar, generic etanercept biosimilar, etodolac, etoricoxib, filgotinib, fosdagrocorate, gerilimzumab, ginsenoside C-K, givinostat, goat polyclonal antibodies, golimumab, GS- 5745, GS-9876, GSK-3196165, HM-71224, HMPL-523, sodium hyaluronate, IB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral, rheumatoid arthritis), Innobioscience, iguratimod, IMD-2560 , imidazole salicylate, infliximab, improved infliximab, infliximab biosimilar, INSIX RA, generic interferon gamma biosimilar, interleukin-2 (injectable), generic interleukin-2 biosimilar, INV-103, IR-501, itolizumab, JNJ-40346527, Ka Shu Ning, KD-025, ketoprofen with omeprazole, leflunomide, lenzilumab, LLDT-8, lumiracoxib, LY-3090106, masitinib, mavrilimumab, MBS-2320, MEDI-5117, meloxicam, methotrexate, MGD-010, misoprostol with diclofenac, MM- A01-01, monalizumab, MORAb-022, MPC-300-IV, MRC-375, nabumetone, namilumab, naproxen with esomeprazole, naproxen with strontium esomeprazole, ocaratuzumab, ofatumumab, OHR-118, olokizumab, OM-89, naproxen once per day (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

- 12 045296 monoclonal antibody to CD22 (intravenous infusion), Lonn Ryonn Pharma/SinoMab Bioscience (Shenzhen), recombinant human interleukin-1 receptor antagonist (rheumatoid arthritis), Shanghai Fudan-Zhangjiang Bio-Pharmaceutical, recombinant human interleukin-2 mutant hybrid recombinant TNF 2-Fc receptor protein, RG-6125, RhuDex, rifabutin with clarithromycin with clofazimine, rituximab, rituximab biosimilar, generic rituximab biosimilar, RPI-78, SAN-300, sarilumab, SBI-087, seliciclib, SHR-0302, sirucum ab , spebrutinib, SSS-07, KDDF-201110-06, Syn-1002, T-5224, TAB-08, tacrolimus, TAK-020, TAK-079, tarenflurbil (transdermal spray gel, skin diseases/rheumatoid arthritis), MIKA Pharma/GALENpharma, tilmanosept technetium Tc 99m, technetium methylene diphosphonate [99Tc], tenoxicam, Debio-0512, tocilizumab, tofacitinib, whipworm 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 eta protein inhibitors such as anti-AGX-020 mAbs (rheumatoid arthritis), Augurex; 5-lipoxygenase inhibitors such as tenoxicam, darbufelone, tebufelone, licofelone, ZD2138, etalocyb, tenidap, tepoxaline, flobufen, SKF-86002, PGV-20229, L-708780, WY-28342, T-0757, T0799, ZM-216800 , L-699333, BU-4601A, SKF-104351, CI-986; Abl tyrosine kinase inhibitors such as imatinib; ACTH receptor agonists such as FAR-404, metenkephalin acetate with tridecactide acetate; adenosine A3 receptor agonists such as CF-101; adenosine deaminase inhibitors such as cladribine, pentostatin, FR-221647; ADP-ribosyl cyclase-1 modulators such as indatuximab ravtansine; ADP-ribosylation factor 6 inhibitors such as NAV-2729; adrenocorticotropic hormone ligands such as corticotropin, Mallinckrodt, FAR-404, metenkephalin acetate with tridecactide acetate; aggrecanase-2 inhibitors such as GIBH-R-001-2; albumin modulators such as ALX-0061, ONS-1210; AP1 transcription factor inhibitors such as T-5224, tarenflurbil, SP10030; basigin inhibitors such as ERG-240; Bcr protein inhibitors such as imatinib; CD19 B lymphocyte antigen inhibitors such as XmAb-5871, MDX-1342; inhibitors of B-lymphocyte antigens CD20, such as ocrelizumab, ofatumumab, rituximab, rituximab biosimilar, veltuzumab, generic rituximab biosimilar, ocaratuzumab, BLX-301, IDEC-102, ABP-798, GP-2013, MK8808, HLX-01, CT- P10, TL-011, PF-05280586, IBPM-001RX, IBI-301, AME-133v, BCD-020, BT-D004, SAIT-101; CD20 B lymphocyte antigen modulators, such as rituximab biosimilar, SBI-087, TRU-015, DXL-625; B-lymphocyte stimulatory ligand inhibitors such as belimumab, RCT-18, blisibimod, tabalumab, atacicept, briobacept; bradykinin receptor modulators such as givinostat; BRAF gene inhibitors such as binimetinib; branched chain amino acid aminotransferase 1 inhibitors such as ERG-240; bromodomain containing protein inhibitors such as RVX-297, ZEN-003694; Btk tyrosine kinase inhibitors such as 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 such as RG-6125; calcineurin inhibitors such as HS-378, cyclosporine; calcium channel inhibitors such as RP-3128; carbonic anhydrase inhibitors such as polmacoxib; cathepsin K inhibitors, such as CRA-013783, T-5224, AM-3876, VEL-0230, NPI-2019; cathepsin S inhibitors, such as MIV-247, AM-3876, RWJ-445380, NPI-2019; CCR1 chemokine antagonists such as BX-471, BMS-817399, BI-638683, CCX-354, MLN-3701, MLN-3897, CP-481715, PS-375179; CCR2 chemokine antagonists such as MK-0812, AZD-6942; CCR3 gene modulators such as CM-102; CCR5 chemokine antagonists such as maraviroc, OHR-118, NIBR-6465, AZD-5672, AZD-8566; CD126 antagonists such as sarilumab; CD29 modulators such as PF-06687234; CD3 modulators such as telixizumab; CD39 agonists such as AAV5-CD39/CD73 (rheumatoid arthritis), Arthrogen; CD4 agonists such as maraviroc; CD4 antagonists such as tregalizumab, zanolimumab, MTRX-1011A, BW-4162W94, EP-1645, clenoliximab; CD40 ligand inhibitors such as dapirolizumab pegol; CD40 ligand receptor antagonists such as BI-655064, anti-CD40-XTEN, teneliximab; CD40 ligand receptor modulators such as CFZ-533; CD52 antagonists such as alemtuzumab; CD73 agonists such as AAV5CD39/CD73 (rheumatoid arthritis), Arthrogen; CD79b modulators such as MGD-010; CD80 antagonists such as RhuDex, XENP-9523, ASP-2408, improved version of abatacept; CD86 antagonists such as ES-210, biosuperior abatacept analogue, ASP-2408, XENP-9523; CD95 antagonists such as DE-098, CS-9507; cell adhesion molecule inhibitors such as natalizumab, alicaforsen, NPC-17923, TK-280, PD-144795; choline kinase inhibitors such as choline kinase inhibitors (rheumatoid arthritis), UC San Diego; clusterin stimulators such as alemtuzumab; complement factor C5 inhibitors such as eculizumab, antisense oligonucleotides (rheumatoid arthritis), Leiden University Medical Center; complement factor stimulants such as CM-101; C-reactive protein inhibitors such as IB-RA (oral, rheumatoid arthritis), Innobioscience, ISIS-353512; CSF-1 antagonists such as masitinib, FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578, PD-360324, JNJ-28312141; CXC10 chemokine ligand inhibitors such as 946414-98-8, BMS-936557; CXCR4 chemokine antagonists such as plerixafor; cyclin-dependent kinase 1 inhibitors such as CDK-1/2/5/7/9 inhibitors (cancer/oncogenesis/rheumatoid arthritis), BioPatterns; cyclin-dependent kinase-2 inhibitors such as seliciclib, BP-14; cyclin-dependent kinase-4 inhibitors, such as

- 13 045296

CDK-4/6 (rheumatoid arthritis), Teijin; cyclin-dependent kinase-5 inhibitors such as BP-14; cyclin-dependent kinase-6 inhibitors such as CDK-4/6 inhibitor (rheumatoid arthritis), Teijin; cyclin-dependent kinase-7 inhibitors such as BP-14, seliciclib; cyclin-dependent kinase-9 inhibitors such as BP-14, seliciclib; cyclooxygenase 2 inhibitors such as celecoxib, etoricoxib, polmacoxib, laflunimus, etodolac, meloxicam, IB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral, rheumatoid arthritis), Innobioscience, SKLB-023, meloxicam, lumiracoxib; cyclooxygenase 2 modulators such as DRGT-46; cyclooxygenase inhibitors such as aceclofenac, diclofenac, imidazole salicylate, naproxinod, naproxen etemesil, misoprostol with diclofenac, nabumetone, naproxen with esomeprazole, naproxen with esomeprazole strontium, naproxen once daily (oral, controlled release, pain), Alvogen, pelubiprofen, LY210073, tenoxicam, licofelone, NS-398, bromfenac, L-746483, LY-255283, tenidap, tepoxaline, flobufen, ibuprofen, flurbiprofen, SKF-86002, SC-57666, WY-28342, CI-986, bermoprofen; cytosolic phospholipase A2 inhibitors such as AVX-002; cytotoxic T-lymphocyte protein-4 modulators such as belatacept, ES-210; cytotoxic T-lymphocyte protein-4 stimulators, such as abatacept, abatacept biosimilar, BMS-188667; DHFR inhibitors such as methotrexate, MPI-2505, MBPY003; diamine acetyltransferase inhibitors such as diminazene aceturate; dihydroorotate dehydrogenase inhibitors such as DHODH inhibitors (rheumatoid arthritis/autoimmune diseases), East China University of Science and Technology, ASLAN-003, laflunimus, leflunomide, HWA-486, ABR224050; elongation factor 2 inhibitors such as denileukin diftitox; eotaxin 2 ligand inhibitors such as CM-102; EP4 prostanoid receptor agonists such as CR-6086; erythropoietin receptor agonists such as cibinetide; Fas ligands such as AP-300; FGF2 ligand inhibitors such as RBM-007; FK506-binding protein-12 modulators such as temsirolimus; folic acid antagonists such as methotrexate, MBP-YOO3; folate receptor antagonists such as folate receptor modulators (chimeric protein, cancer/rheumatoid arthritis), Proda Biotech; folate receptor modulators such as technetium (99mTc) etarfolatide; fractalkine ligand inhibitors such as E-6011; Fyn tyrosine kinase inhibitors such as masitinib, laflunimus; G protein-coupled receptor 15 antagonists such as GPR15 (rheumatoid arthritis/HIV-mediated enteropathy) antagonists, Omeros; GABA A receptor modulators such as laflunimus; glucocorticoid agonists such as prednisolone, phosdagrocorate; glucocorticoid antagonists such as REC-200; glucocorticoid-induced leucine zipper stimulators such as ART-G01; GM-CSF ligand inhibitors such as namilumab, MORAb-022, lenzilumab; GM-CSF receptor antagonists such as mavrilimumab; GM-CSF receptor modulators such as GSK3196165; growth regulatory protein alpha ligand inhibitors such as T-5224; Hwith Kwith ATPase inhibitors, such as naproxen with esomeprazole, naproxen with strontium esomeprazole, ketoprofen with omeprazole, KEO-25001, HC-1004, PN-40020; histamine H4 receptor antagonists such as torephorant, GD-48; histone deacetylase inhibitors such as givinostat, CHR-5154; histone deacetylase-6 inhibitors such as CKD-506; HIV-1 gp120 protein inhibitors such as maraviroc; HLA class II DQ-2 alpha antigen modulators such as NexVax2; HLA class II antigen inhibitors, such as HLA-DR1/DR4 inhibitors (rheumatoid arthritis), Provid; HLA class II antigen modulators such as ARG-301, recombinant T-cell receptor ligand (rheumatoid arthritis), Artielle; Hsp 70 family inhibitors such as gusperimus trihydrochloride; hypoxia-inducible factor-1 inhibitors such as 2-methoxyestradiol; IFNB gene stimulators such as ART-102; betakinase I-kappa B inhibitors such as IMD-2560, IMD-0560; I-kappa B kinase inhibitors such as bardoxolone methyl; IL-1 antagonists such as rilonacept, IBPB-007-IL, antisense oligonucleotides (rheumatoid arthritis), Leiden University Medical Center, recombinant human interleukin-1 receptor antagonist (rheumatoid arthritis), Shanghai Fudan-Zhangjiang Bio-Pharmaceutical; IL-10 agonists such as pegilodecakin; IL-11 agonists such as oprelvekin; IL-12 antagonists such as ustekinumab, briakinumab, ddRNAi therapy (rheumatoid arthritis), Medistem/Benitec; IL-15 antagonists such as AMG-714, BNZ-132-2; IL-17 antagonists such as ixekizumab, secukinumab, KD-025; IL-17 receptor modulators such as CNTO-6785; IL-2 agonists such as generic interleukin-2 biosimilar; IL-2 antagonists such as IB-RA (injectable rheumatoid arthritis), Innobioscience, IB-RA (oral rheumatoid arthritis), Innobioscience, BNZ-132-2; IL-21 antagonists such as NN-8828, BNZ-132-2; IL-23 antagonists such as ustekinumab, briakinumab; IL-3 antagonists such as anti-IL-3 mAbs (rheumatoid arthritis), University of Regensburg; IL-4 agonists such as SER-130-AMI; IL-6 antagonists such as olokizumab, clazakizumab, sirukumab, SA-237, tocilizumab, ALX-0061, FB704A, OP-R003, IL-6 peptide antagonist, MEDI-5117, T-5224, humanized anti-IL-6 mAb , biosimilar tocilizumab, IL-6 neutralizing human antibodies, anti-IL6 antibody, RN-486, BLX-1002, AMG-220, FM-101, K-832, BLX-1025, ezonarimod, TA-383; IL-6 receptor modulators such as tocilizumab, tocilizumab biosimilar, RO-4877533; immunoglobulin antagonists such as iguratimod; immunoglobulin G1 agonists such as canakinumab, improved infliximab, infliximab biosimilar, BX-2922, STI-002, HF-1020; immunoglobulin G1 antagonists such as YHB-1411-2; immunoglobulin G1 modulators such as CFZ-533, lenzilumab; immunoglobulin G2 antagonists,

- 14 045296 such as denosumab; immunoglobulin G2 modulators such as PF-547659; immunoglobulin Fc receptor II modulators such as MGD-010; immunoglobulin gamma Fc receptor IIB antagonists such as XmAb-5871; immunoglobulin kappa modulators such as lenzilumab; immunoglobulin M antagonists such as IB-RA (injectable rheumatoid arthritis), Innobioscience, IB-RA (oral rheumatoid arthritis), Innobioscience; inducible nitric oxide synthase inhibitors such as SKLB-023; inosine monophosphate dehydrogenase inhibitors such as mycophenolate mofetil; insulin sensitizers such as rosiglitazone, THR-0921, HE-3286, BLX-1002; alpha1/beta-1 integrin antagonists such as SAN-300; alpha-4/beta-1 integrin antagonists such as natalizumab; integrin antagonists such as PEG-HM-3, CY-9652; interferon beta ligands such as recombinant interferon beta-1a, TA-383; interferon gamma ligands, such as generic interferon gamma biosimilar; interleukin 17A ligand inhibitors such as ABT-122, bimekizumab, ABBV-257; interleukin 17F ligand inhibitors such as bimekizumab; interleukin 23A inhibitors such as guselkumab; interleukin ligands such as IBPB-007-IL; interleukin 17A receptor antagonists such as brodalumab; interleukin-1 beta ligand inhibitors such as canakinumab, rilonacept, T-5224, gevokizumab, BLX-1002, LY-2189102, PMI-001, K-832, CDP-484; interleukin 10 ligands such as PF-06687234; interleukin 2 ligands such as denileukin diftitox, recombinant interleukin-2, generic interleukin-2 biosimilar, recombinant human interleukin 2, interleukin-2 (injectable); interleukin 4 ligands such as Tetravil; interleukin-6 ligand inhibitors such as gerilimzumab, PF-4236921; Itk tyrosine kinase inhibitors such as ARN-4079; JAK tyrosine kinase inhibitors such as tofacitinib, SHR-0302, cerdulatinib, peficitinib, deuterated tofacitinib analogue, SD-900, CVXL-0074; JAK1 tyrosine kinase inhibitors such as ABT-494, baricitinib, ruxolitinib, filgotinib, tofacitinib, itacitinib, peficitinib, NIP-585, CS-944X, YJC-50018, GLPG-0555, MRK-12; JAK2 tyrosine kinase inhibitors such as baricitinib, ruxolitinib, CT-1578; JAK3 gene inhibitors such as GBL-5b; JAK3 tyrosine kinase inhibitors such as desernotinib, tofacitinib, peficitinib, AC-0025, CS-944X, DNX-04042, MTF-003, ARN4079, PS-020613; N-terminal Jun kinase inhibitors such as IQ-1S; voltage-gated potassium channel-3 KCNA modulators such as MRAD-P1; Kelch-like EC-associated protein 1 modulators, such as dimethyl fumarate; Kit tyrosine kinase inhibitors such as imatinib, masitinib; LanC-like protein 2 modulators such as BT-11; LITAF gene inhibitors such as GBL-5b; lymphocyte function antigen receptor-3 antagonists such as alefacept; Lyn tyrosine kinase inhibitors such as masitinib; macrophage mannose receptor 1 modulators, such as tilmanosept technetium Tc 99m; MAdCAM inhibitors such as PF-547659; MAP kinase modulators such as SKLB-023; MAP3K2 gene inhibitors such as GBL-5b; MAPKAPK5 inhibitors such as GLPG-0259; matrix metalloprotease inhibitors such as GLPG-0259; MCL1 gene inhibitors such as seliciclib; MEK protein kinase inhibitors such as binimetinib, AD-GL0001; MEK-1 protein kinase inhibitors such as binimetinib; MEK-2 protein kinase inhibitors such as binimetinib; inhibitors of membrane copper amine oxidase, such as BTT-1023, PRX-167700, vepalimomab; metalloprotease-2 inhibitors such as ERG-240; metalloprotease-9 inhibitors such as GS5745, ERG-240; midkine ligand inhibitors such as CAB-102; stimulators of mitochondrial heat shock proteins 10 kDa, such as INV-103; mTOR complex 1 inhibitors such as everolimus; mTOR inhibitors such as everolimus, temsirolimus; NAD ADP ribosyltransferase stimulators such as denileukin diftitox; NAMPT gene inhibitors such as ART-D01; NF kappa B inhibitor stimulants such as denosumab; NFAT gene inhibitors such as T-5224; stimulators of the NFE2L2 gene, such as bardoxolone methyl; nicotinic acetylcholine receptor antagonists such as RPI-78, RPI-MN; NK cell receptor modulators such as masitinib; NK receptor activating NKG2 A B antagonists such as monalizumab; NK receptor activating NKG2 D antagonists such as NNC-0142-002; nuclear factor erythroid 2-related factor 2 stimulants such as dimethyl fumarate; nuclear factor kappa B inhibitors such as bardoxolone methyl, IB-RA (injectable, rheumatoid arthritis), Innobioscience, dehydroxymethylepoxyquinomycin, HE-3286, IMD-0560, MP-42, tarenflurbil, 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 modulators such as REM-1086; nuclear factor kappa B p105 inhibitors such as REM-1086; opioid growth factor receptor agonists such as metenkephalin acetate with tridecactide acetate, FAR-404; delta opioid receptor antagonists such as HS-378; osteoclast differentiation factor antagonists such as denosumab, cyclic peptidomimetics (rheumatoid arthritis/osteoporosis), University of Michigan; inhibitors of osteoclast differentiation factor ligands such as denosumab; oxidoreductase inhibitors such as etodolac, imidazole salicylate; P2X7 purinergic receptor agonists such as givinostat; p38 MAP alpha kinase inhibitors such as VX-745, prodrugs BMS-582949, BMS-751324; p38 MAP kinase inhibitors such as BCT-197, losmapimod, ARRY-797; PDE 4 inhibitors such as apremilast; PDE 5 inhibitors, such as PDE5 inhibitors (rheumatoid arthritis), University of Rochester; PDGF receptor agonists such as oprelvekin; PDGF receptor antagonists such as imatinib, masitinib; PDGF-B ligand inhibitors such as SL-1026; inhibitors

- 15 045296 PERK gene, such as binimetinib; delta phosphoinositide 3-kinase inhibitors such as duvelisib, RP-6503, CT-732, INK-007, GNE-293; phosphoinositide 3 kinase gamma inhibitors such as duvelisib, RP-6503; Phospholipase A2 inhibitors such as AVX-002, peptides that inhibit binding of PA type integrin by human secreted phospholipase A2 (rheumatoid arthritis/asthma/Alzheimer's disease/cancer), University of California, Davis, AK-106, varespladib methyl, Ro-31- 4493, BM-162353, Ro-239358, YM-26734; platelet activating factor receptor antagonists such as piperidone hydrochloride; PPAR gamma agonists such as rosiglitazone, TFIR-0921, rosiglitazone XR, etalocyb; programmed cell death protein 1 modulators such as INSIX RA; programmed cell death protein 1 modulators such as HF-0220; protein arginine deiminase inhibitors, such as PAD (rheumatoid arthritis) inhibitors, Leiden University Medical Center/LURIS; protein tyrosine kinase inhibitors such as leflunomide; purine biosynthesis protein inhibitors PurH, such as mycophenolate mofetil; Rho-associated protein kinase 2 inhibitors such as KD-025; seprase inhibitors such as tagged antibodies against fibroblast activation protein (FAP) (rheumatoid arthritis), Hoffmann-La Roche/Radboud University; CD24 signal transducer modulators such as CD24-IgFc; signal transduction inhibitors such as imatinib; sodium glucose transporter-2 inhibitors such as THR-0921; sphingosine 1 phosphate phosphatase modulators such as S1P modulators (oral, multiple sclerosis/ulcerative colitis/rheumatoid arthritis), Akaal Pharma; STAT3 gene inhibitors, such as bardoxolone methyl, vidofludimus; superoxide dismutase stimulants such as manganese imisopasem; SYK family tyrosine kinase inhibitors such as MK-8457; Syk tyrosine kinase inhibitors such as fostamatinib, entospletinib, KDDF-201110-06, HMPL-523, cerdulatinib, AB-8779, GS-9876, PRT-2607, CVXL-0074, CG-103065 and CG-026806; syndecan-1 inhibitors such as indatuximab ravtansine; T-cell receptor antagonists such as TCR inhibitory SCHOOL peptides (systemic/topical, rheumatoid arthritis/dermatitis/scleroderma), SignaBlok, CII modified peptide (rheumatoid arthritis), Peking University; T cell receptor modulators such as ARG-301; CD28 T cell surface glycoprotein inhibitors such as abatacept, belatacept, abatacept biosimilar, RhuDex, BMS-188667; CD28 T cell surface glycoprotein stimulators such as TAB-08; TAK1 binding protein modulators such as epigallocatechin 3-gallate; talin modulators, such as short form talin regulators (rheumatoid arthritis), KayteeBio; CD6 T cell differentiation antigen inhibitors such as itolizumab; CD8 T cell surface glycoprotein inhibitors such as tregalizumab; tenascin modulators such as Tetravil; TGF beta-agonists such as tregalizumab; thymulin agonists such as Syn-1002; TLR-2 antagonists such as VB-201, P-13; TLR-4 antagonists such as VB-201, P-13; TLR-9 antagonists such as P-13; TNF alpha ligand inhibitors such as 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-0512, anti-TNF alpha human monoclonal antibody, improved version of infliximab, UB-721, KN-002, DA-3113, BX-2922, R-TPR-015 , BOW-050, PF-06410293, CKD-760, CHS-1420, GS-071, AVR-710, STI-002, BOW-015, FKB-327, VAX-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, reproducible adalimumab biosimilar, 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, DOM -0200, DOM-0215, AME-527, anti-TNFalpha mAb, GENZ-38167, BLX-1028, CYT-020-TNFQb, CC-1080, CC-1069; TNF alpha ligand modulators such as MM-A01-01, CDP-571, camobukol; TNF antagonists such as etanercept, certolizumab pegol, generic etanercept biosimilar, etanercept biosimilar, DNX-114, TNF antagonist 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 such as GIBH-R-001-2; TNF receptor modulators such as the recombinant TNF receptor fusion protein 2-Fc mutant, T-0001, tgAAV-TNFR:Fc; TNFSF11 gene inhibitors such as denosumab; p65 transcription factor inhibitors such as REM-1086; RelB transcription factor inhibitors such as REM-1086; transferrin modulators such as methotrexate, MBP-Y003; tumor necrosis factor receptor antagonists 13C, such as VAY-736; tumor necrosis factor ligand 15 inhibitors such as anti-TL1A antibodies (rheumatoid arthritis/inflammatory bowel disease), NIAMS; tumor necrosis factor ligand 13 inhibitors such as atacicept; tumor necrosis factor ligand inhibitors such as ABBV-257, etanercept biosimilar, ABT-122; IL-1 receptor antagonists type I, such as anakinra, anakinra biosimilar, generic anakinra biosimilar, AXO; TNF type I receptor antagonists such as NM-9405; TNF type II receptor modulators such as etanercept, SCB-131, etanercept biosimilar, generic etanercept biosimilar, BAX-2200, SCB-808, LBEC-0101, DMB-3853, DWP-422, BT-D001, DA-3853; unspecified GPCR agonists such as NCP-70X; VEGF receptor antagonists such as 2-methoxyestradiol and NSC-650853, SL-1026; VEGF receptor antagonists such as CG-026806; VEGF-2 receptor antagonists such as VEGFR2 neutralizing antibody (rheumatoid arthritis), University of Rochester;

- 16 045296 VEGF-B ligand inhibitors, such as CSL-346; X-linked inhibitors of apoptosis protein inhibitors such as IAP inhibitors (oral), Pharmascience; and Zap70 tyrosine kinase inhibitors such as MK-8457, CT-5332.

Combinations for the treatment of metabolic diseases or conditions.

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, elevated serum cholesterol and elevated triglyceride levels. Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists such as thiazolidinediones such as pioglitazones, biguanides, alpha-glucosidase inhibitors, vitamin E, and incretin mimetics. Thus, one aspect of the present disclosure is a method of treating a metabolic disease, comprising administering a compound according to the present disclosure in combination with one or more compounds used to treat metabolic diseases to a subject, particularly a human, in need thereof.

Pharmaceutical compositions.

Although the active ingredients can be administered separately, it may be preferable to present them in the form of pharmaceutical formulations (compositions). Formulations for both veterinary and human use contain 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 terms of compatibility with the other ingredients of the composition and physiologically harmless to its recipient.

Compositions include those suitable for the above routes of administration. The compositions may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Methods and formulations can usually be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of combining the active ingredient with inactive ingredients (eg, a carrier, pharmaceutical excipient, etc.) that constitute one or more additional ingredients. Typically, formulations are prepared by uniformly and thoroughly combining the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

In some embodiments, formulations suitable for oral administration are presented in discrete units, such as capsules, starch capsules, or tablets, each containing a predetermined amount of the active ingredient.

In some embodiments, the pharmaceutical formulations include one or more compounds of the present invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended route of administration. When used for oral administration, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions for oral administration may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, colors and preservatives, to provide a palatable agent. Tablets containing the active ingredient mixed with a non-toxic pharmaceutically acceptable excipient that are suitable for tablet manufacture are acceptable. These excipients may, for example, be inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or gum acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated using known techniques, including microencapsulation, to slow disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a longer lasting material such as glycerol monostearate or glycerol distearate, alone or with a wax, can be used.

The amount of active ingredient that can be combined with inactive ingredients to form a dosage form will vary depending on the patient being treated and the particular route of administration. For example, in some embodiments, a dosage form for oral administration to humans contains from about 1 to 1000 mg of active material formulated with a suitable and convenient amount of carrier material (e.g., inactive

- 17 045296 ingredient or auxiliary material). In some embodiments, the carrier material ranges from about 5% to about 95% of the total composition (weight:weight). In some embodiments, the pharmaceutical compositions described herein contain from about 1 to 800 mg, from 1 to 600 mg, from 1 to 400 mg, from 1 to 200 mg, from 1 to 100 mg, or from 1 to 50 mg of a compound formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein contain no more than about 400 mg 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.

It should be understood that in addition to the ingredients specifically mentioned above, the compositions described herein may include other agents conventional in the art, taking into account the type of composition in question, for example, compositions that are suitable for oral administration may include flavorings .

Also provided are compositions for veterinary use containing at least one active ingredient as defined above together with a carrier suitable for veterinary use.

Veterinary-grade carriers are materials used to administer the composition and may be solid, liquid or gaseous materials that are otherwise inert or veterinarily acceptable and compatible with the active ingredient. These compositions for veterinary use may be administered orally, parenterally, or any other desired route.

The effective dose of the active ingredient will depend at least on the nature of the condition being treated, the toxicity, whether the compound is being used prophylactically (lower doses), the mode of delivery and the pharmaceutical composition, and will be determined by the physician using conventional enhancement testing techniques. doses.

Routes of administration.

One or more compounds of formula I (referred to herein as active ingredients) or a pharmaceutically acceptable salt thereof is administered by any route appropriate for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like.

It should be understood that the preferred route may vary, for example, depending on the condition of the recipient. The compounds of the present invention have the advantage that they are orally bioavailable and can be administered orally. Accordingly, in one embodiment, the pharmaceutical compositions described herein are oral dosage forms. In some embodiments, the pharmaceutical compositions described herein are solid dosage forms for oral administration.

Composition example 1.

Prepare hard gelatin capsules containing the following ingredients: Quantity

Ingredient (mg/capsule)

Active Ingredient Zoo

Starch 305.0

Magnesium stearate 5 0

The above ingredients are mixed and filled into hard gelatin capsules.

Composition example 2.

The tablet composition was prepared using the following ingredients:

Quantity

Ingredient (mg/tablet) Active Ingredient 25.0 Microcrystalline cellulose 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components were mixed and tablets were pressed.

Composition example 3.

A composition for a dry powder inhaler was prepared containing the following components:

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Ingredient Weight %

Active ingredient 5

Lactose 95

The active ingredient was mixed with lactose and the mixture was added to a dry powder inhalation device.

Composition example 4.

Tablets, each containing 30 mg of the active ingredient, were prepared as follows:

Quantity

Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg

(as a 10% solution in sterile water)

Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg

Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20 mesh US sieve and mixed thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powders, which were then passed through a 16 mesh US sieve. The granules thus obtained were dried at a temperature of 50 to 60°C and passed through a 16 mesh US sieve. Sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 30 mesh US sieve, were then added to the granules, which, after mixing, were compressed on a tableting machine to produce tablets each weighing 120 mg.

Composition example 5.

Suppositories, each containing 25 mg of the active ingredient, were prepared as follows:

Ingredient Quantity

Active ingredient 25 mg

Saturated fatty acid glycerides up to 2,000 mg

The active ingredient is passed through a No. 60 mesh US sieve and suspended in saturated fatty acid glycerides previously melted using the minimum heat required. The mixture was then poured into a suppository mold with a nominal capacity of 2.0 g and allowed to cool.

Composition example 6.

Suspensions, each containing a dose of 50 mg of active ingredient per 5.0 ml, were prepared as follows:

Ingredient Quantity

Active Ingredient 50.0 mg Xanthan gum 4.0 mg

Sodium carboxymethylcellulose (11%)

Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavoring and coloring how much is needed Purified water 5.0 mg

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The active ingredient, sucrose and xanthan gum were mixed, passed through a No. 10 mesh US sieve, and then mixed with the previously prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose in water. Sodium benzoate, flavor and color were diluted with a small amount of water and added with stirring. Then water was added in an amount sufficient to obtain the required volume.

Composition example 7.

The subcutaneous formulation may be prepared as follows: Ingredient Amount

Active ingredient 5.0 mg

Corn oil 1.0 ml

Composition example 8.

The injection composition was prepared from the following composition:

Ingredients Quantity Active Ingredient 2.0 mg/ml Mannitol, USP 50 mg/ml Gluconic Acid, USP as needed (pH 5-6) Water (distilled, sterile) how much is needed up to 1.0 ml Nitrogen gas, NF how much is needed Composition example 9. The composition for topical use was prepared from the following composition: Ingredients grams Active Ingredient 0.2-10 Span 60 2.0 Twin 60 2.0 Mineral oil 5.0 Liquid paraffin 0.10 Methylparaben 0.15 Propylparaben 0.05 BHA (butylated hydroxyanisole) 0.01

Water as needed up to 100

All of the above ingredients, except water, were combined and heated to 60°C with stirring. Sufficient water at 60°C was then added with vigorous stirring to emulsify the ingredients, then water was added as needed up to 100g.

Composition example 10.

Sustained release composition.

Ingredient Range wt.%

Active ingredient 50-95

Microcrystalline cellulose 1-35 (filler)

Methacrylic acid copolymer 1-35

Sodium hydroxide 0.1 -1.0

Hydroxypropylmethylcellulose 0.5-5.0

Magnesium stearate 0.5-5.0

Sustained release formulations according to the present disclosure can be prepared

- 20 045296 we as follows: the compound and the pH-dependent binder and any optional excipients were thoroughly mixed (dry mixed). The dry mixture was then granulated in the presence of an aqueous solution of a strong base, which was sprayed onto the mixed powder. The granulate was dried, sieved, mixed with optional lubricants (such as talc or magnesium stearate) and compressed into tablets. Preferred aqueous solutions of strong bases are solutions of alkali metal hydroxides such as sodium or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent for identification, taste, and ease of swallowing. The film-forming agent is usually present in an amount of 2 to 4% by weight of the tablet. Suitable film-forming agents are well known in the art and include hydroxypropyl methylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate/methylbutyl methacrylate copolymers - Eudragit® E Rohm. Pharma), and the like. These film-forming agents may optionally contain dyes, plasticizers and other additional ingredients.

The compressed tablets preferably have a hardness sufficient to withstand a compression of 8 kPa. The tablet size will depend primarily on the amount of compound in the tablet. The tablets will include from 300 to 1100 mg of the free base of the compound. Preferably the tablets include amounts of the free base of the compound ranging from 400-600, 650-850 and 900-1100 mg.

To influence the rate of dissolution, the time during which the powder containing the compound is wet mixed is controlled. Preferably, the total mixing time of the powder, that is, the time during which the powder is exposed to the sodium hydroxide solution, is from 1 to 10 minutes, and preferably from 2 to 5 minutes. After granulation, the particles are removed from the granulator and placed in a fluid bed dryer to dry at a temperature of approximately 60°C.

Composition example 11.

The tablet composition was prepared using the following ingredients:

Quantity

Ingredient (mg/tablet)

Active ingredient300.0

Microcrystalline cellulose100.0

Colloidal silicon dioxide10.0

Stearic acid5.0

The components were mixed and pressed into tablets.

Examples

The following examples are included to demonstrate specific embodiments of the present invention. Those skilled in the art will appreciate that the methods disclosed in the examples that follow are methods for performing well in the practice of the invention and, thus, may be considered to constitute preferred modes for its use. However, those skilled in the art should, in light of the present disclosure, appreciate that many changes may be made to the specific embodiments described and still obtain the same or similar result without departing from the spirit and scope of the present invention.

List of abbreviations and acronyms.

Abbreviation Meaning °C Degree Celsius

Ac Acetyl aq.

ATP

VgRtg

VOS

Vg

Water

Adenosine triphosphate Bis(pinacolato)diborone tert-Butoxycarbonyl

Widened

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B.S.A. Bovine serum albumin d Doublet DXM Dichloromethane dd Double doublet ddd Two double doublets DIPEA Ν,Ν-Diisopropylethylamine (Hunig's base) DMA Dimethylacetamide DME 1,2-Dimethoxyethane DMF Dimethylformamide DMSO Dimethyl sulfoxide dt Doublet-triplet DTT Dithiothreitol (Cleland's Reagent) ec ₅₀ Half-maximal effective concentration EDC 1 -(3-d methylaminopropyl)-3-ethylcarbodiimide EDTA Ethylenediaminetetraacetic acid EGFR Epidermal growth factor receptor Eq. Equivalents 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 HC1 Hydrochloric acid HPLC High performance liquid chromatography 4 Watch HTRF® Homogeneous fluorescence with time resolution, registered trademark of Cisbio Bioassays, pare marcel boiteux 30200 codolet, France Hz Hertz

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IBD Inflammatory bowel disease IC ₅₀ Half-maximal inhibitory concentration i-pr Isopropyl J Interaction constant (MHz) K3PO4 Tripotassium phosphate KOtBu Potassium tert-butoxide KOAc Potassium acetate LCMS Liquid chromatography-mass spectrometry Li HMDS Lithium bis(trimethylsilyl)amide LiOH Lithium hydroxide Lil Lithium iodide LPS Lipopolysaccharide M Mole m multiplet M+ Mass spectrum maximum M+H+ Mass spectrum maximum + hydrogen Me Methyl MeCN Acetonitrile MeOH Methanol (Methyl alcohol) MeLi Methyllithium MeMgX Methylmagnesium halide halide (Grignard reagent), where X represents fluorine, chlorine, bromine, or iodine MeeSni Hexamethyldistannan (hexamethyldiotin) ΜΓ Milligram _MgSO4 Magnesium sulfate MHz Megahertz min Minute ml/ml Milliliter mm Millimolar mmol Millimole MS Mass spectrometry MsCl Methyl sulfonyl chloride N.B.S. N-bromosuccinimide n- Normal nBu/Bu n-butyl (normal butyl)

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n-BuLi n-butyllithium NaH Sodium hydride _NaHCO3 Bicarbonate of soda NaN ₃ Sodium azide _{Na3PO4 _} Trisodium phosphate _{Na2SO4 _} Sodium sulfate NL nanoliter H.M. nanometer NMP 1-methylpyrrolidin-2-one NMR Nuclear magnetic resonance NP-40 Nonyl phenoxypolyethoxyethanol Pd-PEPPSI™ -IPent [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3 chloropyridyl)palladium(P) dichloride Pen-Strep Penicillin-Streptomycin (5000 units of penicillin G sodium salt and 5000 mcg streptomycin sulfate in 0.85% saline solution) Ph Phenyl q Quartet q.s. Quantity sufficient to achieve the stated function OF Reverse phase RPMI Roswell Park Memorial Institute Wednesday Rt Room temperature s Singlet us. Saturated Selectfluor® 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis (trade name Air Products and Chemicals) SFC Supercritical liquid chromatography SiliaMetS® Thiol Silicon Dioxide Palladium Absorber, Registered Trademark from Silicycle T Triplet THF Tetrahydrofuran TFU Trifluoroacetic acid XPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1 biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(P) methanesulfonate

1. Comparative example A.

Comparative Example A is shown as Example 193 in international patent application PCT/US2016/038861, published as WO 2016/210036 A1.

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The structure of Comparative Example A is

Example A

2. Synthesis of intermediate compounds. Preparation of intermediate I-1.

I-1A I-1B I-1C I-1D I-1E _χ NB ₂ Pin ₂ KOAcN

NBS Pd(PPh ₃ ) ₂ CI ₂ l

PCM _r || Dioxane/DMF 'y θ n ^B ^J

I-1F1-1

Potassium salt of 3,3-diethoxy-2-formylpropionitrile (I-1C).

To a stirred solution of 3,3-diethoxypropanenitrile (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 At 10°C, 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2 mol) was added. The temperature was maintained between 10 and 15°C during the 45 min addition. After addition, the resulting suspension was stirred for 2 hours at ambient temperature. Hexane (400 ml) was then added and stirring was continued for another 20 minutes. The suspension was filtered, the filter cake was washed with 1/1 hexane/THF and dried overnight at 60°C in a vacuum oven to give I-1C.

1H-NMR (CD ₃ OD) was consistent with the desired structure.

Pyrrolo[1,2-b]πpyridazine-3-carbonitrile (I-1E).

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 such a rate that the internal reaction temperature does not exceed 20°C. After addition was complete, the reaction mixture 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 addition, the reaction mixture was refluxed at 90°C for 2 hours. After heating was complete, the reaction mixture was cooled to room temperature and concentrated to approximately half the original volume. A saturated aqueous solution of sodium bicarbonate was carefully added to the resulting residue until the formation of bubbles stopped. The solution was extracted with two portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and the resulting residue was purified by silica gel chromatography (eluent: EtOAc/hexane) to give I-1E.

¹ H 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, 1.4 Hz, 1H).

7-Bromopyrrolo[1,2-b]niridazine-3-carbonitrile (I-1F).

N-bromosuccinimide was added in one part 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. The reaction mixture was stirred at room temperature for 30 minutes, then poured into a saturated aqueous sodium bicarbonate solution. The solution was concentrated in vacuo to remove acetonitrile. The resulting aqueous layer was extracted with three parts of 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=2.1 Hz, 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)nirrolo[1,2-b]niridazin-3-carbonitrile (I-1).

7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1F, 416.5 mg, 1.9 mmol), bis(pinacolato)diborone (762.1 mg, 3. 0 mmol), potassium acetate (552.3 mg, 5.6 mmol) and bis(triphenylphosphine) palladium(P) dichloride (65.8 mg, 0.094 mmol). Dioxane (8.0 ml) and DMF were added

- 25 045296 (4.0 ml) and the reaction mixture was degassed with bubbling argon for 2 minutes. The vessel was sealed and the reaction mixture 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 part of EtOAc and the combined organic layers were dried over sodium sulfate, filtered through a pad of celite and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluent: EtOAc/hexanes) to give I-1.

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.

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 lithium hydroxide (2.93 g, 119.77 mmol) in water (68 ml). The solution was heated to 43°C overnight and then cooled to room temperature. Aqueous hydrochloric acid (1 M, 120 ml) was added and volatiles were removed in vacuo. The resulting suspension was filtered and washed with H ₂ O to obtain 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).

(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 at room temperature overnight and then diluted with ethyl acetate. The organic solution was washed with saturated aqueous lithium chloride (3 times), then dried over Na ₂ SO ₄ and then concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc/hexanes) to give (R)-6-bromo-4-chloro-N-(2fluoro-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=7.0 Hz, 6H).

(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-3carbonitrile (0.24 g, 0.9 mmol), XPhos Pd G3 (0.05 g, 0.06 mmol) and aqueous tribasic potassium phosphate (2 M, 0.59 ml, 1.18 mmol). The resulting solution was degassed with argon and heated to 120°C for 12 min in a microwave reactor. 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+).

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3. Example methods and examples of connections.

Method 1: example 1.

(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4(methylamino)nicotinamide.

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 under vacuum and diluted with ethyl acetate. The resulting solution was washed with water and an aqueous sodium chloride solution. The resulting organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting material was purified by normal phase SiO ₂ chromatography (eluent: ethyl acetate/hexanes) to obtain the desired product.

ES/MS: 201.180 (M+H+).

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 (1 N, 5 ml) and concentrated to dry under vacuum. The resulting crude material was used in the next step.

ES/MS: 187.070 (M+H+).

(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-3fluoro-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). The resulting solution was stirred at room temperature for 1 hour and diluted with ethyl acetate. The 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 SiO ₂ chromatography (eluent: ethyl acetate/hexanes) to obtain the desired product.

ES/MS: 290.472 (M+H+).

(R)-6-(3-cyanopyrrolo[1,2-b]pyridazine-7-uh)-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) an aqueous solution of potassium phosphate (2 M, 0.10 ml, 0.20 mmol) was added to DME (1 ml). The resulting solution was degassed with argon for 2 min and heated in a microwave oven for 20 min at 120°C. The reaction mixture was filtered and the resulting solids were washed with DMF. The filtrates were then concentrated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN x 0.1% TFA) to give the product as the trifluoroacetate salt.

ES/MS: 397.283 (M+H+).

¹ H NMR (400 MHz, Methanol-d ₄ ) 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,

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2.2 Hz, 1H), 3.48 (ddd, J=16.2, 14.5, 9.4 Hz, 1H), 3.19 (s, ZN), 1.28 (d, J=1 .7 Hz, 6H).

Method 2: example 2.

(R)-4-((cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3methylbutyl)nicotinamide.

(R)-6-chloro-4-((cyαnomethyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

To a suspension 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 K,K-diisopropylethylamine (0.2 ml, 1.12 mmol). The resulting solution was then heated in a microwave oven for 30 min at 150°C. Additionally, aminoacetonitrile hydrochloride (47.03 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.12 mmol) were added and the reaction mixture was heated under thermal conditions for 16 h at 130°C. The solution was cooled to room temperature and diluted with ethyl acetate. The resulting suspension was filtered and the solid was washed with EtOAc. The resulting filtrates were combined and washed with an aqueous solution of ammonia chloride. The resulting organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting material was purified by chromatography on _SiO2 with normal phase (eluent: ethyl acetate/hexanes) to obtain the desired product.

ES/MS: 315.159 (M+H+).

(R)-4-((cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3methylbutyl)nicotinamide.

To a solution of (R)-6-chloro-4-((cyanomethyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamideα (53 mg, 0.17 mmol), 7-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-3carbonitrile (68 mg, 0.25 mmol) and Xphos Pd G3 (16 mg, 0.019 mmol ) to DME (2 ml) was added an aqueous solution of potassium phosphate (2 M, 0.17 ml, 0.34 mmol). The resulting solution was degassed with argon for 2 min and heated in a microwave oven for 20 min at 120°C. The reaction mixture was filtered and the resulting solids were washed with DMF and MeOH. The filtrates were then concentrated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCNx0.1% TFA) to give the product as the trifluoroacetate salt. The material was further purified by normal phase chromatography on SiO ₂ (eluent: methanol/dichloromethane) and lyophilized from acetonitrile and water (0.1% trifluoroacetic acid) to obtain the desired product.

ES/MS: 422.250 (M+H+).

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.79 (d, J=2.2 Hz, 1H), 8.70 (d, J=2.0 Hz, 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, 2.2 Hz, 1H), 3.60 - 3.41 (m, 1H), 1.31 (d, J=1.7 Hz, 6H).

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Method 3: example 3.

4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy- 3methylbutyl)nicotinamide.

DIPEA

4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N-((R)-2-fluoro-3-hydroxy-3 methylbutyl)nicotinamide.

To a suspension 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 heated in a microwave oven for 60 min at 150°C. The resulting material was purified by RP-HPLC (eluent: water/MeCNχ 0.1% TFA) to obtain the product in the form of trifluoroacetate salt.

ES/MS: 347.521 (M+H+).

Table 1

Connections

Compound ES/MS m/z Methodology Name 1 397.3 1 (C)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-M-(2fluoro-3-hydroxy-3-methylbutyl)-4(methylamino)nicotinamide 2 422.3 2 (R)-4-((cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2b]pyrid azin-7-yl)-X-(2-fluoro-3-hydroxy-3 methylbutyl)nicotinamide 3 436.4 3 4-(((R)-1 -cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2b]pyridazi n-7-yl)-N-((Κ.)-2-φτορ-3-hydroxy -3 methylbutyl)nicotinamide 4 436.3 3 4-(((S)-1 -cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2b]pyr idazi n-7-yl)-N-((Κ.)-2-φτορ-3-hydroxy -3 methylbutyl)nicotinamide 5 450.4 3 4-(((R)-1 -cyanopropyl)amino)-6-(3-cyanopyrrolo[1,2b]pyridazi n-7-yl)-N-((Κ.)-2-φτορ-3-hydroxy -3 methylbutyl)nicotinamide

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6 450.3 3 4-(((S)-1 -cyanopropyl)amino)-6-(3-cyanopyrrolo[1,2b]pyridazin-7-yl)-X-((K)-2-fluoro-3-hydroxy-3 methylbutyl )nicotinamide 7 436.5 2 (R)-4-((2-cyanoethyl)amino)-6-(3-cyanoπippolo[l,2b]pyridazin-7-yl)^-(2-fluoro-3-hydroxy-3 methylbutyl)nicotinamide 8 450.7 2 (R)-4-((3-cyanopropyl)amino)-6-(3-cyanopyrrolo[1,2b]pyridazin-7-yl)-M-(2-fluoro-3-hydroxy-3 methylbutyl)nicotinamide 9 450.5 3 (I)-4-((2-cyanopropan-2-yl)amino)-6-(3cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3hydroxy-3-methylbutyl) nicotinamide 10 448.5 2 (C)-4-((1-cyanocyclopropyl)amino)-6-(3cyanopyrrolo[1,2-b]pyridazin-7-yl)-M-(2-fluoro-3hydroxy-3-methylbutyl)nicotinamide

table 2

NMR data for example compounds

Compound 1H-NMR 1 1H NMR (400 MHz, Methanol-44) 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) 2 1H NMR (400 MHz, Methanol-44) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.0 Hz, 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, 2.2 Hz, 1H), 3.60 - 3.41 (m , 1H), 1.31 (d, J = 1.7 Hz, 6H). 3 1H NMR (400 MHz, Methanol-44) δ 8.79 (d, J = 2.1 Hz, 1H), 8.73 (s, 1H), 8.71 (d, J = 2.1 Hz, 1H ), 8.09 (d, J = 5.1 Hz, 1H), 8.07 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.15 (q, J = 6.9 Hz, 1H), 4.47 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.97 (ddd, J = 36.4, 14.6, 2 ,2 Hz, 1H), 3.54 (ddd, J = 16.2, 14.5, 9.3 Hz, 1H), 1.85 (d, J = 7.0 Hz, ZN), 1.32 (d, J = 1.7 Hz, 6H) 4 1H NMR (400 MHz, Methanol-44) δ 8.79 (d, J = 2.2 Hz, 1H), 8.73 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H ), 8.09 (d, J = 5.0 Hz, 1H), 8.07 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.15 (q, J = 7.0 Hz, 1H), 4.46 (ddd, J = 49.0, 9.4, 2.2 Hz, 1H), 3.99 (ddd, J = 36.3, 14.5, 2 ,1 Hz, 1H), 3.60 - 3.43 (m, 1H), 1.85 (d, J = 7.0 Hz, ZN), 1.32 (d, J = 1.7 Hz, 6H ). 5 1H NMR (400 MHz, Methanol-44) δ 8.77 (t, J = 1.8 Hz, 1H), 8.73 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 5.2, 1.4 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.23 (dd , J = 5.1, 1.4 Hz, 1H), 5.05 (t, J = 6.9 Hz, 1H), 4.45 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.94 (ddd, J = 36.5, 14.6, 2.3 Hz, 1H), 3.52 (td, J = 15.2, 9.3 Hz, 1H), 2 .17 (p, J = 7.2 Hz, 2H), 1.29 (d, J = 1.6 Hz, 6H), 1.25 (td, J = 7.4, 1.4 Hz, ZN) .

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6 1H NMR (400 MHz, Methanol-d4) δ 8.71 (d, J = 2.7 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.24 (s, 1H), 7.93 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 5.0 Hz, 1H), 4.80 (d, J = 6.3 Hz, 1H), 4.43 (ddd, J = 49.0, 9.2, 2.4 Hz, 1H), 4.09 - 3.80 (m, 1H), 3.49 (ddd, J = 15.8, 14.3, 9.7 Hz, 1H), 2.14 (p, J = 7.2 Hz, 2H), 1.29 (d, J = 1.8 Hz, 6H), 1.27 - 1.18 (m, 3H). 7 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.63 (s, 1H ), 8.09 (d, J = 5.0 Hz, 1H), 7.96 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.46 (ddd, J = 49.1, 9.4, 2.2 Hz, 1H), 4.10 - 3.85 (m, 3H), 3.52 (ddd, J = 16.2, 14.5, 9.4 Hz , 1H), 2.97 (t, J = 6.5 Hz, 2H), 1.31 (d, J = 1.7 Hz, 6H). 8 1H NMR (400 MHz, Methanol^4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H ), 8.05 (d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.45 (ddd, J = 49.0, 9.3, 2.2 Hz, 1H), 3.97 (ddd, J = 36.3, 14.6, 2.2 Hz, 1H), 3.74 (t, J = 7 ,1 Hz, 2H), 3.51 (ddd, J = 16.2, 14.6, 9.3 Hz, 1H), 2.67 (t, J = 7.0 Hz, 2H), 2.13 (p, J = 7.0 Hz, 2H), 1.31 (d, J = 1.7 Hz, 6H). 9 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.77 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H ), 8.57 (s, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.46 (ddd, J = 49.1, 9.4, 2.1 Hz, 1H), 3.96 (ddd, J = 36.5, 14.6, 2.1 Hz, 1H), 3.53 (ddd, J = 16 ,1, 14.6, 9.4 Hz, 1H), 1.98 (s, 6H), 1.31 (d, J = 1.7 Hz, 6H). 10 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.69 (s, 1H ), 8.50 (s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.43 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.94 (ddd, J = 36.3, 14.6, 2.1 Hz, 1H), 3.49 (ddd, J = 16 ,2, 14.6, 9.3 Hz, 1H), 1.97 - 1.84 (m, 2H), 1.64 - 1.53 (m, 2H), 1.29 (d, J = 1 ,6 Hz, 6H).

Biological analyses.

Biological assays were performed to measure activity against TNFa and IRAK4. As shown in table. 3, the tested compounds are IRAK4 inhibitors.

TNFa IRAK4 Monocyte Cell Based Assay Procedure.

Cryopreserved human monocytes (Stem Cell Technologies) were thawed, diluted in RPMI with GlutaMAX™ (Gibco® 200 mM L-alanyl-L-glugamine) (10 mM HEPES, 1X Pen-Strep, 55 μM β-mercaptoethanol, 1 mM sodium pyruvate ) containing 10% FBS to 0.125x106 cells/ml and reconstituted at 37°C for 2 hours. The cell suspension was then seeded at a density of 5000 cells/well into 384-well black Greiner clear-bottom plates. The plates were preloaded with test compounds and serially diluted in DMSO, with 40 nL/well delivered using an Echo 550 acoustic liquid dispenser (Labcyte®) to a final DMSO concentration of 0.1%. The seeded cells were treated with the compound for 1 hour at 37°C. Cells were then stimulated with 50 μg/ml LPS (Sigma) except for the outer rows of the plate used for wells containing unstimulated cells. Cells were incubated for another 4 h at 37°C. Cells were then centrifuged from the medium, a 5 μl sample was collected, and analyzed for total TNFa using the TR-FRET Human TNFa Detection System (CisBio). This system uses two labeled antibodies (cryptate and XL665) that bind to two different epitopes of the TNFa molecule and produce a FRET signal proportional to the concentration of TNFa in the sample. Detection antibodies are mixed in a 50:50 ratio, and 5 μl is added to each well. The plates were covered with transparent lids and incubated at room temperature overnight. The next morning, plates were read using an Envision 2103 Multilabeled reader (PerkinElmer) with FRET excitation/emission/emission at 340/615/665 nm, respectively. Fluorescence intensities at emission wavelengths of 615 and 665 nm were expressed as a ratio (665/615 nm). The percentage of control was calculated as follows:

- 31 045296 % Control = 100x (Ratio _{of sample} - Ratio of ₀ % _stimulation ) / (Ratio of stimulation - Ratio of % stimulation), where unstimulated cells (0% stimulation) were the negative control and stimulated cells (100% stimulation) were used as positive control.

Biochemical analysis procedure for IRAK4.

IRAK4 enzyme activity (Carna Biosciences, Chuo-ku, Kobe, Japan) was measured by detecting the formation of phosphorylated peptide substrate using an antibody against phosphorylated peptide substrate. This is a time-resolved fluorescence resonance energy transfer (TR-FRET) enzyme-linked immunosorbent assay based on the STK1 KinEASE assay (Cisbio, Bedford, MA). The assay was designed as a simple two-step endpoint assay (5 μL enzyme reaction mixture followed by 5 μL stop and detect solution) performed in ProxiPlate-384 Plus plates (Perkin Elmer, Waltham, MA). Staurosporine, a nonselective kinase inhibitor, was used as a positive control. Compounds reconstituted in DMSO were plated into 384-well plates using a Labcyte® Echo 550 liquid handling system before adding IRAK4 enzyme and peptide substrate. Reaction solutions were delivered using Multi-Flo (Bio-Tek Instruments). The enzyme and peptide solution was incubated with the compound for 15 min at room temperature before the reaction was initiated by the addition of ATP. 5 μl of the standard reaction mixture contained 500 μM ATP, 2 μM peptide (STK1 peptide), 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 MgCl ₂ , 0.025% NP-40, 1 mM DTT). After 120 min of incubation at room temperature, 5 μl of stop and detection solution (1:100 solution of cryptate-labeled antiphosphorylated peptide antibody and 125 nM indicator in 50 mM HEPES detection buffer pH 7.0 containing sufficient EDTA) was added. The plate was then incubated for 60 min at room temperature and read using an Envision 2103 Multilabeled reader (PerkinElmer) with FRET excitation/emission/emission at 340/615/665 nm, respectively. Fluorescence intensities at emission wavelengths of 615 and 665 nm were expressed as a ratio (665/615 nm). The percentage of inhibition was calculated as follows:

% Inhibition = 100x ( _Sample Ratio - ₀ % _Inhibition Ratio)/ ^{(100% Inhibition Ratio -} 0% Inhibition Ratio)

An inhibition value of 0% corresponds to control wells containing no inhibitor. The 100% inhibition value was obtained from control wells containing a saturating amount of the known inhibitor staurosporine.

Stability in the liver.

Metabolic stability in cryopreserved hepatocytes: Complete HT medium was prepared by adding 1 ml of Torpedo Antibiotic Mixture to 45 ml of InVitroGRO™ HT medium. Supplemented KHB medium consisted of Krebs-Henseleit buffer with amikacin (84 μg/ml), calcium chloride (1 mM), gentamicin (84 μg/ml), HEPES (20 mM), heptanoic acid (4.2 μM), and bicarbonate sodium (28.5 mM), and the pH was adjusted to 7.4 at 37°C using 1 M NaOH or 1 M HCl. Cryopreserved human hepatocytes from ten adult donors were pooled (Celsis, Lot: HBZ).

Vials containing cryopreserved hepatocytes were removed from liquid nitrogen and immediately immersed in a water bath at 37°C. The vials were shaken gently until the contents thawed and then immediately poured into 48 mL of prewarmed Complete HT medium in a 50 mL conical tube. Cells remaining in the vial were resuspended in 1.0 ml of prewarmed Complete HT medium and added to a conical tube. The tube was capped and then carefully inverted several times to resuspend the hepatocytes. The cell suspension was centrifuged at 50xg at room temperature for 5 min, and the supernatant was discarded. The cell pellet was loosened by gently rotating the centrifuge tube, and KNV medium with supplements was added to obtain a target density of 2x10 ⁶ cells/ml. The total number of cells and the proportion of viable cells were determined by trypan blue dye exclusion using a hemocytometer.

For incubation, aliquots of the hepatocyte suspension (250 μl containing 500,000 cells) were added to 250 μl of 2 μM test compound or metabolic stability controls in spiked KNV wells in duplicate in a 24-well plate. The final incubation concentration was 1x10 ⁶ cells/ml and 1 μM test compound. 7-hydroxycoumarin and testosterone, compounds known to be efficiently metabolized by hepatocytes, were used as positive controls in parallel incubations (2 μM final concentration of each compound). Incubation was carried out with gentle shaking at 37°C in a humidified atmosphere of 95% air/5% CO2 (v/v). Aliquots (50 μL) were removed at 0, 1, 3, and 6 h and added to 100 μL of IS/Q quenching solution. Once complete, 150 μl of water was added, the plates were centrifuged at 3000xg for 10 min, and aliquots of the supernatant were analyzed on a Micromass Quattro Premier mass spectrometer connected to an Agilent 1200 series HPLC system with a Leap Technologies HTC PAL autosampler as described below.

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Liquid chromatography - mass spectrometry.

Test compound quantitation and metabolic stability monitoring were performed using analyte/internal standard peak area ratio (PAR) measured on a Micromass Quattro Premier XL tandem triple quadrupole mass spectrometer coupled to an Agilent 1200 series HPLC system with a Leap Technologies HTC PAL autosampler. The column used was Phenomenex® MercuryMS™, Synergi Max-RP (100 A pore size, 2.5 µm particle size, 20 x 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 achieved by the following series of linear gradients: starting conditions of 0% B, holding for 30 s, then increasing to 100% B over 90 s, and then returning to starting conditions for 1 s. The system was allowed to re-equilibrate for a minimum of 60 s between injections. The sample injection volume was 10 μL.

Plasma protein binding LTP.

A stock solution of the test compound was prepared in dimethyl sulfoxide (DMSO) at a final concentration of 10 mM and used in all experiments.

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

Analysis by equilibrium dialysis.

Pooled plasma (from at least 3 males and 3 females) was obtained from humans, beagle dogs, Sprague-Dawley rats, cynomolgus monkeys and rhesus monkeys. Sodium EDTA was used as an anticoagulant.

Competitive equilibrium dialysis was performed at 37°C using human plasma versus SCM containing 10% FBS, with sample added to both sides of the matrix at final concentrations of 2 μM. Before testing, the dialysis membrane was soaked for approximately one hour in 0.133 M phosphate buffer, pH 7.4. The added plasma (1 ml) and SSM (1 ml) were placed on opposite sides of the assembled dialysis cells. To assess recovery after a 24-hour equilibration period in a 37°C water bath, plasma samples were decanted into preweighed polypropylene tubes containing 1 ml of SSM (without compound), and SSM samples were decanted into preweighed tubes containing 1 ml of the corresponding blank plasma. Plasma mass and SSM after dialysis were measured and recorded for calculations.

Liquid chromatography - mass spectrometry.

Quantification of the test compound was performed using analyte/internal standard peak area ratio (PAR) measured on a Q-Exactive mass spectrometer coupled to an Agilent 1260 Series HPLC system 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). The sample injection volume was 10 μL.

Definitions of pK _a .

Sample preparation.

A stock solution of the test compound was prepared in dimethyl sulfoxide (DMSO) at a final concentration of 10 mM and used in all experiments. The starting materials in DMSO were thawed, centrifuged and sonicated in a water bath at 40°C to facilitate dissolution.

pKa analysis.

Stock solutions of 10 mM in DMSO were diluted 100-fold with 10 mM HCl to obtain a final compound concentration of 100 μM and 1% DMSO. Compounds were then transferred into 24 consecutive wells of a 96-well PCR plate for aqueous analysis. For compounds that did not produce high quality data using the aqueous method, stock solutions of 10 mM in DMSO were diluted 100-fold with 2 mM HCl and methanol, so the final concentration of methanol was 60%, the compound concentration was 100 μM, and the concentration DMSO was 1%. Compounds were transferred into 24 consecutive wells of a 96-well plate for analysis using the cosolvent method.

Analysis.

All data were obtained using a pKa PRO analyzer (AATI, Ames, IA). For the aqueous method, electrophoretic separations were performed in parallel at 24 different pH values, providing a direct measurement of the overall charge of a compound as a function of pH. Compounds were detected by UV light at 228 nm. The average pH interval between buffer points was 0.4 pH units, corresponding to a typical pH range of 1.7–11.2.

The cosolvent method is suitable for the analysis of compounds that have low solubility in water (typically calculated intrinsic solubility <10 µg/mL). Average pH interval between buffers

- 33045296 points was 0.4 pH units in the pH range 1.7-11.2. For each compound, four consecutive CE cycles were performed, starting with 60% cosolvent buffers and decreasing to 30% cosolvent buffers.

Norfloxacin was used as a daily efficacy standard.

Calculation of results.

Total pKa values were predicted by correlating the mobility and molecular weight of the compound using pKa Estimator® software (AATI, Ames, IA).

Automated hERG analysis via Charles River - Cleveland (formerly ChanTest).

The FASTPatch® assay (Charles River) was used to study the in vitro effects of various compounds on the cloned hERG potassium channel encoded by the KCNH2 gene and stably expressed in HEK293T cells. Vehicle, test, and control formulations were prepared by diluting stock solutions in DMSO in HB-PS (HEPES buffered physiological saline) and delivered to cells using a QPatch robotic pipetting system to a final DMSO concentration of 0.3%. Final test compound concentrations of 0.3, 1, 3, 10, and 30 μM were applied to cells (n>3, where n=number of cells/concentration) in ascending order at at least three-minute intervals, separated by solution changes. The positive control, 50 nM cisparide, was added in the same way. Cell membrane currents were recorded at room temperature using up to 48 parallel patch clamp amplifiers on the QPatch HT® or QPatch HTX® system, and only cells with proven cell integrity data (seal resistance >200 MΩ and leakage current <25% of channel current) were used. The onset and blocking of hERG current was measured using a stimulus voltage pattern consisting of a 500 ms prepulse to −40 mV, a 2-second activation pulse to +40 mV, followed by a 2-second test pulse to −40 mV. The pulse train was repeated continuously at 10-s intervals at a holding potential of −80 mV. TurboSol test compound solubility analysis 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 to be indicative of the presence of particles in suspension.

The results of in vitro tests are presented in table. 3 below.

Table 3

compound 1C ₅ o HTRF (nM) EU ₅ about TNF (nM) Protein Adj.EC50 TNF (nM) Hep stability person (l/h/kg) pK _a hERG IC50 (µM) A <1 23 504 0.20 6.1 3.9 1 2 50 383 0.05 6.6 1.7 2 <1 19 232 0.13 5.1 >10 3 <1 14 191 0.08 4.9 >30 4 2 115 5 1 60 6 5 267 7 164 8 <1 33 0.14 5.9 3.5 9 <1 49 0.26 4.8 10 <1 35 0.22

Claims (6)

1. Compound of formula (II) or a pharmaceutically acceptable salt thereof, in which R ¹ represents H or methyl, R ² represents H or methyl, or R ¹ and R ² together with the carbon atoms to which they are attached form cyclopropyl. 2. The compound according to claim 1, characterized in that R ¹ represents H. 3. A compound according to claim 1, characterized in that R ¹ represents methyl. 4. Compound of formula III or a pharmaceutically acceptable salt thereof, characterized in that R ¹ represents H or methyl, and R ² represents H or methyl. 5. Connection or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition containing a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.