Pyrimid-2-yl-pyrazole compounds as IRAK inhibitors

Abstract

Disclosed embodiments relate to novel interleukin receptor associated kinase (IRAK) inhibitor compounds and compositions comprising such compounds. The compounds may have a structure according to Formula I (I). Methods of making and using the compounds and compositions are also disclosed. The compounds and / or compositions of the disclosure may be used to treat or prevent diseases or conditions associated with IRAK. TIFF2025513716000044.tif64165

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the earlier filing date of U.S. Provisional Patent Application No. 63 / 322,955, filed March 23, 2022, which is incorporated by reference in its entirety.

[0002] Field The present disclosure relates to embodiments of pyrazole compounds, and methods for making and using the compounds, for example, for inhibiting interleukin receptor-associated kinase (IRAK) and for treating diseases and conditions associated with IRAK. [Background technology]

[0003] Interleukin-1 receptor-associated kinases (IRAKs) are key mediators of signal transduction processes such as Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signal transduction processes. IRAKs are involved in regulating signal transduction networks that control inflammation, apoptosis, and cell differentiation. Four IRAK genes have been identified in the human genome (IRAK1, IRAK2, IRAK3, and IRAK4), and studies have revealed distinct, non-redundant biological roles. IRAK1 and IRAK4 have been shown to exhibit kinase activity. Summary of the Invention

[0004] Disclosed herein are embodiments of compounds having a structure according to Formula I, or a pharma- ceutically acceptable salt or solvate thereof. TIFF2025513716000002.tif64165 Regarding formula I, R 1is H, aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkyl phosphoramidate, or alkyl phosphate, e.g., H, alkyl, or -alkylOP(O)(OR)2, e.g., -CH(CH3)OP(O)(OR)2 or -CH2OP(O)(OR)2, where each OR is -OH, -Oalkyl, -Oaryl, -Oheteroaryl, -Oaralkyl, or -O - M + where M + is a single positively charged counterion, and R 2 But, C 1-6 In some embodiments, R 2 is C 1-4 In some embodiments, the compound has a structure according to Formula II, or a pharma- ceutically acceptable salt or solvate thereof.

[0005] In one embodiment, R 1 is H. In another embodiment, R 1 is C 1-6 In a further embodiment, R 1 is -CH2OP(O)(OR)2, and -CH2OP(O)(OH)2, -CH2OP(O)(OC 1-6 alkyl)2, or -CH2OP(O)(O - M + )2, for example, -CH2OP(O)(O - Na + ) 2. In a further embodiment, R 1 is -CH(CH3)OP(O)(OR)2, and -CH(CH3)OP(O)(OH)2, -CH(CH3)OP(O)(OC 1-6 alkyl)2, or -CH(CH3)OP(O)(O - M + )2, for example, -CH(CH3)OP(O)(O - Na + )2.

[0006] The compound may be in free base form, or in a salt form, such as a co-crystal form, such as a tartrate co-crystal or a tris salt co-crystal.

[0007] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein and a pharma- ceutically acceptable excipient.

[0008] Methods for inhibiting IRAK enzyme are disclosed herein. The methods can include contacting the enzyme with an effective amount of a compound disclosed herein. In some embodiments, contacting the enzyme includes administering the compound to a subject.

[0009] Also disclosed herein is a method for treating a subject with a disease or condition for which an IRAK inhibitor is indicated.The method may comprise administering to the subject an effective amount of the compound disclosed herein or a pharmaceutical composition thereof.The disease or condition may comprise autoimmune disease, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, allergic disorder, multiple organ failure, kidney disease, platelet aggregation, hyperproliferative disorder, transplantation, sperm motility, red blood cell deficiency, graft rejection, lung injury, respiratory disease, ischemic condition, bacterial infection, viral infection, immunoregulatory disorder, or combination thereof.In some embodiments, the disease or condition comprises aplastic anemia, atopic dermatitis, pustular psoriasis, palmoplantar pustulosis, primary biliary cirrhosis, pyoderma, sclerosing cholangitis, systemic juvenile idiopathic arthritis, hidradenitis suppurativa, cytokine release syndrome, or myelodysplastic syndrome (MDS).

[0010] In some embodiments, the disease or condition comprises a lymphoid neoplasm. The lymphoid neoplasm may be selected from lymphoid neoplasms selected from myeloproliferative neoplasms (MPN) excluding polycythemia vera, myeloid / lymphoid neoplasms with PDGFRA rearrangements, myeloid / lymphoid neoplasms with PDGFRB rearrangements, myeloid / lymphoid neoplasms with FGFR1 rearrangements, myeloid / lymphoid neoplasms with PCM1-JAK2, myelodysplastic / myeloproliferative neoplasms (MDS / MPN), myeloid sarcoma, myeloproliferation associated with Down's syndrome, blastic plasmacytoid dendritic cell neoplasm, B lymphoblastic leukemia / lymphoma, and / or T lymphoblastic leukemia / lymphoma. In some embodiments, the lymphoid neoplasm is a myeloproliferative neoplasm selected from chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), primary myelofibrosis (PMF), essential thrombocythemia, chronic eosinophilic leukemia, or a combination thereof. In certain embodiments, the lymphoid neoplasm is chronic myelogenous leukemia.

[0011] In any embodiment, the method may further include identifying the subject from a lymphoid neoplasm. In certain embodiments, the lymphoid neoplasm is chronic myelomonocytic leukemia, and identifying the subject comprises a 1×10 9 This includes identifying subjects with persistent peripheral blood monocytosis of ≥ 10% / L and monocytes accounting for ≥ 10% of the white blood cell (WBC) differential, and no observed rearrangements of PDGFRA, PDGFRB, or FGFR1 genes and PCM1-JAK2 fusion gene.

[0012] The foregoing and other objects, features, and advantages of the technology will become more apparent from the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description I. Definition The following explanations of terms and methods are provided to better describe the present disclosure and guide those skilled in the art in the practice of the present disclosure. The singular forms "a," "an," and "the" refer to one or more, unless the context clearly dictates otherwise. The term "or" refers to a single element of the described alternative elements or a combination of two or more elements, unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "including A or B" means "including A, B, or A and B," without excluding additional elements. All references cited herein, including patents and patent applications, are incorporated by reference.

[0014] Unless otherwise indicated, all numerical values ​​expressing properties such as amounts, molecular weights, proportions of ingredients, temperature, time, etc. used in the specification or claims should be understood as being modified by the term "about". Thus, unless otherwise indicated, numerical parameters implicitly or explicitly indicated are approximations that may depend on the desired properties and / or limits of detection sought under standard testing conditions / methods. When directly and explicitly distinguishing the embodiments from the prior art discussed, the numerical values ​​of the embodiments are not approximations unless the word "about" is recited.

[0015] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0016] When chemical structures are depicted or described, unless expressly stated otherwise, all carbons are assumed to contain hydrogen, so that each carbon corresponds to a valence of 4. For example, in the structure on the left of the schematic below, there are 9 implied hydrogen atoms. The 9 hydrogen atoms are depicted in the structure on the right. TIFF2025513716000003.tif37165

[0017] In some cases, certain atoms within a structure are described in textual form as having a hydrogen or hydrogen atom, e.g., -CH2CH2-. It will be appreciated by those skilled in the art that the foregoing descriptive techniques are common in the chemical arts to provide brevity and simplicity in describing organic structures.

[0018] One of ordinary skill in the art will understand that the definitions can be combined to further describe a particular compound, for example, hydroxyaliphatic refers to an aliphatic group substituted with a hydroxy (-OH) group, haloalkylaryl refers to an aryl group substituted with an alkyl group, where the alkyl group is also substituted with a halogen, and aryl is the base name of the substituent, such that the point of attachment to the parent structure is through the aryl moiety.

[0019] As used herein, for example, "substituted aryl C 1-8 The term "substituted" in the term "alkyl" refers to all subsequent modifiers, and the substitution is 1-8 The alkyl group, "C 1-8 It may occur in the "alkyl" portion, the "aryl" portion, or both portions. Also by way of example, alkyl includes substituted cycloalkyl groups.

[0020] "Substituted", when used to modify a specified group or moiety, means that at least one, and possibly more than one, hydrogen atom of the specified group or moiety is independently replaced with the same or different substituents as defined below. In certain embodiments, a group, moiety, or substituent may be substituted or unsubstituted unless expressly defined as either "unsubstituted" or "substituted". Thus, any of the groups specified herein may be unsubstituted or substituted. In certain embodiments, a substituent may or may not be expressly defined as substituted, but it is still contemplated that it may be substituted. For example, an "alkyl" substituent may be unsubstituted or substituted, but an "unsubstituted alkyl" may not be substituted.

[0021] In one embodiment, a substituted group has one substituent, two substituents, a substituent, or four substituents.

[0022] Additionally, in embodiments where a group or moiety is substituted with a substituted substituent, the nesting of such substituted substituents is limited to three, thereby preventing the formation of a polymer.Thus, in a group or moiety that includes a first group that is a substituent of a second group that is itself a substituent of a third group, attached to a parent structure, the first (outermost) group can only be substituted with unsubstituted substituents.For example, in a group that includes -(heteroaryl-1)-(heteroaryl-2)-(heteroaryl-3), heteroaryl-3 can only be substituted with a substituent that is itself unsubstituted.

[0023] "Aliphatic" refers to a substantially hydrocarbon-based group or moiety, including alkyl, alkenyl, alkynyl groups, cyclic versions thereof such as cycloalkyl, cycloalkenyl, or cycloalkynyl, further including straight and branched chain configurations, as well as all stereoisomers and positional isomers. Unless expressly stated otherwise, aliphatic groups contain 1-25 carbon atoms, e.g., 1-15, 1-10, 1-6, or 1-4 carbon atoms, and cyclic aliphatic groups contain 3-25 carbon atoms, e.g., 3-15, 3-10, 3-6, or 3-4 carbon atoms.

[0024] "Acyl" refers to the group -C(O)R, where R is H, aliphatic, heteroaliphatic, heterocyclic, or aromatic. Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C1-C6 alkyl, -C(O)C1-C6 haloalkyl-C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0025] "Alkyl" refers to saturated aliphatic hydrocarbyl groups having 1 to 25 carbon atoms, typically 1 to 10 carbon atoms, such as 1 to 6 carbon atoms (C1-C6 alkyl). The alkyl portion can be substituted or unsubstituted. The term includes, by way of example, straight and branched chain hydrocarbyl groups, cycloalkyl groups, and combinations thereof, such as -CH2cyclopropyl groups, unless otherwise specified. Cycloalkyl refers to cyclic aliphatic groups having 3 to 15 carbon atoms, typically 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 4 carbon atoms. Cycloalkyl groups can be a single ring (e.g., cyclohexyl) or can include multiple rings, such as in fused, bridged, or spirocyclic systems, at least one of which is aliphatic, provided that the point of attachment is to an atom in the aliphatic region of the cycloalkyl group. Exemplary alkyl groups include, but are not limited to, methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), t-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), neopentyl (-CH2C(CH3)3), cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, -CH2cyclopropyl, -CH2cyclobutyl, -CH2cyclopentyl, or -CH2cyclohexyl.

[0026] "Amido" refers to the group -N(H) acyl, or -C(O) amino.

[0027] "Aliphatic" refers to an aryl group attached to a parent through an aliphatic moiety. Aliphatic includes aralkyl or arylalkyl groups such as benzyl and phenylethyl.

[0028] "Aralkyl" refers to an aryl group linked to a parent through an alkyl moiety. Aralkyls include groups such as benzyl and phenylethyl.

[0029] "Aryl" refers to an aromatic group of 5-15 ring atoms, having a single ring (e.g., phenyl) or multiple fused rings in which at least one ring is aromatic (e.g., naphthyl), unless otherwise specified. For groups having multiple rings, at least one of which is aromatic and one of which is not, such groups are nevertheless referred to as "aryl", provided that the point of attachment to the remainder of the compound is through an atom of the aromatic portion of the aryl group. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, aryl groups can be substituted or unsubstituted.

[0030] "Carboxyl", "carboxy", or "carboxylate" means -COH, -C(O)O - or its salt.

[0031] "Carboxyl ester" or "carboxy ester" refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, and heterocyclic, including aryl and heteroaryl.

[0032] "Alicyclic" refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl) or multiple rings, such as in a fused, bridged, or spirocyclic system, at least one of which is aliphatic, provided that the point of attachment is through an atom in the aliphatic region of the alicyclic group. Alicyclics include saturated and unsaturated systems including cycloalkyl, cycloalkenyl, and cycloalkynyl. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0033] "Halo," "halide," or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0034] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. An exemplary haloalkyl moiety is CF3.

[0035] "Heterocyclyl" and "heterocycle" refer to aromatic and non-aromatic ring systems, and more specifically to stable 3- to 15-membered ring moieties containing carbon atoms and at least one heteroatom, such as 1-5. Heterocyclyl moieties can be monocyclic moieties or can contain multiple rings, such as in bicyclic or tricyclic ring systems, provided that at least one of the rings contains a heteroatom. Such polycyclic moieties can include fused or bridged ring systems, as well as spirocyclic systems, and the nitrogen, phosphorus, carbon, silicon, or sulfur atoms of the heterocyclyl moiety can be optionally oxidized to various oxidation states. For convenience, nitrogens, specifically, but not limited to, those defined as cyclic aromatic nitrogens, are meant to include their corresponding N-oxide forms, although not expressly defined as such in specific instances. In addition, cyclic nitrogen atoms can be optionally quaternized. Heterocycles include heteroaryl or aromatic heterocyclyl moieties, and non-aromatic heterocyclyl moieties which are partially or fully saturated heterocyclyl rings, such as heterocycloalkyl.

[0036] "Heteroaryl" refers to an aromatic group or moiety of 5 to 15 ring atoms, containing at least one carbon atom and at least one heteroatom, such as N, S, O, P, or Si, unless otherwise specified. A heteroaryl group or moiety can contain a single ring (e.g., pyridinyl, pyrimidinyl, or pyrazolyl) or multiple condensed rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). A heteroaryl group or moiety can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, a heteroaryl group or moiety can be substituted or unsubstituted.

[0037] "Heterocycloalkyl" refers to a stable 3-15 membered non-aromatic ring moiety containing at least one carbon atom, typically multiple carbon atoms, and at least one heteroatom, such as 1-5. The heteroatom(s) may be nitrogen, phosphorus, oxygen, silicon, or sulfur atom(s). A heterocycloalkyl moiety may be a monocyclic moiety or may contain multiple rings, such as a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such polycyclic moieties may include fused or bridged ring systems, as well as spirocyclic systems, and any nitrogen, phosphorus, carbon, silicon, or sulfur atom of the heterocycloalkyl moiety may be optionally oxidized to various oxidation states, unless expressly excluded or excluded by context. For convenience, nitrogen, specifically, but not limited to, those defined as cyclic aromatic nitrogens, are meant to include their corresponding N-oxide forms, although not expressly defined as such in specific instances. In addition, cyclic nitrogen atoms may be optionally quaternized.

[0038] Examples of heterocycloalkyl groups include, but are not limited to, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, pyrrolidinyl, 4-piperidonyl, dihydropyridinyl, tetrahydropyridinyl, morpholinyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuryl, and tetrahydropyranyl.

[0039] A "phosphate" refers to an alkyl group in which each -OR' is independently an -O-aliphatic group such as -OH, -O-alkyl, -O-aryl, or -O-aralkyl; or - M + where M + refers to the group -OP(O)(OR')2, which is a counter ion having a single positive charge, as disclosed herein. For example, each M + is K + , Na + , Li + Alkaline ions such as +N(R")4 (wherein each R" can be independently H, aliphatic, e.g., alkyl, hydroxyalkyl, or combinations thereof), heterocyclyl, or aryl, amino acids such as arginine or lysine, amino sugars such as meglumine, or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The alkyl phosphate can be an alkaline earth ion such as -CH2O-P(O)(OR')2 or -CH2(CH3)OP(O)(OR')2, such as a group-alkyl-phosphate, e.g., -CH2OP(O)(O-isopropyl)2, -CH2OP(O)(OH)(O-tert-butyl), -CH2OP(O)(O-tert-butyl), -CH2OP(O)(OCHOCO2isopropyl)2, -CH2OP(O)(OH), or -CH2OP(O)(O - Na + )2, -CH2OP(O)(O - ) 2Mg 2+ , or -CH2OP(O)(OH)(O - Na + ) and its salts.

[0040] "Phosphoramidates" are groups in which each R' is independently an aliphatic group such as H, alkyl, aryl, or aralkyl, or -OR' is -O - M + where M + refers to the group -OP(O)(OR')(N(R')2), which is a counterion having a single positive charge, as disclosed herein. For example, each M + is K + , Na + , Li + Alkaline ions such as + N(R")4 (wherein each R" can be independently H, aliphatic, e.g., alkyl, hydroxyalkyl, or combinations thereof), heterocyclyl, or aryl, amino acids such as arginine or lysine, amino sugars such as meglumine, or [Ca2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The alkyl phosphoramidate may be an alkaline earth ion such as, for example, -CH2O-P(O)(OR')(N(R'2)) or -CH2(CH3)OP(O)(OR')(N(R'2)), for example, -CH2OP(O)(O-phenyl)[NHC(CH3)CO2isopropyl], or -CH2OP(O)(OH)(N(H)alkyl), or a salt thereof, for example, -CH2OP(O)(O - Na + )(N(H)alkyl).

[0041] "Patient" or "subject" refers to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable to both human therapy and veterinary uses.

[0042] A "pharmaceutical acceptable excipient" refers to a substance, other than an active ingredient, that is included in a formulation of an active ingredient. As used herein, an excipient may be incorporated within or physically mixed with a particle of a pharmaceutical composition. An excipient may be used, for example, to dilute an active agent and / or to modify the properties of a pharmaceutical composition. Excipients may include, but are not limited to, anti-adherents, binders, coatings, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, adsorbents, preservatives, adjuvants, carriers, or vehicles. Excipients may be starches and modified starches, cellulose and cellulose derivatives, sugars and derivatives of sugars such as disaccharides, polysaccharides, and sugar alcohols, proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids, or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxymethylcellulose, dipalmitoyl phosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

[0043] An "adjuvant" is an excipient that modifies the effect of another agent, typically an active ingredient. Adjuvants are often pharmacological and / or immunological agents. Adjuvants can modify the effect of an active ingredient by increasing the immune response. Adjuvants can also act as stabilizers for the formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants such as Freund's complete or incomplete adjuvants.

[0044] "Pharmaceutically acceptable carrier" refers to an excipient that is a carrier or vehicle, such as a suspending aid, a solubilizing aid, or an aerosolizing aid. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21 st Edition (2005), incorporated herein by reference, describes exemplary compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0045] Generally, the nature of the carrier will depend on the particular mode of administration used. For example, parenteral formulations usually contain an injectable fluid, which contains pharma- ceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol, etc., as a vehicle. In some instances, the pharma-ceutically acceptable carrier can be sterilized so as to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, for example, sodium acetate or sorbitan monolaurate.

[0046] "Pharmaceutically acceptable salts" refers to pharma-ceutically acceptable salts of a compound derived from a variety of organic and inorganic counterions, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, where the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc., as would be known to one of ordinary skill in the art. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed with acid partners while retaining the biological effectiveness of the free base. In particular, the disclosed compounds form salts with a variety of pharma- ceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, adipic acid, aspartic acid, trifluoroacetic acid, propionic acid, gentisic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, and the like. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts.Salts derived from pharma-ceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference.) In particularly disclosed embodiments, the pyrazole compound may be a formate or sodium salt.

[0047] An "effective amount" with respect to a compound or composition refers to an amount of the compound or composition sufficient to achieve a particular desired result, for example, to inhibit a protein or enzyme, particularly interleukin-1 receptor-associated kinase, to elicit a desired biological or medical response in a tissue, system, subject, or patient, to treat or prevent a named disorder or disease, to ameliorate or eradicate one or more of its symptoms, and / or to prevent the occurrence of a disease or disorder. The amount of compound that constitutes an "effective amount" will vary depending on the compound, the desired result, the condition and its severity, the age of the patient being treated, and the like.

[0048] "Solvate" refers to a complex formed by the combination of a solvent molecule with a molecule or ion of a solute. The solvent may be an organic solvent, an inorganic solvent, or a mixture of both. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, propanol, amides such as N,N-dialiphatic amides such as N,N-dimethylformamide, alkyl sulfoxides such as tetrahydrofuran, dimethyl sulfoxide, water, and combinations thereof. The compounds described herein may exist in unsolvated as well as solvated forms when combined with pharma- ceutically acceptable or non-acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds of the present disclosure are within the scope of the embodiments disclosed herein.

[0049] As used herein, "treating" or "treatment" refers to the treatment of a disease or condition of interest in a patient or subject, particularly a human having the disease or condition of interest, including, for example, (i) inhibiting a disease or condition, e.g., preventing or delaying its onset; (ii) alleviating the disease or condition, e.g., causing regression of the disease or condition or its symptoms; or (iii) stabilizing a disease or condition, including, but not limited to,

[0050] "Preventing" as used herein specifically relates to preventing a disease or condition from occurring in a patient or subject where such patient or subject is susceptible to the condition but has not yet been diagnosed as having the disease or condition.

[0051] As used herein, the terms "disease," "disorder," and "condition" may be used interchangeably or may differ in that a particular illness or condition may not have a known causative agent (and thus the etiology has not yet been determined) and thus is not yet recognized as a disease, but only as an undesirable state or syndrome in which a more or less specific set of symptoms has been identified by clinicians.

[0052] The above definitions and the general formula below are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups) that would be readily recognized by one of ordinary skill in the art.

[0053] Any of the groups mentioned herein may be substituted with at least one, and optionally two or more, substituents, as defined herein, i.e., a substituent has at least one, and optionally two or more, replaceable hydrogens, replaced by one or more substituents, as defined herein, unless the context indicates otherwise or a particular structural formula precludes substitution.

[0054] Those skilled in the art will understand that compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may contain one or more chiral centers and / or double bonds, and may therefore exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. As various compound names, formulae, and compound diagrams within the specification and claims may represent only one of the possible tautomeric, conformational, optical, or geometric isomeric forms, it will be understood that the disclosed compounds encompass any tautomeric, conformational, optical, and / or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. In cases of restricted rotation, for example around an amide bond or between two directly bonded rings such as pyrazole and pyridinyl rings, atropisomers are possible and are also specifically included in the compounds of the present disclosure.

[0055] Certain examples of compounds of the present disclosure include one or more asymmetric centers. Thus, these compounds can exist in different stereoisomeric forms. Thus, compounds and compositions can be provided as individual pure enantiomers or diastereomers, or as stereoisomeric mixtures, including racemic mixtures. In certain embodiments, compounds disclosed herein are synthesized or purified to be in substantially enantiomerically pure form, such as at least 90% enantiomeric excess, 95% enantiomeric excess, 97% enantiomeric excess, 98% enantiomeric excess, 99% enantiomeric excess, 99.5% enantiomeric excess, or more than 99.5% enantiomeric excess.

[0056] In any embodiment, any or all hydrogens present in a compound, or in a particular group or moiety within a compound, can be replaced with deuterium or tritium. Thus, the recitation of alkyl includes deuterated alkyls, where one to a maximum number of hydrogens present can be replaced with deuterium. For example, ethyl can be C2H5, or C2H5 where one to five hydrogens are replaced with deuterium.

[0057] II. Compounds Disclosed herein are compounds, methods of making the compounds, and methods of using the compounds. In one embodiment, the disclosed compounds are kinase inhibitors, particularly tyrosine kinase inhibitors. In certain embodiments, the compounds are useful for blocking one or more cytokine signaling pathways, such as the IL-17 signaling pathway. In certain embodiments, the disclosed compounds are useful for treating conditions in which inhibition of the interleukin-1 receptor associated kinase (IRAK) pathway is therapeutically useful. In some embodiments, the compounds directly inhibit IRAK proteins, such as IRAK1, IRAK2, IRAK3, and / or IRAK4.

[0058] Exemplary compounds within the scope of the present disclosure have the general formula I TIFF2025513716000004.tif64165, or a pharma- ceutically acceptable salt or solvate thereof.

[0059] With respect to formula I, R 1 is H, aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkyl phosphoramidate, or alkyl phosphate. 1 is not H or alternatively, R 1 is hydrogen. 1 When R is hydrogen, the compound may be in the form of a free base or a salt. 1 is alkyl, acyl, carboxyl ester, amide, non-aromatic heterocyclyl, alkyl phosphoramidate, or alkyl phosphate. 1 When a compound in which R is not H is administered to a subject, for example, 1 It is understood that prodrugs of compounds where is H may be effected.

[0060] R 2 is C 1-4 C such as alkyl 1-6 It is an alkyl.

[0061] In some embodiments, R 2 is ethyl.

[0062] In some embodiments, R 1 , H, C 1-4 Alkyl phosphate, C 1-4 Alkyl phosphoramidate, C 1-6 Alkyl, C 1-6 Acyl, -C(O)OC 1-6 Aliphatic, -C(O)N(R b ) 2, or 5- or 6-membered non-aromatic heterocyclyl, but in certain embodiments, R 1 is not H or R 1 is H and the compound is a salt.

[0063] R 1 Regarding the part, C 1-6 The alkyl portion can be unsubstituted or can be a 5- or 6-membered non-aromatic heterocyclyl, OH, -OC(O)-R a , -N(R b )2, -OC(O)-R c , carboxyl, or combinations thereof, C 1-6 The acyl moiety can be unsubstituted or -C(O)OC 1-4 Alkyl, -C(O)OC 1-4 Alkyl-N(R b )2, N(R b )2, -NHC(O)C 1-4 alkyl, or combinations thereof; The 5- or 6-membered heterocyclyl moiety may be a 5- or 6-membered oxygen-containing heterocyclyl and / or may be substituted with hydroxyl, hydroxymethyl, or combinations thereof, or -C(O)OC 1-6 Aliphatic is -OC(O)C 1-4 Alkyl or N(R b )2 may be substituted with -C(O)OC 1-6 It may be alkyl or -C(O)OC 1-6 Aliphatic is C 1-4 -C(O)OC optionally substituted with alkyl 3-6 It may be cycloalkyl.

[0064] In any embodiment, each R a are independently 5-membered nonaromatic heterocyclyl, -CHN(R b ) 2-substituted aryl, carboxyl-substituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, unsubstituted C 1-6 Alkyl or one or more, e.g., one, two, or three, N(R b )2, Carboxyl, Carboxyl ester, -OC 1-6 Acyl, -NHC(O)(NH2)C 1-6Alkyl, or -(OCH2CH2) 1-8 N(R b )2 replaced by C 1-6 is alkyl, Each R b are independently H, unsubstituted C 1-6 Alkyl, -N(R g )2 replaced by C 1-6 alkyl, carboxyl ester, or 5- or 6-membered non-aromatic heterocyclyl, or two R b together with the nitrogen to which they are attached, one or two -O- or -N(R g ) optionally interrupted by 3-6 forming a non-aromatic heterocyclyl moiety, R g But H or C 1-4 is alkyl, -OC(O)-R c is derived from an amino acid, -OC(O)-R c The -OC(O)- portion of R corresponds to the acid moiety on the amino acid. c But -N(R b )2 or nitrogen-containing non-aromatic heterocyclyl, e.g., 5- or 6-membered unsaturated nitrogen-containing heterocyclyl, e.g., pyrrolidinyl. The amino acid may be any amino acid, such as a naturally occurring amino acid, selected from glycine, valine, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine, or proline. One of skill in the art will appreciate that when an amino acid contains one or more chiral centers, all enantiomers, diastereomers, and / or mixtures thereof are contemplated. For example, the amino acid may be an L-amino acid, a D-amino acid, or a mixture thereof. In some embodiments, the amino acid is an L-amino acid. Also, in certain embodiments, -OC(O)-R c is -OC(O)CH(NH2)R d , TIFF2025513716000005.tif27165, or -OC(O)-(CH2) 1-2 C(NH2)CO2H, where R d is an amino acid side chain, and / or H, -CH3, isopropyl, -CH2CH(CH3)2, -CH(CH3)Et, -CH2CH2SCH3, TIFF2025513716000006.tif32165, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(O)(NH)NH2, TIFF2025513716000007.tif22165, -CH2CH2CH2CH2NH2, -CH2CO2H, or CH2CH2CO2H.

[0065] In some embodiments, R 1 is H, alkyl, or -alkylOP(O)(OR), where each OR is independently -OH, -Oalkyl, -Oaryl, -Oheteroaryl, -Oaralkyl, or -O - M + where M + is a counterion with a single positive charge. Each OR is independently -OH, -O(C 1-6 alkyl), -OC6 aryl, -O(3-15 membered heteroaryl), -OC7 aralkyl, or -O - M + In some embodiments, the two OR moieties are different, while in other embodiments, the two OR moieties are the same.

[0066] In some embodiments, R 1 , H, C 1-6 Alkyl, or H, C 1-6 Alkyl, -C such as -CH2OP(O)(OR)2 1-4 alkylOP(O)(OR)2, or -CH(CH3)OP(O)(OR)2, and in certain embodiments, R 1 , H, C 1-6alkyl, or -CH2OP(O)(OR)2.

[0067] In certain embodiments, the compound has a structure according to Formula II, or a pharma- ceutically acceptable salt or solvate thereof. TIFF2025513716000008.tif64165 Regarding Equation II, R 1 is as previously defined with respect to formula I.

[0068] In some embodiments of Formulas I and II, R 1 is H.

[0069] In other embodiments of Formulas I and II, R 1 is C 1-6 Alkyl or C 1-4 It is alkyl, such as alkyl, which may be methyl or ethyl.

[0070] In some other embodiments of Formulas I and II, R 1 -C 1-4 It is -alkylOP(O)(OR)2, such as alkylOP(O)(OR)2, which can be -CH2OP(O)(OR)2, or -CH(CH3)OP(O)(OR)2.

[0071] In some embodiments, R 1 is -CHOP(O)(OR). In one embodiment, R 1 is -CHOP(O)(OH). In another embodiment, R 1 is -CH2OP(O)(OH)(O - M + In another embodiment, R 1 is -CH2OP(O)(O - M + )2, -CH2OP(O)(O - Na + ) 2. In another embodiment, R 2 is -CH2OP(O)(OC 1-6 alkyl)2.

[0072] In some embodiments of Formulas I and II, R 1 is -CH(CH3)OP(O)(OR). In one embodiment, R 1 is -CH(CH3)OP(O)(OH). In another embodiment, R 1 is -CH(CH3)OP(O)(OH)(O - M + In another embodiment, R 1 is -CH(CH3)OP(O)(O - M + )2, -CH(CH3)OP(O)(O - Na + ) 2. In another embodiment, R 2 is -CH(CH3)OP(O)(OC 1-6 alkyl)2.

[0073] In one embodiment disclosed herein, the compound comprises an IRAK inhibitory moiety and a means for releasing or delivering the IRAK inhibitory moiety in vivo. 1 In some embodiments, where R is not H, 1 includes a means for delivering an IRAK inhibitor, such as compound I-1, disclosed herein. Exemplary embodiments of formulas I and II that include such a means will be readily apparent to one of skill in the art in view of the formulas and examples disclosed herein. By way of example, embodiments of formulas I and II that include a means for delivering an IRAK inhibitor moiety include, but are not limited to, compounds I-2, I-3, I-6, I-7, and I-8.

[0074] In any embodiment, the compound may be in free base form or may be a salt. In some embodiments, the salt is an acid addition salt, such as, but not limited to, an acid addition salt as defined herein. In certain embodiments, the compound is a tartrate salt.

[0075] In another embodiment, the compound is in the form of a base addition salt, such as, but not limited to, a base addition salt as defined herein, in some embodiments, the compound is a sodium salt, e.g., a disodium salt, or a tris salt.

[0076] Exemplary compounds according to Formula I include, but are not limited to, the following: TIFF2025513716000009.tif171165

[0077] Some exemplary compounds according to Formula 1 include: I-1: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, I-2: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, I-3: sodium (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, I-4: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide tartrate, I-5: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium (tris salt), I-6: 1-(4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate, I-7: sodium 1-(4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate, or I-8: 1-(4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl hydrogen phosphate 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium (tris salt).

[0078] In some embodiments, the compound according to any one of formulas I and II, or a salt thereof, has at least one improved property compared to other IRAK inhibitors. The one or more improved properties may include, but are not limited to, physical properties, including but not limited to melting point, glass transition temperature, flowability, and / or stability, such as, for example, thermal stability, mechanical stability, shelf life, stability against polymorphic transitions, etc.; chemical properties, including but not limited to, hygroscopic properties, solubility in water and / or organic solvents, reactivity, compatibility with excipients and / or delivery vehicles, etc.; and / or pharmacokinetic properties, including but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity, including cytotoxicity, dissolution rate, selectivity, such as selectivity for one IRAK protein over different IRAK proteins, activities, and / or half-lives.

[0079] III.Synthesis The disclosed pyrazole compounds can be prepared as illustrated below and as would be understood by one skilled in the art of organic synthesis. An exemplary synthesis can include the following first reaction step according to Scheme 1: TIFF2025513716000010.tif53165

[0080] The acetyl compound 2 is reacted with dimethylformamide dimethylacetal 4 to form intermediate compound 6 at a suitable temperature to facilitate the reaction. Suitable temperatures are typically between 85° C. and 130° C. Intermediate compound 6 is then reacted with hydrazine hydrate 8 to form pyrazole compound 10. The reaction is carried out in a suitable solvent, for example an alcohol such as ethanol, methanol, or isopropanol, and is typically heated to reflux.

[0081] The second reaction step in an exemplary synthesis is provided below according to Scheme 2. TIFF2025513716000011.tif53165

[0082] Compound 10 is nitrated using a suitable nitration reagent or mixture of reagents 12 to form compound 14. Suitable nitration conditions include reacting compound 10 with nitric acid, such as fuming nitric acid, optionally in the presence of sulfuric acid. Typically, compound 10 and nitric acid are added slowly, one to the other. Cooling, such as with an ice bath, may be used to maintain the reaction temperature within a suitable range, such as about 0° C. to less than 50° C., 0° C. to 20° C., or 0° C. to 10° C. After the addition is complete, the reaction may be allowed to proceed until it is substantially complete, and may be allowed to warm to room temperature to facilitate the reaction. Optionally, additional nitration reagent, or mixture of nitration reagents, may be added to facilitate the reaction proceeding to completion. The reaction is then quenched, such as by addition to water and / or ice, and the product is separated or extracted from the aqueous and purified as necessary. Suitable purification techniques for purifying the product from any reaction disclosed herein include, but are not limited to, crystallization, distillation, and / or chromatography.

[0083] Continuing with Scheme 2, compound 14 is reacted with compound 16 to form compound 18. Compound 16 can be used to obtain the desired R 1 The moiety and a suitable leaving group, LG, are also suitable for the coupling of R 1 The leaving group may be any group that acts as a leaving group to facilitate the addition of a moiety. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodo, as well as tosylate or mesylate bases. Compound 14 is reacted with compound 16 in a suitable solvent and typically in the presence of a base. Suitable solvents include any solvent that facilitates the reaction, such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that will facilitate the reaction of a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction may be heated to 50° C., 100° C. or higher, etc., as needed, or the reaction may proceed at room temperature. Compound 18 is then isolated from the reaction mixture and purified as needed.

[0084] Compound 18 is then reacted with a suitable reducing agent 20 to reduce the nitro moiety to an amine. Suitable reducing agents include, but are not limited to, hydrogen gas in the presence of a catalyst such as a palladium catalyst, borohydride such as sodium borohydride, optionally in the presence of a catalyst such as a nickel catalyst, metallic zinc in acetic acid, or iron powder in water or water and acid. In certain embodiments, hydrogen gas is used in the presence of palladium on a carbon catalyst and in a suitable solvent such as ethyl acetate or methanol. In some embodiments, a combination of reducing agents and / or techniques is used. For example, the reduction may be first carried out using a first method involving a first reducing agent and / or technique, but results in a mixture of products. The first method may be repeated and / or a second method involving a second reducing agent and / or technique may be carried out. Once the reaction is complete, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product compound 22 is isolated and purified as necessary.

[0085] The third step of an exemplary reaction sequence is provided below according to Scheme 3. TIFF2025513716000012.tif48165

[0086] Compound 22 is reacted with carboxylic acid 24 to form compound 26. Carboxylic acid 24 is activated by any suitable method and then reacted with the amine on compound 22. Suitable activation methods include, but are not limited to, formation of an acid chloride by treatment with thionyl chloride, by treatment with a base such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and diisopropylethylamine (DIPEA), by treatment with carbonyldiimidazole (CDI), or by treatment with a carbodiimide such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0087] Compound 26 is then coupled with compound 28 to form compound 30 using any suitable coupling reaction to form a bond between the two rings. In the above example, boronic acid coupling is shown, and the leaving group LG on compound 26 is typically bromo or iodo. Other suitable coupling functional groups include trialkyltin or boronic acid esters. The coupling reaction typically proceeds in the presence of a suitable catalyst. For boronic acid coupling, the catalyst is typically a palladium catalyst such as PdCl2(dppf)2, Pd[P(Ph)3]2Cl2, palladium acetate, and triphenylphosphine, or tetrakis(triphenylphosphine)palladium(0). The reaction is carried out in the presence of a base such as sodium, potassium, or cesium carbonate, and in a suitable solvent or solvent mixture such as dioxane, dioxane / water, or DME / ethanol / water. The reaction can be heated at a suitable temperature, for example, between 50° C. and 125° C., typically about 100° C., and / or stirred for a suitable period of time, for example, between 1 hour and 3 days, 6 hours to 24 hours, or 12 hours to 18 hours, to facilitate the reaction proceeding to completion. Compound 30 is then isolated from the reaction mixture and purified by a suitable technique.

[0088] An alternative exemplary synthesis may comprise the following first reaction step according to Scheme 4: TIFF2025513716000013.tif48165

[0089] Compound 32 is nitrated using a suitable nitration reagent or mixture of reagents 34 to form compound 36. Suitable nitration conditions include reacting compound 32 with nitric acid, such as fuming nitric acid, optionally in the presence of sulfuric acid. Typically, compound 32 and nitric acid are added slowly, one to the other. Cooling, such as with an ice bath, may be used to maintain the reaction temperature within a suitable range, such as about 0° C. to less than 50° C., 0° C. to 20° C., or 0° C. to 10° C. After the addition is complete, the reaction may be allowed to proceed until it is substantially complete, and may be allowed to warm to room temperature to facilitate the reaction. Optionally, additional nitration reagent, or mixture of nitration reagents, may be added to facilitate the reaction proceeding to completion. The reaction is then quenched, such as by addition to water and / or ice, and the product is separated or extracted from the aqueous and purified as necessary. Suitable purification techniques for purifying the product from any reaction disclosed herein include, but are not limited to, crystallization, distillation, and / or chromatography.

[0090] Continuing with Scheme 4, compound 36 is reacted with compound 38 to form compound 40. Compound 38 contains a desired ring, such as a cyclobutyl, cyclopentyl, or cyclohexyl ring, and a suitable leaving group LG. Suitable leaving groups include any group that serves as a leaving group to facilitate the addition of a ring to compound 36. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodine, as well as tosylate or mesylate bases. Compound 36 is reacted with compound 38 in a suitable solvent and typically in the presence of a base. Suitable solvents include any solvent that facilitates the reaction, such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that will facilitate the reaction of a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be optionally heated to 50° C., 100° C. or higher, etc., or the reaction can proceed at room temperature. Compound 40 is then isolated from the reaction mixture and optionally purified.

[0091] Compound 40 is then reacted with a suitable reducing agent 42 to reduce the carbonyl moiety to a hydroxyl. Suitable reducing agents include, but are not limited to, sodium borohydride, diisobutylaluminum hydride, or lithium aluminum hydride. The reaction is carried out in a suitable solvent to facilitate the reaction, such as an alcohol, particularly methanol or ethanol, THF, or diethyl ether. The reaction can be optionally heated, such as to 50° C., 100° C. or higher, or cooled to less than 20° C., less than 10° C., less than 0° C., or the reaction can proceed at room temperature. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product compound 44 is optionally isolated and purified by a suitable technique, such as column chromatography.

[0092] Optionally, compound 44 can be reacted with compound 46 to form compound 48. Compound 46 can be reacted with compound 46 to form compound 48. x The moiety and a suitable leaving group, LG, are included. Suitable leaving groups include R x The leaving group may be any group that serves as a leaving group to facilitate the addition of a moiety. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodo, as well as tosylate or mesylate bases. Compound 44 is reacted with compound 46 in a suitable solvent and typically in the presence of a base or other reagent(s) that facilitates the reaction. Suitable solvents include any solvent that facilitates the reaction, such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases or reagents that facilitate the reaction include, but are not limited to, silver triflate, 2,6-di-t-butylpyridine, sodium hydride, or combinations thereof. Typically, compound 46 is combined slowly with the reactants. Cooling, such as with an ice bath, may be used to maintain the reaction temperature within a suitable range, such as about 0° C. to less than 50° C., 0° C. to 20° C., or 0° C. to 10° C. After the addition is complete, the reaction can be allowed to proceed until substantially complete or can be allowed to warm to room temperature or can be heated, for example to 50° C., 100° C. or higher, to facilitate the reaction. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC or HPLC, the product compound 48 is isolated and purified, if necessary, by a suitable technique, such as column chromatography.

[0093] Alternatively, compound 40 can be prepared by the exemplary synthetic route according to Scheme 5. TIFF2025513716000014.tif59165

[0094] With reference to scheme 5, compound 36 is reacted with compound 50 to form compound 52. Compound 50 includes a desired ring, such as a cyclobutyl, cyclopentyl, or cyclohexyl ring, a suitable leaving group, LG, and a protected carbonyl moiety, such as an acetal or ketal. In the above example, a cyclic ketal moiety is shown. Suitable leaving groups include any group that serves as a leaving group to facilitate the addition of a ring to compound 36, including, but not limited to, halogens, typically bromo, chloro, or iodo, as well as tosylate or mesylate groups. Compound 36 is reacted with compound 50 in a suitable solvent, and typically in the presence of a base. Suitable solvents include any solvent that facilitates the reaction, such as an aprotic solvent. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that will promote the reaction of a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be heated, if desired, to 50° C., 100° C. or higher, etc., or the reaction can proceed at room temperature. Compound 52 is then isolated from the reaction mixture and purified, if desired, by a suitable technique, such as column chromatography.

[0095] Compound 52 is then reacted with a suitable reagent 54 to form compound 40. Reagent 54 can be any suitable reagent for removing a protecting group and / or forming a carbonyl moiety. In the exemplary synthesis shown in Scheme 5, the protecting group is a cyclic ketal and suitable reagents 54 include, but are not limited to, pyridinium tosylate (PPTS), para-toluenesulfonic acid, hydrochloric acid, or acetic acid. The reaction is carried out in a suitable solvent or mixture of solvents to facilitate the reaction, such as acetone, THF, acetic acid, water, or combinations thereof. The reaction can be heated, for example, to 50° C., 100° C. or higher, or at reflux, as appropriate, or the reaction can proceed at room temperature. Compound 40 is then isolated from the reaction mixture and purified as appropriate by a suitable technique, such as column chromatography.

[0096] The second step of an exemplary reaction sequence is provided below according to Scheme 6. TIFF2025513716000015.tif59165

[0097] Compound 48 is then reacted with a reducing agent 56 suitable for reducing the nitro moiety to an amine. In certain embodiments where the desired product compound contains a hydroxyl moiety, compound 44 may be used in place of compound 48. Suitable reducing agents include, but are not limited to, hydrogen gas in the presence of a catalyst such as a palladium catalyst, borohydride such as sodium borohydride, optionally in the presence of a catalyst such as a nickel catalyst, zinc metal in acetic acid, or iron powder in water or water and acid. In certain embodiments, hydrogen gas is used in the presence of palladium on a carbon catalyst and in a suitable solvent such as ethyl acetate or methanol. In some embodiments, a combination of reducing agents and / or techniques is used. For example, the reduction may be first carried out using a first method involving a first reducing agent and / or technique, but results in a mixture of products. The first method may be repeated and / or a second method involving a second reducing agent and / or technique may be carried out. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product compound 58 is isolated and purified as necessary.

[0098] Compound 58 is reacted with carboxylic acid 60 to form compound 62. Carboxylic acid 60 is activated by any suitable method and then reacted with the amine on compound 58. Suitable activation methods include, but are not limited to, formation of an acid chloride by treatment with thionyl chloride, by treatment with a base such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and diisopropylethylamine (DIPEA), by treatment with carbonyldiimidazole (CDI), or by treatment with a carbodiimide such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0099] Compound 62 is then coupled with compound 64 to form compound 66 using any suitable coupling reaction to form a bond between the two rings. In the above example, boronic acid coupling is shown, and the leaving group LG on compound 62 is typically bromo or iodo. Other suitable coupling functional groups include trialkyltin or boronic acid. The coupling reaction typically proceeds in the presence of a suitable catalyst. For boronic ester or boronic acid coupling, the catalyst is typically a palladium catalyst such as PdCl2(dppf)2, Pd[P(Ph)3]2Cl2, palladium acetate, and triphenylphosphine, or tetrakis(triphenylphosphine)palladium(0). The reaction is carried out in the presence of a base such as sodium, potassium, or cesium carbonate, and in a suitable solvent or solvent mixture such as dioxane, dioxane / water, or DME / ethanol / water. The reaction can be heated at a suitable temperature, for example, 50° C. to 125° C., typically about 100° C., and / or stirred for a suitable period of time, for example, 1 hour to 3 days, 6 hours to 24 hours, or 12 hours to 18 hours, to facilitate the reaction proceeding to completion. Compound 66 is then isolated from the reaction mixture and purified by a suitable technique.

[0100] Certain embodiments may include a phosphate moiety. Scheme 7 provides an exemplary synthesis of certain such embodiments. TIFF2025513716000016.tif89165

[0101] Compound 68 is reacted with compound 70 to form compound 72. Compound 70 can be used to obtain the desired R y Exemplary R moieties include the aryl group and a suitable leaving group, LG. y The moieties include, but are not limited to, alkyl, aliphatic, typically methyl, ethyl, propyl, isopropyl, or t-butyl, aryl, heteroaliphatic, or heterocyclic. yThe moieties can be the same or different. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodo, as well as tosylate or mesylate bases. Compound 68 is reacted with compound 70 in a suitable solvent and typically in the presence of a base. Suitable solvents include any solvent that will facilitate the reaction, such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that will facilitate the reaction of a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be heated, as needed, to 50° C., 100° C. or higher, or the reaction can proceed at room temperature. Compound 72 is then isolated from the reaction mixture and purified as needed.

[0102] Compound 72 is then reacted with compound 74 to form compound 76. Compound 74 can be any compound suitable for forming the acid moiety in compound 76. Compound 74 can be an acidic reagent such as trifluoroacetic acid, hydrochloric acid, or hydrobromic acid, or it can be a basic reagent such as sodium hydroxide, lithium hydroxide, or potassium hydroxide. Suitable solvents include, but are not limited to, chlorinated solvents such as dichloromethane and chloroform, alcohols such as methanol and ethanol, water, or combinations thereof. The reaction can be heated as needed, such as to 50° C., 100° C. or higher, or cooled to less than 20° C., less than 10° C., less than 0° C., or the reaction can proceed at room temperature. Once the reaction is complete, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product compound 76 is isolated and purified as needed by suitable techniques, such as by agitation, such as by stirring or sonication, in a suitable solvent or solvent system. Suitable solvents or solvent systems include, but are not limited to, acetone / water, acetone, diethyl ether, or alcohol / water.

[0103] Compound 76 is then reacted with compound 78 to form salt compound 80. Compound 78 can be any compound that provides a suitable counterion CA for salt compound 80, such as calcium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, trimethylamine, tris(hydroxymethyl)aminomethane, or an amino acid such as lysine or arginine. One of skill in the art will appreciate that the counterion CA may be Na + , K + , Li + , or NH4 + When compound 80 contains two CA ions and the counter ion CA is 2+ It will be understood that when compound 80 has two positive charges, such as in, compound 80 contains one CA ion.

[0104] IV. Therapeutic Combinations The compounds of the present disclosure may be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single composition, or as an adjunct to or in combination with other established therapies. The compounds may be administered once or multiple times. In another aspect, the compounds of the present disclosure may be used in combination with other therapeutic agents useful for the disorder or condition being treated. These compounds and / or agents may be administered simultaneously, sequentially in any order, by the same route of administration or by different routes. In sequential administration, the compound(s) and / or agent(s) may be administered such that the effective period of at least one compound and / or agent overlaps with the effective period of at least one other compound and / or agent. In an exemplary embodiment of a combination comprising four components, the effective period of the first component administered may overlap with the effective periods of the second, third, and fourth components, but the effective periods of the second, third, and fourth components may or may not overlap with each other independently. In another exemplary embodiment of a combination comprising four components, the effective period of the first component administered overlaps with the effective period of the second component but not with the third or fourth components, the effective period of the second component overlaps with the effective periods of the first and third components, and the effective period of the fourth component overlaps only with the effective period of the third component. In some embodiments, the effective periods of all of the compounds and / or agents overlap with each other.

[0105] In some embodiments, the disclosed compounds are administered with another therapeutic agent, such as an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof. In certain embodiments, the second therapeutic agent can be an anti-inflammatory agent, an immunosuppressant, and / or a steroid.

[0106] The anti-inflammatory agent may be a steroid or a non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylate, cyclooxygenase inhibitor, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immune inhibitor is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0107] In some embodiments, the compounds may be used with anti-cancer or cytotoxic agents.Various classes of anti-cancer and anti-neoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, multiple hormones and hormone antagonists, and hypomethylating agents, e.g., DNMT inhibitors such as azacitidine and decitabine.Exemplary alkylating agents include, but are not limited to, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimine, methylmelamine, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, by way of example and not limitation, the folic acid analog methotrexate; pyrimidine analogs fluorouracil, cytosine albinoside; purine analogs mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkyloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. Exemplary enzymes effective as antineoplastic agents include L-asparaginase. Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and not limitation, the adrenal corticosteroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

[0108] These and other useful anti-cancer compounds are described in the Merck Index, 13th Ed. (O'Neil MJ et al., ed.) Merck Publishing Group (2001), and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0109] Among the CTLA4 antibodies that may be used in combination with the inhibitors of the present disclosure is ipilimumab, available commercially as YERVOY® by Bristol-Myers Squibb.

[0110] Other chemotherapeutic agents for combination include tumor immunotherapy agents such as checkpoint pathway inhibitors, e.g., PD-1 inhibitors such as nivolumab and lambrolizumab, and PD-L1 inhibitors such as pembrolizumab, MEDI-4736, and MPDL3280A / RG7446. Additional checkpoint inhibitors for combination with the compounds disclosed herein include anti-LAG-3 agents such as BMS-986016 (MDX-1408).

[0111] Additional chemotherapeutic agents for combination with the inhibitors of the present disclosure include anti-SLAMF7 agents, such as the humanized monoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such as the anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137 agents, such as the fully human monoclonal antibody urelumab (BMS-663513).

[0112] Additional anti-proliferative compounds useful in combination with the compounds of the present disclosure include, by way of example and not limitation, antibodies against growth factor receptors (e.g., anti-Her2); cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

[0113] Additional chemotherapeutic agents useful in combination with the present compounds include proteasome inhibitors, such as bortezomib, carfilzomib, and marizomib.

[0114] Examples of kinase inhibitors that are useful in combination with the compounds of the present disclosure, particularly in the treatment of malignant tumors, include Btk inhibitors such as ibrutinib; CDK inhibitors such as palbociclib; EGFR inhibitors such as afatinib, erlotinib, gefitinib, lapatinib, osimertinib, and vandetinib; Mek inhibitors such as trametinib; Raf inhibitors such as dabrafenib, sorafenib, and vemurafenib; VEGFR inhibitors such as axitinib, lenvatinib, nintedanib, and pazopanib; BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib, and nilotinib; Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib.

[0115] In other embodiments, the second therapeutic agent may be selected from any of the following: Analgesics-morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone; Antibiotics - aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, cef tazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefoviprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancitin), lincosamides (e.g., clindamycin and incomysin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), monobactams (e.g., azoxymethylene ... threonam), nitrofurans (e.g., furazolidone and nitrofurantoin), penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), penicillin combinations (e.g., amoxicillin / clavulanate, ampicillin / sulfactam, piperacillin / tazobactam, and ticarcillin / clavulanate), Polypeptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfonamide chrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole,sulfanilimides, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamine, amide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinuplicin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and timidazole; Antibodies - anti-TNF-α antibodies, e.g., infliximab (Remicade™), adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g., rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1 antibodies, e.g., anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, e.g., nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fretikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab; Anticoagulants--warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin; Anti-inflammatory agents - steroids such as budesonide, non-steroidal anti-inflammatory agents such as aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin; Immunosuppressants - agents designed to inhibit cellular immunity while leaving the recipient's humoral immune response intact, including corticosteroids such as mercaptopurine, dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisone; alkylating agents such as cyclophosphamide; calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus; inhibitors of inosine monophosphate dehydrogenase (IMPDH) such as mycophenolic acid, mycophenolate mofetil, and azathioprine; and various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3)), as well as radiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the trade name Imuran; antibodies are currently available from Ortho It is available from Biotech under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab), and from Roche under the trade name Zenapax (daclizumab); Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, are sold under the name Linzess.

[0116] In certain embodiments, the second therapeutic agent is or includes a steroid, such as a corticosteroid, including, but not limited to, a glucocorticoid and / or a mineralocorticoid. Steroids suitable for use in combination with the disclosed compounds include synthetic and non-synthetic glucocorticoids. Exemplary steroids, such as glucocorticoids, suitable for use in the disclosed methods include, but are not limited to, alclomethasone, algestone, beclomethasone (e.g., beclomethasone dipropionate), betamethasone (e.g., betamethasone 17-valerate, betamethasone sodium acetate, betamethasone sodium phosphate, betamethasone valerate), budesonide, clobetasol (e.g., clobetasol propionate), clobetasone, clocortolone (e.g., clocortolone pivalate), cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone (e.g., dexamethasone 21-phosphate, dexamethasone acetate, dexamethasone sodium phosphate), diflorasone (e.g., diflorasone diacetate), diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flu Drocortisone (e.g., fludrocortisone acetate), flumethasone (e.g., flumethasone pivalate), flunisolide, fluocinolone (e.g., fluocinolone acetonide), fluocinonide, fluocortin, fluocortolone, fluorometholone (e.g., fluorometholone acetate), fluperolone (e.g., fluperolone acetate), fluprednidene, fluprednisolone, flurandrenolide, fluticasone (e.g., fluticasone propionate), formocol Tar, halcinonide, halobetasol, halometasone, halopredone, hydrocortamate, hydrocortisone (e.g., hydrocortisone 21-butyrate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone hemisuccinate, hydrocortisone probutate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate,hydrocortisone valerate), loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone (methylprednisolone aceponate, methylprednisolone acetate, methylprednisolone hemisuccinate, methylprednisolone sodium succinate), mometasone (e.g., mometasone furoate), paramethasone (e.g., paramethasone acetate), prednicarb, prednisolone (e.g., prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisolone 21-hemisuccinate, prednisolone acetate; prednisolone farnesylate prednisolone hemisuccinate, prednisolone-21 (beta-D-glucuronide), prednisolone metasulfobenzoate, prednisolone stearate, prednisolone tebutate, prednisolone tetrahydrophthalate), prednisone, prednibar, prednylidene, rimexolone, tixocortol, triamcinolone (e.g., triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, triamcinolone acetonide 21-palmitate, triamcinolone diacetate), or any combination thereof. Further information regarding steroids and their salts can be found, for example, in Remington's Pharmaceutical Sciences, A. Osol, ed., Mack Pub. Co., Easton, Pa. (16th ed. 1980).

[0117] In some examples, the steroid is a glucocorticoid and may be selected from cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or a combination thereof. In a particular example, the steroid is or includes prednisone. In another particular example, the steroid is or includes dexamethasone.

[0118] These various agents may be used according to standard or customary dosages as specified in the prescribing information accompanying the commercially available drug form (see also the formulation information in the 2006 Edition of The Physician's Desk Reference), the disclosures of which are incorporated herein by reference.

[0119] V. Compositions Containing the Disclosed Compounds The disclosed compounds may be used alone, in any combination, and in combination with or adjunctive to at least one second therapeutic agent. Furthermore, one or more of the disclosed compounds and / or at least one second therapeutic agent may be used in combination with any suitable excipient useful for forming a composition for administration to a subject. Excipients may be included in pharmaceutical compositions for a variety of purposes, such as diluting the composition for delivery to a subject, facilitating processing of the formulation, providing advantageous material properties to the formulation, promoting dispersion from a delivery device, stabilizing the formulation (e.g., antioxidants or buffers), providing a pleasant or palatable taste or consistency to the formulation. The pharmaceutically acceptable excipient(s) may include pharmaceutically acceptable carrier(s) and / or pharmaceutically acceptable adjuvant(s).Exemplary excipients include mono-, di-, and polysaccharides, sugar alcohols, and other polyols such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants such as sorbitol, diphosphatidylcholine, and lecithin; bulking agents; buffers such as phosphate and citrate buffers; anti-adherents such as magnesium stearate; binders such as sugars (including disaccharides such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coatings (such as hydroxypropyl methylcellulose, shellac, corn protein zein, and cellulose ethers including gelatin); release aids (such as enteric coatings); disintegrating agents (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavorings and sweeteners (such as mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla); lubricants (such as minerals exemplified by talc or silica, vegetable stearins, magnesium stearate, or fats exemplified by stearic acid); preservatives (such as antioxidants exemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids exemplified by cysteine ​​and methionine, citric acid and sodium citrate, parabens exemplified by methylparaben and propylparaben); colorants; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0120] VI. Method of Use A. Disease / Disorder The disclosed compounds, as well as combinations and / or compositions thereof, may be used to ameliorate, treat, and / or prevent a variety of diseases, conditions, and / or disorders. In certain embodiments, the disclosed compounds, combinations of the disclosed compounds, or compositions thereof may be useful for treating conditions in which inhibition of the interleukin-1 receptor associated kinase (IRAK) pathway is therapeutically useful. In some embodiments, the compounds directly inhibit IRAK proteins, such as IRAK1, IRAK2, IRAK3, and / or IRAK4. In certain embodiments, the disclosed compounds are useful for treating, preventing, and / or ameliorating autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, graft rejection, lung injury, respiratory diseases, ischemic conditions, and bacterial and viral infections.

[0121] In some embodiments, the disclosed compounds, combinations of the disclosed compounds, or compositions thereof can be used to treat or prevent allergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, or asthma.

[0122] The disclosed compounds, combinations of the disclosed compounds, or compositions thereof may also be useful in improving, treating, and / or preventing immune dysregulation associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immune dysregulation disorders that can be treated with the compounds include organ or tissue transplantation, graft-versus-host disease resulting from transplantation, autoimmune syndromes including rheumatoid arthritis, lupus including systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczema, and psoriasis. Eruptive dermatitis, Seborrheic dermatitis, Lichen planus, Pemphigus, Bullous pemphigoid, Epidermolysis bullosa, Urticaria, Angioedema, Vasculitis, Erythema, Cutaneous eosinophilia, Lupus erythematosus, Acne, Alopecia areata, Keratoconjunctivitis, Vernal keratoconjunctivitis, Uveitis associated with Behçet's disease, Keratitis, Herpetic keratitis, Keratoconus, Corneal epithelial dystrophy, Corneal leukoplakia, Ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, Sarcoidosis, Pollen allergy, Reversible obstructive airway disease, Bronchial asthma, Allergic asthma, Intrinsic asthma Asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage caused by ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uraemic syndrome, diabetic nephropathy, polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuropathy, polyneuropathy, mononeuropathy, Neuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granuloma,Sjogren's syndrome, adiposity, eosinophilic fasciitis, lesions of the gums, periodontium, alveolar bone, dental cementum, glomerulonephritis, male pattern baldness or senile alopecia by preventing hair loss or providing hair germination and / or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemic reperfusion injury of organs occurring during storage, transplantation, or ischemic diseases, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, intoxication caused by pulmonary oxygen or drugs, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burns, dermatitis erythema multiforme multiforme), linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinomas, and altitude sickness, diseases caused by histamine or leukotriene-C4 release, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock or anoxia, B-viral hepatitis, non-A / non-B hepatitis, liver cirrhosis These conditions include, but are not limited to, pulmonary hypertension, alcoholic cirrhosis, alcoholic liver disease including nonalcoholic steatohepatitis (NASH), liver failure, fulminant liver failure, delayed liver failure, acute exacerbation of chronic liver failure, enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, chronic bacterial infection, palmoplantar pustulosis, hidradenitis suppurativa, cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), renal insufficiency, or thrombosis.

[0123] In some embodiments, the disease or condition is a lymphoid neoplasm selected from hidradenitis suppurativa, or myeloproliferative neoplasms (MPN) excluding polycythemia vera, myeloid / lymphoid neoplasms with PDGFRA rearrangements, myeloid / lymphoid neoplasms with PDGFRB rearrangements, myeloid / lymphoid neoplasms with FGFR1 rearrangements, myeloid / lymphoid neoplasms with PCM1-JAK2, myelodysplastic / myeloproliferative neoplasms (MDS / MPN), myeloid sarcoma, myeloproliferative disorders associated with Down's syndrome, blastic plasmacytoid dendritic cell neoplasms, B lymphoblastic leukemia / lymphoma, and / or T lymphoblastic leukemia / lymphoma. In some embodiments, the lymphoid neoplasm is a myeloproliferative neoplasm selected from chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), primary myelofibrosis (PMF), essential thrombocythemia, chronic eosinophilic leukemia, or a combination thereof. In other embodiments, the lymphoid neoplasm is a myelodysplastic / myeloproliferative neoplasm selected from chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia (aCML), juvenile myelomonocytic leukemia (JMML), MDS / MPN with ringed sideroblasts and thrombocytosis (MDS / MPN-RS-T), or a combination thereof.

[0124] In certain embodiments, the compounds are useful for treating neuropathic pain, including inflammation-induced pain.

[0125] In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof are useful for the treatment and / or prevention of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, particularly pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout flare, pseudogout, Saffo's syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0126] Proliferative disorders that may be treated by the disclosed compounds, combinations of the disclosed compounds, or compositions thereof include benign and malignant tumors, solid tumors, carcinomas of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, urogenital tract, esophagus, larynx, skin, bone, or thyroid, sarcomas, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancers, particularly colon carcinomas or colorectal adenomas, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial neoplasms, adenomas, adenocarcinomas, keratoacanthomas, and the like. , epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin and non-Hodgkin, breast carcinoma, follicular carcinoma, anaplastic carcinoma, papillary carcinoma, seminoma, melanoma, disorders caused by IL-1, disorders caused by MyD88 (ABC diffuse large B-cell lymphoma (DLBCL) and Waldenstrom's macroglobulinemia), Hodgkin lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), smoldering or asymptomatic multiple myeloma, or hematological malignancies (leukemia, acute myeloid leukemia (AML), DLBCL, ABC and other cancers, including DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma. In particular, the compounds of the present disclosure are useful for treating drug-resistant malignancies, such as those resistant to the JAK inhibitor ibrutinib-resistant malignancies, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia.

[0127] Examples of allergic disorders that may be treated using the disclosed compounds, combinations of the disclosed compounds, or compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by a pathophysiological disorder, essential asthma of unknown or undetermined cause, emphysema-like asthma, exercise-induced asthma, emotion-induced asthma, asthma caused by environmental factors, and the like. asthma caused by or associated with bacterial, fungal, protozoan, or viral infections, incipient asthma, wheezing infant syndrome, bronchitis, cough variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis.

[0128] As another example, rheumatoid arthritis (RA) typically results in generalized swelling, pain, loss of motion, and tenderness of target joints. RA is characterized by a chronically inflamed synovium that is densely packed with lymphocytes. The synovium, typically one cell layer thick, appears to be cellular and similar in morphology to lymphoid tissue, including clusters of dendritic cells, T, B, and NK cells, macrophages, and plasma cells. This process, as well as a number of immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately results in the destruction of joint integrity, resulting in deformity, permanent loss of function, and / or bone erosion at or near the joint. The disclosed compounds, combinations of the disclosed compounds, or compositions thereof, may be used to treat, ameliorate, or prevent any one, some, or all of these symptoms of RA. Thus, in the context of RA, a compound is considered to provide a therapeutic benefit if it achieves a reduction or amelioration of any of the symptoms commonly associated with RA, regardless of whether the treatment results in a treatment associated with the underlying RA and / or a reduction in the amount of circulating rheumatoid factor ("RF").

[0129] The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission in RA. Such parameters, ACR20 (ACR criteria for 20% clinical improvement), require a 20% improvement in tender and swollen joint counts, and a 20% improvement in three of the following five parameters: patient's global assessment, physician's global assessment, patient's pain assessment, degree of disability, and level of acute phase reactants. These criteria are expanded for 50% and 70% improvement, respectively, with ACR50 and ACR70. Other criteria include Paulu's criteria and radiographic progression (e.g., Sharp score).

[0130] In some embodiments, therapeutic benefit in a patient with RA is achieved when the patient exhibits an ACR20. In certain embodiments, an ACR improvement of ACR50 or even ACR70 can be achieved.

[0131] Cytokine release syndrome (CRS) is a potentially life-threatening condition that can result from a variety of factors, including severe viral infections such as influenza, administration of antibodies used for immunotherapy such as cancer immunotherapy, and non-protein-based cancer drugs such as oxaliplatin and lenalidomide. Immunotherapies can involve high levels of immune activation that exceed naturally occurring levels, and CRS is a non-antigen-specific toxicity that can result. As immune-based therapies become more potent, CRS is increasingly being diagnosed. CRS has also been observed in the setting of haploidentical donor stem cell transplantation and graft-versus-host disease. Shimabukuro-Vornhagen et al.,Journal for ImmunoTherapy of Cancer 6:56(2018).CRS is associated with elevated circulating levels of several cytokines, including interleukin (IL)-6 and interferon-gamma. Lee et al.,Blood 124(2):188-195(10 July 2014;Epub 29 May 2014).

[0132] CRS is typically observed clinically when a significant number of lymphocytes and / or myeloid cells are activated and release inflammatory cytokines. Cytokine release can be induced by chemotherapy or biotherapy and / or associated with therapeutic antibody therapy, such as, for example, immunotherapy for cancer treatment. Exemplary immunotherapies that can result in CRS include, but are not limited to, therapies in which cells express recombinant receptors, such as chimeric antigen receptors (CARs) and / or other transgenic receptors, such as T cell receptors (TCRs). CRS induced by CAR T therapy generally occurs within a few days of infusion of T cells, at the peak of CAR T cell proliferation. Giavridis et al., Nat Med. 24(6):731-738 (June 2018; Epub 28 May 2018). Examples of CAR T therapies that can induce CRS include axicabtagene ciloreucel (commercially available as YESCARTA®) and tisagenlecleucel (commercially available as KYMRIAH®).

[0133] Highly elevated interleukin 6 (IL-6) levels have also been observed in patients with CRS and in mouse models of the disease, indicating that IL-6 may have a role in the pathophysiology of CRS. Shimabukuro-Vornhagen,J Immunother Cancer 6(1),56(2018).IL-6 can signal through two distinct modes. Classical IL-6 signaling involves binding of IL-6 to the membrane-bound IL-6 receptor. However, the IL-6 receptor does not have an intracellular signaling domain. Instead, after soluble IL-6 binds to the membrane-bound IL-6 receptor, the IL-6 / IL-6 receptor complex binds to membrane-bound gp130, which initiates signaling through its intracellular domain. In trans-signaling, IL-6 binds to a soluble form of the IL-6 receptor, which is typically cleaved from the cell surface by metalloproteinases. The resulting soluble IL-6 / IL-6 receptor complex binds to gp130 and is therefore capable of inducing signaling even in cell types that do not express membrane-bound IL-6 receptors.

[0134] IL-6 contributes to many of the major symptoms of CRS. Through trans-signaling, IL-6 leads to the hallmark symptoms of severe CRS, namely vascular leakage, and activation of complement, as well as the coagulation cascade that induces disseminated intravascular coagulation (DIC). In addition, IL-6 likely contributes to the cardiomyopathy often observed in CRS patients by promoting myocardial dysfunction. In mouse models, CRS develops within 2-3 days of CAR T cell infusion and can be fatal. Giavridis et al., Nat Med. 24(6):731-738(2018). CRS symptoms can begin within minutes or hours of initiation of antibody treatment and can include fever that may reach or exceed 40°C, nausea, fatigue, headache, tachycardia, hypotension, rash, shortness of breath, and / or muscle pain. However, in certain cases, additional and potentially more serious complications may develop, including cardiac dysfunction, adult respiratory distress syndrome, neurological toxicity, renal and / or hepatic failure, and / or disseminated intravascular coagulation.

[0135] The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v.5.0, pub. November 27, 2017) includes a grading system for CRS. Grade 1: Fever with or without constitutional symptoms. Grade 2: Hypotension in response to fluids; hypoxia in response to O2 less than 40%. Grade 3: Hypotension managed with one pressor, hypoxia requiring O2 >40%. Grade 4: Life-threatening consequences; urgent intervention is indicated. Grade 5: Death.

[0136] The subject may not exhibit signs or symptoms of CRS and / or may be at risk for developing CRS, in such embodiments, administering the compound substantially prevents the onset of CRS or prevents the onset of Grade 2 or higher CRS.

[0137] Alternatively, the subject may exhibit at least one sign or symptom of CRS, and at least one sign or symptom of grade 1 CRS. Or, the subject may exhibit at least one sign or symptom of grade 2 or higher CRS, such as grade 3 or higher CRS. The disclosed compound(s) may be administered within 24 hours of the onset of the sign or symptom, and / or administering the compound(s) may improve the sign or symptom of CRS, as compared to the severity of the sign or symptom before administration of the compound(s), such as reducing the grade of CRS from 4 to 3, 2, or 1, or from 3 to 2 or 1, or from 2 to 1. Alternatively, the CRS symptoms are substantially reduced below grade 1 level, such that the subject no longer experiences symptoms associated with CRS. In some embodiments, the sign or symptom is fever, and may be a fever of 40° C. or higher.

[0138] The disclosed compound(s) may be administered to a subject who has previously been administered a first therapy for which CRS is a known, suspected, or potential side effect. Administration of the first therapy may begin from 0 to 10 days prior to administration of the compound(s). Alternatively, the compound(s) may be administered to a subject who is being administered or is being administered simultaneously with a first therapy for which CRS is a known, suspected, and / or potential side effect. The first therapy may include cellular therapy, including but not limited to chimeric antigen receptor (CAR) expression therapy and / or transgenic receptor therapy. Acellular antibodies are also known to induce antibodies that activate T cells in this syndrome, particularly, including but not limited to CAMPATH 1-H, blinatumomab, and / or rituximab.

[0139] A second therapeutic agent, such as a steroid, an anti-inflammatory agent, an immunosuppressant, or a combination thereof, may also be administered to treat or prevent CRS. The steroid may be, for example, a corticosteroid, such as dexamethasone or prednisone, or a combination thereof. The disclosed compound(s) may be administered substantially simultaneously with the second therapeutic agent, or the compound(s) and the second therapeutic agent may be administered sequentially in any order.

[0140] Acute respiratory distress syndrome (ARDS) is a syndrome characterized by severe shortness of breath, abnormally rapid forced breathing, hypotension, confusion, and extreme fatigue. The syndrome can be diagnosed based on a PaO2 / FiO2 ratio of less than 300 mmHg despite a PEEP of more than 5 cm H2O (Fan et al JAMA.319:698-71).

[0141] ARDS occurs when fluid accumulates in the alveoli. The fluid prevents the lungs from filling with enough air, limiting the amount of oxygen that reaches the bloodstream, thereby depriving organs of the oxygen they need to function. ARDS symptoms can vary in intensity depending on its cause and severity. The severe shortness of breath that characterizes ARDS usually develops within hours to days after infection with some respiratory viruses, e.g., COVID-19 and influenza. Many people who develop ARDS do not survive, and the risk of death increases with age and the severity of the disease. Some patients who survive ARDS recover completely, while others are left with permanent damage to their lungs. ARDS may be referred to as acute lung injury (ALI) in some publications.

[0142] Acute kidney injury (AKI), also known as acute kidney injury (ARI) or acute renal failure (ARF), is a syndrome characterized by a sudden decrease in renal function, including, for example, the ability to excrete waste products from the patient's blood. AKI is characterized by a decrease in glomerular filtration rate, urine output, or both. This decrease in filtration capacity results in retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products normally excreted by the kidney, a decrease in urine output, or both. AKI can be classified in causation as prerenal, intrinsic renal, or postrenal. Intrinsic renal disease can be further divided into glomerular, tubular, interstitial, and vascular abnormalities. AKI involves an inflammatory response that, if not suppressed, can lead to renal fibrosis and chronic renal failure. AKI usually occurs over a period of hours or days and is potentially reversible. AKI may be characterized as an abrupt (e.g., within 14 days, 7 days, 72 hours, or 48 hours) reduction in renal function identified by an absolute increase in serum creatinine of 0.3 mg / dl or more (26.4 μmol / l or more), a percentage increase in serum creatinine of 50% or more (1.5-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 ml / kg per hour for at least 6 hours). Risk factors include, for example, subjects undergoing or having major vascular surgery, coronary artery bypass, or other cardiac surgery, subjects with pre-existing congestive heart failure, pre-eclampsia, eclampsia, diabetes, hypertension, coronary artery disease, proteinuria, renal failure, glomerular filtration not above the normal range, liver cirrhosis, serum creatinine above the normal range, or sepsis, or subjects exposed to NSAIDs, cyclosporine, tacrolimus, aminoglycosides, foscarnet, ethylene glycol, hemoglobin, myoglobin, ifosfamide, heavy metals, methotrexate, radiopaque contrast agents, or streptozotocin. This list is not limiting.

[0143] Renal insufficiency includes, but is not limited to, kidney damage, kidney disease, kidney dysfunction, kidney cancer, the absence of at least one kidney due to accident, surgical removal or genetic disorder, or other conditions in which one or both kidneys do not function properly. Renal insufficiency can include acute kidney injury.

[0144] Thrombosis is a clotting disorder that is contributed by excess platelets. Thrombosis may refer to the formation of a thrombus (blood clot) in a blood vessel. This term includes arterial and venous thrombosis, including but not limited to deep vein thrombosis, portal vein thrombosis, jugular vein thrombosis, renal vein thrombosis, stroke, myocardial infarction, Budd-Chiari syndrome, Paget-Schroetter disease, and cerebral venous sinus thrombosis. In some embodiments, the patient is at higher risk (e.g., as measured by recognized risk factors) of a thrombotic event compared to the general population. In some embodiments, the patient has one or more risk factors that put the patient at higher risk of developing thrombosis compared to the general population. Risk factors for thrombosis include, for example, classic cardiovascular disease risk factors: dyslipidemia, smoking, diabetes, hypertension, and abdominal obesity; strong classic venous thromboembolism risk factors: trauma or fracture, major orthopedic surgery, and oncological surgery; moderate classic venous thromboembolism risk factors: non-oncological surgery, oral contraceptives and hormone replacement therapy, pregnancy and the puerperium, hypercoagulability, and previous venous thromboembolism; and weak classic venous thromboembolism risk factors: age, bed rest (>3 days), prolonged travel, and metabolic syndrome. Additional risk factors include genetic, acquired and mixed coagulation or metabolic risk factors for thrombosis, such as, for example, genetic: antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden, prothrombin G20210A; acquired: antiphospholipid syndrome; mixed: hyperhomocysteinemia, elevated fibrinogen levels, elevated factor VIII levels, elevated factor IX levels, etc. In some cases, the use of heparin may increase the risk of thrombosis, including, for example, heparin-induced thrombocytopenia (HIT).Diseases and conditions related to thrombosis include, but are not limited to, acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic dermonecrosis, acute or chronic disseminated intravascular coagulation (DIC), sepsis-induced coagulopathy (SIC), blood clot formation from surgery, prolonged bed rest, prolonged immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic stroke, acute coronary artery occlusion, acute peripheral artery occlusion, extensive pulmonary embolism, axillary vein thrombosis, iliac-femoral vein thrombosis, occluded arterial cannula, occluded venous cannula, cardiomyopathy, hepatic veno-occlusive disease, hypotension, reduced cardiac output, reduced vascular resistance, pulmonary hypertension, reduced lung compliance, leukopenia, blood microcytopenia (e.g., immune microcytopenia), and immune microcytopenia. In subjects at risk for thrombosis, subjects can be monitored using methods well known to those skilled in the art to maintain hemostasis in patients at risk for thrombosis. Examples of methods for monitoring patients at risk for thrombosis include, but are not limited to, digital subtraction angiography, in vitro assays, or non-invasive methods. Examples of in vitro assays useful for identifying and monitoring subjects at risk for thrombosis and treating them using the present methods include, but are not limited to, functional assays and antibody detection assays.

[0145] Thrombotic event refers to any disorder that involves the occlusion or partial occlusion of artery or vein with thrombosis.Thrombotic event includes, but is not limited to, thrombotic disorders such as myocardial infarction, unstable angina, stroke, pulmonary embolism, transient ischemic attack, deep vein thrombosis, thrombotic reocclusion and peripheral vascular thrombosis.Thrombotic event also includes thrombotic reocclusion that occurs after coronary intervention procedure or thrombolytic therapy.

[0146] COVID-19 is the disease caused by infection with SARS-CoV-2 (previously known as 2019-nCoV), which first emerged in Wuhan, China.

[0147] COVID-19 associated ARDS refers to ARDS caused by infection with SARS-CoV-2. Patients with COVID-19 associated ARDS may have been diagnosed with COVID-19, may have been exposed to another person with COVID19, or may be suspected of having COVID-19 based on their symptoms.

[0148] COVID-19-associated AKI refers to AKI caused by SARS-CoV-2 infection. A patient with COVID-19-associated AKI may have been diagnosed with COVID-19, may have been exposed to another person with COVID-19, or may be suspected of having COVID-19 based on their symptoms. In some cases, COVID-19-associated AKI includes symptomatic AKI, for example, as described in Batlle et al. J.AM.SOC.NEPHROL. 2020,31(7):1380-1383 and Gabarre et al. Intensive Care Med. 2020,46(7):1339-1348, the disclosures of which are incorporated herein by reference in their entirety.

[0149] COVID-19 associated thrombosis refers to thrombosis caused by infection with SARS-CoV-2. A patient with COVID-19 associated thrombosis may have been diagnosed with COVID-19, may have been exposed to another person with COVID-19, or may be suspected of having COVID-19 based on their symptoms. In some cases, COVID-19 associated thrombosis includes any of the symptoms described, for example, in Connors et al. Blood 2020, 135(23):2033-2040 and Bikdeli et al. J. Am. Coll. Cardiol. 2020, 75(23):2950-73, the disclosures of which are incorporated herein by reference in their entirety.

[0150] The term "COVID-19 associated" refers to symptoms or indications that typically develop within 28 days of hospitalization due to / signs of COVID-19.

[0151] For COVID-19 associated ARDS, successful treatment may include reduced shortness of breath, reduced forced breathing or respiratory rate, increased blood pressure, reduced confusion, and / or reduced fatigue. Treatment may be administered prophylactically, i.e., prior to the onset of ARDS. Prophylactic treatment prevents ARDS and can be administered to patients who have or are suspected of having COVID-19 infection but do not have severe symptoms of ARDS. For example, prophylactic treatment can be administered to patients who have a cough without other symptoms of ARDS.

[0152] For COVID-19-associated AKI, successful treatment may include an increase in renal function. Renal function may be assessed by measuring serum creatinine levels, serum creatinine clearance, or blood urea nitrogen levels. In some cases, successful treatment may include a reduction in metabolic acidosis, hyperkalemia, oliguria or anuria, azotemia, restoration of fluid balance, and improved effects on other organ systems. Treatment may be administered prophylactically, i.e., before the onset of AKI. Prophylactic treatment prevents AKI and may be administered to patients who have or are suspected of having COVID-19 infection but do not have severe symptoms of AKI. For example, prophylactic treatment may be administered to patients who have one or more of the following symptoms without other symptoms of AKI: increased serum or urinary creatinine, hematuria, hypoproteinemia, decreased antithrombin III levels, hypoalbuminemia, leukotsuuria, or proteinuria.

[0153] For COVID-19-associated thrombosis, successful treatment may include improving the subject's clotting profile or preventing, slowing, delaying, or arresting a worsening of the clotting profile for which the subject is at risk. The clotting profile may be assessed by measuring one or more clotting parameters, including, for example, the subject's serum levels of one or more of D-dimer, factor II, factor V (e.g., factor V Leiden), factor VII, factor VIII, factor IX, factor XI, factor XII, factor XIII, F / fibrin degradation products, thrombin-antithrombin 111 complex, fibrinogen, plasminogen, prothrombin, and von Willebrand factor. Additional clotting parameters that may be measured for the clotting profile include, for example, prothrombin time, thromboplastin time, activated partial thrombosis time (aPTT), antithrombin activity, platelet count, protein C levels, and protein S levels. In addition, the level of C-reactive protein may also be assessed in the patient prior to treatment, and if elevated, this may be used as a further indicator of an increased risk of thrombosis in the patient.

[0154] Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by dysregulation of the immune response to infection. A severe form of sepsis, "septic shock," is characterized by critical reduction in tissue perfusion and acute failure of multiple organs, including the lungs, kidneys, and liver. Common causes in immunocompetent patients include many different species of gram-positive and gram-negative bacteria. Immunocompromised patients may have uncommon bacterial or fungal species as causes. Signs include fever, hypotension, oliguria, and confusion. Diagnosis is primarily clinically combined with culture results indicating infection, and early detection and treatment are important. Treatment is aggressive fluid resuscitation, antibiotics, surgical resection and drainage of infected or necrotic tissue, and supportive care.

[0155] Influenza is a disease commonly known as "the flu." Influenza is caused by a group of viruses that can be divided into four separate groups, influenza A, influenza B, influenza C, and influenza D, which are separated based on their nucleoproteins and matrix proteins. Influenza causes a viral respiratory infection, resulting in fever, runny nose, cough, headache, and malaise.

[0156] Influenza A, B, and C can all infect humans, but there have been no documented cases of human influenza D infection. Influenza C, on the other hand, does not cause the typical influenza illness seen in individuals infected with influenza A, B, or C.

[0157] Influenza A strains are further classified based on two surface proteins, hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes (H1-H18 and N1-N11, respectively). There are potentially 198 different influenza A subtype combinations, but in practice, only 131 subtypes have been detected. Current subtypes of influenza A viruses that routinely circulate in humans include A(H1N1) and A(H3N2).

[0158] Influenza-associated cytokine release-associated conditions refer to any influenza-associated condition that results in high levels of cytokine release in the lungs and / or kidneys, including, but not limited to, influenza-associated ARDS, influenza-associated AKI, influenza-associated thrombosis, influenza-associated sepsis, influenza-associated septic shock, etc.

[0159] Influenza-associated ARDS is ARDS caused by influenza infection.Patients with influenza-associated ARDS may have been diagnosed with influenza infection, may have been exposed to another person with influenza infection, or may be suspected of having influenza infection based on their symptoms.

[0160] Influenza-associated AKI is AKI caused by influenza infection. A patient with influenza-associated AKI may have been diagnosed with influenza infection, may have been exposed to another person with influenza infection, or may be suspected of having influenza infection based on their symptoms. In some cases, influenza-associated AKI includes symptomatic AKI, for example, as described in Batlle et al. J.AM.SOC.NEPHROL.2020,31(7):1380-1383 and Gabarre et al. Intensive Care Med.2020,46(7):1339-1348 (the disclosures of which are incorporated herein by reference in their entirety).

[0161] Influenza-associated thrombosis is thrombosis caused by influenza infection. A patient with influenza-associated thrombosis may have been diagnosed with influenza infection, may have been exposed to another person with influenza infection, or may be suspected of having influenza infection based on their symptoms. In some cases, influenza-associated thrombosis includes any of the symptoms described, for example, in Connors et al. Blood 2020, 135(23):2033-2040 and Bikdeli et al. J. Am. Coll. Cardiol. 2020, 75(23):2950-73 (the disclosures of which are incorporated herein by reference in their entirety).

[0162] Influenza-associated sepsis is sepsis caused by influenza infection. A patient with influenza-associated sepsis may have been diagnosed with influenza infection, may have been exposed to another person with influenza infection, or may be suspected of having influenza infection based on their symptoms. In some cases, influenza-associated thrombosis includes any of the symptoms described, for example, in Florescu et al. Virulence. 2014 Jan 1; 5(1): 137-142 and Gu et al. Eur Respir Rev. 2020 Jul 21; 29(157): 200038 (the disclosures of which are incorporated herein by reference in their entirety).

[0163] The term "influenza-associated" refers to symptoms or indications that develop within 28 days of hospitalization / signs of influenza infection.

[0164] For influenza-associated ARDS, successful treatment may include a reduction in shortness of breath, a reduction in forced breathing or a reduction in respiratory rate, an increase in blood pressure, a reduction in mental confusion, and / or a reduction in fatigue. Treatment may be administered prophylactically, i.e., before the onset of ARDS. Prophylactic treatment prevents ARDS and can be administered to patients who have or are suspected of having influenza infection but do not have severe symptoms of ARDS. For example, prophylactic treatment can be administered to patients who have a cough that is not accompanied by other symptoms of ARDS.

[0165] For influenza-associated AKI, successful treatment may include an increase in renal function. Renal function may be assessed by measuring serum creatinine levels, serum creatinine clearance, or blood urea nitrogen levels. In some cases, successful treatment may include a reduction in metabolic acidosis, hyperkalemia, oliguria or anuria, azotemia, restoration of fluid balance, and improved effects on other organ systems. Treatment may be administered prophylactically, i.e., before the onset of AKI. Prophylactic treatment prevents AKI and may be administered to patients who have or are suspected of having influenza infection but do not have severe symptoms of AKI. For example, prophylactic treatment may be administered to patients who have one or more of the following, without other symptoms of AKI: increased serum or urinary creatinine, hematuria, hypoproteinemia, decreased antithrombin III levels, hypoalbuminemia, leukotsuuria, or proteinuria.

[0166] For influenza-associated thrombosis, successful treatment may include improving the subject's clotting profile, or preventing, slowing, delaying, or preventing the deterioration of the clotting profile for which the subject is at risk. The clotting profile may be assessed by measuring one or more clotting parameters, including, for example, the subject's serum levels of one or more of D-dimer, factor II, factor V (e.g., factor V Leiden), factor VII, factor VIII, factor IX, factor XI, factor XII, factor XIII, F / fibrin degradation products, thrombin-antithrombin 111 complex, fibrinogen, plasminogen, prothrombin, and von Willebrand factor. Additional clotting parameters that may be measured for the clotting profile include, for example, prothrombin time, thromboplastin time, activated partial thrombosis time (aPTT), antithrombin activity, platelet count, protein C level, and protein S level. In addition, the level of C-reactive protein may also be assessed in the patient prior to treatment, and if elevated, this may be used as a further indicator of increased risk of thrombosis in the patient.

[0167] For influenza-associated sepsis or septic shock, successful treatment may include reducing fever, reducing high or moderately high heart rate (e.g., tachycardia), reducing sweating (i.e., diaphoresis), reducing confusion and / or fatigue, and / or reducing shortness of breath, reduced forced breathing, or reduced respiratory rate. Treatment may be administered prophylactically, i.e., before the onset of sepsis or septic shock. Prophylactic treatment prevents sepsis or septic shock and can be administered to patients who have or are suspected of having influenza infection but do not have severe symptoms of sepsis or septic shock. For example, prophylactic treatment can be administered to patients who have a cough that is not accompanied by other symptoms of sepsis or septic shock.

[0168] Additionally, the disclosed compounds, combinations of the disclosed compounds, or compositions thereof can be used to treat sickle cell disease, particularly to reduce the immunological response manifested in the disease. In some embodiments, the subject may exhibit one or more of the following symptoms: anemia, sickle cell crisis, vaso-occlusive crisis, splenic sequestration crisis, splenic sequestration crises, acute chest syndrome, acute chest syndrome, aplastic crisis, hemolytic crisis, dactylitis, pneumonia, respiratory infection, bone marrow embolism, or atelectasis.

[0169] Sickle cell disease (SCD) is a group of blood disorders that are typically inherited. The most common type is known as sickle cell anemia, which results in an abnormality in the oxygen-carrying protein hemoglobin found in red blood cells. This results in a rigid, sickle-shaped shape under certain circumstances. Problems with sickle cell disease typically begin around 5-6 months of age and can result in a number of health problems, including attacks of pain (known as sickle cell crises), anemia, swelling of the hands and feet, bacterial infections, and strokes. Long-term pain can result as people get older.

[0170] Sickle cell disease occurs when a person inherits two abnormal copies of the beta-globin gene (HBB), which makes hemoglobin, one from each parent. The gene is located on chromosome 11. There are several subtypes, depending on the exact mutation in each hemoglobin gene. Attacks can be triggered by temperature changes, stress, dehydration, and high altitude.

[0171] Care for people with sickle cell disease may include prevention of infection with vaccinations and antibiotics, plenty of fluid intake, folic acid supplements, and painkillers. Other measures may include blood transfusions and the drug hydroxycarbamide (hydroxyurea). A small number of people can be cured by transplantation of bone marrow cells. People with sickle cell disease may present with the following symptoms:

[0172] Sickle cell crisis: The term "sickle cell crisis" or "erythrocyte sickling crisis" may be used to describe several independent acute conditions that occur in subjects with SCD, which result in anemia and crises that can be of many types, such as vaso-occlusive crisis, aplastic crisis, spleno-occlusive crisis, and hemolytic crisis. Most episodes of sickle cell crisis last for 5-7 days. Infection, dehydration, and acidosis (all of which predispose to red blood cell sickling) may act as triggers, but in most cases, no predisposing factor is identified.

[0173] Vaso-occlusive crises: Vaso-occlusive crises are caused by sickle cells that block capillaries and restrict blood flow to organs, causing ischemia, pain, necrosis, and often organ damage. The frequency, severity, and duration of these crises vary widely. Painful crises are treated with hydration, analgesics, and blood transfusions, and pain management requires opioids administered at regular intervals until the crisis subsides. For milder crises, a subgroup of subjects are administered nonsteroidal anti-inflammatory drugs such as diclofenac or naproxen. For more severe crises, most subjects require intrasubject management with intravenous administration of opioids. In these situations, subject-controlled analgesia devices are commonly used. Vaso-occlusive crises involving organs such as the penis or lungs are considered emergencies and are treated with red blood cell transfusions. Incentive spirometry, a technique that encourages deep breathing to minimize the development of atelectasis, is recommended.

[0174] Splenic obstructive crisis: The spleen is frequently affected in sickle cell disease because sickle cells cause narrowing of blood vessels and a reduced ability to remove defective cells. Infarction usually occurs by the end of childhood in individuals with sickle cell anemia. This splenic damage increases the risk of infection by encapsulated organisms, and prophylactic antibiotics and vaccinations are recommended for those who lack adequate splenic function.

[0175] Splenic obstructive crisis is an acute, painful enlargement of the spleen caused by trapping of red blood cells within the spleen, leading to a rapid fall in hemoglobin concentration and potentially hypovolemic shock. An obstructive crisis is considered an emergency. If untreated, the subject may die within 1-2 hours due to circulatory failure. Management is supportive and sometimes involves blood transfusion. These crises are episodic, lasting 3-4 hours and can last up to a day.

[0176] Acute chest syndrome: Acute chest syndrome is defined by at least two signs or symptoms: chest pain, fever, pulmonary infiltrates or focal abnormalities, respiratory symptoms, or hypoxemia. It is the second most common complication and accounts for approximately 25% of deaths in subjects with SCD. Most cases present with a vaso-occlusive crisis followed by acute chest syndrome. Nevertheless, approximately 80% of individuals will have a vaso-occlusive crisis during acute chest syndrome.

[0177] Aplastic crisis: Aplastic crisis is an example of an acute worsening of a subject's baseline anemia, manifesting as paleness, rapid heart rate, and fatigue. The crisis is usually caused by parvovirus B19, which directly affects red blood cell production by invading, multiplying in, and destroying red blood cell precursors. Parvovirus infection almost completely prevents red blood cell production for 2-3 days. In healthy individuals, this rarely causes problems, but in SCD subjects, the shortened life span of red blood cells can suddenly become life-threatening. Reticulocyte counts drop dramatically during the disease (leading to reticulocytopenia), and rapid turnover of red blood cells leads to a decrease in hemoglobin. The crisis takes 4-7 days to resolve. Most subjects can be managed supportively, and some require blood transfusions.

[0178] Hemolytic crisis: Hemolytic crisis is an acute accelerated drop in hemoglobin levels. Red blood cells break down at a faster rate. This is especially common in people with coexisting G6PD deficiency. Another effect of hemolytic crisis in sickle cell disease is oxidative stress on red blood cells, white blood cells, and platelets. When there is not enough red blood cell production in the bone marrow, the oxygen the body receives, processes, and transports becomes imbalanced with the body's antioxidants. There is an imbalance in oxygen reactive species within the cells, leading to more production of red blood cells that are not properly oxygenated or formed. Oxidative stress can lead to anemia because of the imbalance of oxygen in the tissues. Management is supportive and sometimes involves blood transfusions.

[0179] In addition, one of the earliest clinical symptoms is dactylitis, which may occur as early as 6 months of age in children with sickle cell trait. The crisis may last up to a month. Considering that both pneumonia and sickling of red blood cells in the lungs may produce symptoms of acute chest syndrome, subjects are treated for both conditions. This may be caused by painful crises, respiratory infections, bone marrow embolism, or possibly atelectasis, opiate administration, or surgery. Hematopoietic ulcers may also occur.

[0180] Additionally, the disclosed compounds, combinations of the disclosed compounds, or compositions thereof can be used to treat lung injury, which can be chemical or radiation induced lung injury.

[0181] In some embodiments, the subject may inhale or be expected to be exposed to a pulmonary irritant. In some embodiments, the subject may inhale or be expected to inhale a choking agent. Pulmonary agents, or choking agents, are chemical agents designed to impede the subject's ability to breathe. These compounds generally act by causing the accumulation of fluid in the lungs, which then leads to choking. Inhalation of these agents causes a burning throat, coughing, vomiting, headache, chest pain, chest tightness, and respiratory and circulatory failure. Examples of such agents include chlorine gas, chloropicrin (PS), diphosgene (DP), phosgene (CG), decafluoride disulfide, perfluoroisobutene, acrolein, and diphenylcyanoarsine. Phosgene-induced acute lung injury (P-ALI) is generally associated with short-term phosgene inhalation. Long-term exposure can cause chronic hypoventilation, refractory pulmonary edema, and other associated lung damage, ultimately leading to ARDS. Chemical pneumonitis is inflammation of the lungs or difficulty breathing caused by inhaling chemical fumes or choking on certain chemicals.

[0182] Additionally, the disclosed compounds, combinations of the disclosed compounds, or compositions thereof can be used to treat or prevent acute inhalation injury (AII) and e-cigarette, or vapor, product use associated lung injury (EVALI).

[0183] In other embodiments, the subject is exposed to or is expected to be exposed to ionizing radiation. In these embodiments, the subject may have or be expected to develop radiation-induced lung injury (RILI). In some embodiments, the subject may have radiation pneumonitis or radiation pulmonary fibrosis. In these embodiments, the subject may have undergone or has undergone chest radiotherapy, and may have inhaled a radiopharmaceutical or may have been directly exposed to ionizing radiation. For example, the subject may have inhaled a radiopharmaceutical, for example, or may have been directly exposed to ionizing radiation as a result of a nuclear weapon or may have been leaked at a nuclear power plant.

[0184] The disclosed compounds, combinations of the disclosed compounds, or compositions thereof can also be used to treat or prevent hemorrhagic fevers, including Ebola virus disease, Alkhurma hemorrhagic fever, Chapare hemorrhagic fever, Crimean-Congo hemorrhagic fever, Hantavirus pulmonary syndrome (HPS), hemorrhagic fever with renal syndrome (HFRS), Kyasanur Forest disease (KFD), Lassa fever, Lujo hemorrhagic fever, Marburg hemorrhagic fever, Omsk hemorrhagic fever, Rift Valley fever, yellow fever, or dengue fever, such as severe dengue fever (dengue hemorrhagic fever), or symptoms thereof.

[0185] B. Formulation and Administration Pharmaceutical compositions containing one or more active compounds of the disclosure may be manufactured by any suitable method, such as mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. One or more physiologically acceptable excipients, diluents, carriers, adjuvants, or auxiliaries may be used to formulate the compositions to provide a preparation that can be used pharma- ceutically.

[0186] The active compound(s) may be formulated in a pharmaceutical composition per se or in the form of a hydrate, solvate, N-oxide, or pharma- ceutically acceptable salt. Typically, such salts are more soluble in aqueous solution than the corresponding free acids and bases, although salts having lower solubility than the corresponding free acids and bases may also be formed.

[0187] Pharmaceutical compositions containing the disclosed compound(s) can be in a form suitable for virtually any mode of administration, including, for example, topical, ophthalmic, oral, buccal, systemic, nasal, by injection, such as intravenous or intraperitoneal, transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0188] For topical administration, the active compound(s) (or hydrates, solvates, N-oxides, or pharma- ceutically acceptable salts thereof) may be formulated as solutions, gels, ointments, creams, suspensions, etc. as known in the art.

[0189] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

[0190] Useful injectable preparations include sterile suspensions, solutions, or emulsions of active compound(s) in aqueous or oily vehicles. The compositions may also contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. The formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, and may contain added preservatives.

[0191] Alternatively, injectable formulations may be provided in powder form for reconstitution with a suitable vehicle including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc. before use. To this end, the active compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

[0192] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0193] For oral administration, the pharmaceutical compositions may take the form of lozenges, tablets, or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated, for example, with sugar, film, or enteric coatings by methods well known in the art.

[0194] Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups, or suspensions, or they may be provided as dry products for constitution with water or other suitable vehicles before use.Such liquid preparations may be prepared by conventional means using pharma-ceutically acceptable excipients, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats and oils); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore™, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoic acid or sorbic acid).Preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweetening agents, as necessary.

[0195] Preparations for oral administration can be suitably formulated to give controlled release of the active compound, as is well known.

[0196] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0197] For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0198] For nasal administration or administration by inhalation or insufflation, the active compound(s), hydrates, solvates, N-oxides, or pharma- ceutically acceptable salts can be conveniently delivered in the form of an aerosol spray from a pressurized pack or a nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (e.g., capsules and cartridges composed of gelatin) can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0199] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution.

[0200] In accordance with the present disclosure, the disclosed compound(s), solvates, N-oxides, pharma- ceutically acceptable salts, or prodrug(s) forms thereof may also be used in the preparation of pharmaceutical compositions and compositions described in, for example, U.S. Pat. No. 6,241,969, U.S. Pat. No. 6,060,069, U.S. Pat. No. 6,238,647, U.S. Pat. No. 6,335,316, U.S. Pat. No. 5,364,838, U.S. Pat. No. 5,672,581, WO96 / 32149, WO95 / 24183, U.S. Pat. No. 5,654,007, U.S. Pat. No. 5,404,871, U.S. Pat. No. 5,672,581, U.S. Pat. No. 5,743,250, U.S. Pat. No. 5,419,315, U.S. Pat. No. 5,558,085, WO98 / 33480, U.S. Pat. No. 5,518,998, U.S. Pat. No. 5,506,203, U.S. Pat. No. 5,661,130, U.S. Pat. No. 5,655,523, U.S. Pat. No. 5,645,051, U.S. Pat. No. 5,622,166, U.S. Pat. No. 5,577,497, U.S. Pat. No. 5,492,112, U.S. Pat. No. 5,327,883, U.S. Pat. No. 5,277,195, U.S. Patent Publication No. 20010041190, U.S. Patent Publication No. 20020006901, and U.S. Patent Publication No. 20020034477.

[0201] Among the devices that can be used to administer the active compound(s) form are those well known in the art, such as, for example, metered dose inhalers, liquid nebulizers, dry powder inhalers, nebulizers, thermal vaporizers, etc. Other suitable techniques for administration of certain 2,4-pyrimidinediamine compounds include electrohydrodynamic aerosolizers.

[0202] In addition, the inhalation device is preferably practical in the sense that it is easy to use, small enough to be conveniently carried, capable of providing multiple doses, and durable. Some specific examples of commercially available inhalation devices are Turbohaler (Astra, Wilmington, DE), Rotahaler (Glaxo, Research Triangle Park, NC), Diskus (Glaxo, Research Triangle Park, NC), Ultravent nebulizer (Mallinckrodt), Acorn II nebulizer (Marquest Medical Products, Totowa, NJ), Ventolin metered dose inhaler (Glaxo, Research Triangle Park, NC), etc. In one embodiment, the disclosed compound(s), their solvates, N-oxides, pharma- ceutically acceptable salts, or prodrug(s) can be delivered by dry powder inhaler or nebulizer.

[0203] As those skilled in the art will recognize, the formulation of the disclosed compound(s), their solvates, N-oxides, pharma- ceutically acceptable salts, or prodrug(s), the amount of the formulation delivered, and the duration of administration of a single dose depend on the type of inhalation device used and other factors. In some aerosol delivery systems, such as nebulizers, the frequency of administration and the length of time the system is activated depend primarily on the concentration of the disclosed compound(s) in the aerosol. For example, shorter administration periods can be used with higher concentrations of the disclosed compound(s) in the nebulizer solution. Devices such as metered dose inhalers can generate higher aerosol concentrations and, in some embodiments, can be operated for shorter periods to deliver a desired amount of active compound. Devices such as dry powder inhalers deliver active agent until a predetermined amount of agent is expelled from the device. In this type of inhaler, the amount of the disclosed compound(s), their solvates, N-oxides, pharma- ceutically acceptable salts, or prodrug(s) in a given amount of powder determines the dose delivered in a single administration. Formulations of the disclosed compound(s) are selected to obtain the desired particle size in the selected inhalation device.

[0204] Formulations of the disclosed compounds for administration from a dry powder inhaler will typically include a finely divided dry powder containing the disclosed compound(s), although the powder may also include bulking agents, buffers, carriers, excipients, other additives, and the like. Additives may be included in the dry powder formulation, for example, to dilute the powder as necessary for delivery from a particular powder inhaler, to facilitate processing of the formulation, to provide advantageous powder properties to the formulation, to facilitate dispersion of the powder from the inhalation device, to stabilize the formulation (e.g., antioxidants or buffers), to provide taste to the formulation, and the like. Typical additives include mono-, di-, and polysaccharides; sugar alcohols and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitol, diphosphatidylcholine, or lecithin.

[0205] The disclosed method can be carried out to produce a pharmaceutical composition comprising the disclosed compound(s) suitable for administration by inhalation. For example, dry powder formulations can be produced in several ways using conventional techniques such as those described in any of the above publications and expressly incorporated herein by reference, see, for example, U.S. Patent No. 5,700,904 to Baker et al., the entire disclosure of which is expressly incorporated herein by reference. Particles in a size range suitable for maximum deposition in the lower respiratory tract can be produced by micronization, milling, etc. Also, liquid formulations can be produced by dissolving the compound in a suitable solvent, such as water, at the appropriate pH with a buffer or other excipients.

[0206] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device contains the following ingredients: active compound (0.5-20 mg / ml); benzalkonium chloride (0.1-0.2 mg / mL); polysorbate 80 (TWEEN® 80, 0.5-5 mg / ml); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg / ml); phenylethanol (1-4 mg / ml); and dextrose (20-50 mg / ml). The pH of the final suspension can be adjusted to a range of about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

[0207] Another specific example of an aqueous suspension suitable for administration of a compound via inhalation contains 20 mg / mL of a disclosed compound(s), 1% (v / v) polysorbate 80 (TWEEN® 80), 50 mM citrate, and / or 0.9% sodium chloride.

[0208] For ocular administration, active compound(s) can be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye.Various vehicles suitable for administering compounds to the eye are known in the art.Specific non-limiting examples are described in U.S. Patent Nos. 6,261,547, 6,197,934, 6,056,950, 5,800,807, 5,776,445, 5,698,219, 5,521,222, 5,403,841, 5,077,033, 4,882,150, and 4,738,851, which are incorporated herein by reference.

[0209] For long-term delivery, the active compound(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with suitable polymers, or hydrophobic materials (e.g., as an emulsion in acceptable oil), or ion exchange resins, or as a poorly soluble derivative, e.g., as a poorly soluble salt. Alternatively, a transdermal delivery system can be used, which is manufactured as an adhesive disk or patch that slowly releases the active compound(s) for percutaneous absorption. To this end, a penetration enhancer can be used to promote the percutaneous penetration of the active compound(s). Suitable transdermal patches are described, for example, in U.S. Pat. Nos. 5,407,713, 5,352,456, 5,332,213, 5,336,168, 5,290,561, 5,254,346, 5,164,189, 5,163,899, 5,088,977, 5,087,240, 5,008,110, and 4,921,475, which are incorporated herein by reference.

[0210] Alternatively, other pharmaceutical delivery systems can be used.Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compound(s).Certain organic solvents such as dimethylsulfoxide (DMSO) can also be used, but usually at the expense of higher toxicity.

[0211] The pharmaceutical composition may be present in a pack or dispenser device, which may contain one or more unit dosage forms containing the active compound(s), if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0212] C. Dosage The disclosed compounds or combinations of disclosed compounds will generally be used in an effective amount to achieve the intended result, e.g., an effective amount to treat, prevent, or ameliorate a particular condition. The disclosed compound(s) or compositions thereof may be administered therapeutically to achieve a therapeutic benefit, or prophylactically to achieve a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the underlying disorder during treatment, and / or eradication or amelioration of one or more of the symptoms associated with the underlying disorder, such that the patient reports a sensory or conditional improvement, even though the patient may still be suffering from the underlying disorder. For example, administration of a compound to a patient suffering from allergies provides therapeutic benefit not only when the underlying allergic response is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of symptoms associated with the allergy following exposure to an allergen. As another example, therapeutic benefit in the context of asthma includes improved breathing following the onset of an asthma attack, or a reduction in the frequency or severity of asthma episodes. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.

[0213] As known by those skilled in the art, the preferred dosage of the disclosed compounds may depend on a variety of factors, including age, weight, general health, and the severity of the condition of the patient or subject being treated. Dosage may also need to be adjusted for the gender of the individual and / or the lung capacity of the individual when administered by inhalation. Dosage may also be adjusted for individuals suffering from more than one condition, or individuals with additional conditions that affect lung capacity and normal breathing ability, such as emphysema, bronchitis, pneumonia, and respiratory infections. The dosage and frequency of administration of the disclosed compound(s) or compositions thereof will also depend on whether the disclosed compound(s) are formulated for the treatment of acute episodes of a condition or for the prophylactic treatment of a disorder. Those skilled in the art will be able to determine the optimal dose for a particular individual.

[0214] In prophylactic administration, the disclosed compounds, combinations of disclosed compounds, or compositions thereof can be administered to a patient or subject at risk of developing one of the aforementioned conditions. For example, if it is unknown whether a patient or subject is allergic to a particular drug, the disclosed compounds, combinations of disclosed compounds, or compositions thereof can be administered prior to administration of the drug to avoid or ameliorate an allergic reaction to the drug. Alternatively, prophylactic administration can be used to avoid or ameliorate the onset of symptoms in a patient diagnosed with an underlying disorder. For example, the disclosed compounds(s) or compositions thereof can be administered to an allergy sufferer prior to anticipated exposure to an allergen. The disclosed compounds, combinations of disclosed compounds, or compositions thereof can also be administered prophylactically to a healthy individual who is repeatedly exposed to a known agent for one of the above diseases to prevent the onset of the disorder. For example, the disclosed compounds, combinations of disclosed compounds, or compositions thereof can be administered to a healthy individual who is repeatedly exposed to an allergen known to induce allergies, such as latex, to prevent the individual from developing an allergy. Alternatively, a disclosed compound, a combination of disclosed compounds, or a composition thereof can be administered to a patient suffering from asthma prior to participating in activities that induce asthma attacks in order to reduce the severity of, or avoid altogether, an asthma episode.

[0215] Effective doses can be estimated initially from in vitro assays. For example, the initial dose for use in subjects may be determined based on the IC 50 or EC 50The active compound may be formulated to achieve a circulating or serum concentration that is equal to or greater than 100 mg / kg. Taking into account the bioavailability of a particular compound, the dosage that achieves such a circulating or serum concentration can be calculated. Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and references cited therein provide additional guidance regarding effective dosages.

[0216] In some embodiments, the disclosed compounds have an EC of greater than 0 to 20 μM, such as greater than 0 to 10 μM, greater than 0 to 5 μM, greater than 0 to 1 μM, greater than 0 to 0.5 μM, greater than 0 to 0.1 μM, or greater than 0 to 0.05 μM, with respect to a kinase protein, such as an IRAK protein. 50 has.

[0217] Initial dosage can also be estimated from in vivo data such as animal models. Animal models useful for testing the effectiveness of compounds for treating or preventing various diseases mentioned above are well known in the art. Suitable animal models of hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50(21Suppl):6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol. 107(6):1025-1033. Suitable animal models of allergic rhinitis are described in Szelenyi et al., (2000), Arzneimittelforschung 50(11):1037-42, Kawaguchi et al., (1994), Clin. Exp. Allergy 24(3):238-244, and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7. Those skilled in the art can adapt such information to determine suitable dosages for administration to humans.

[0218] Dosages of the disclosed compounds will typically range from about 0 mg / kg / day, such as 0.0001 mg / kg / day, or 0.001 mg / kg / day, or 0.01 mg / kg / day, up to at least about 100 mg / kg / day. More typically, dosages (or effective amounts) can range from about 0.0025 mg / kg to about 1 mg / kg per at least one daily administration, such as 0.01 mg / kg to about 0.5 mg / kg, or about 0.05 mg / kg to about 0.15 mg / kg. Total daily dosages typically range from about 0.1 mg / kg to about 5 mg / kg, or to about 20 mg / kg per day, such as 0.5 mg / kg to about 10 mg / kg per day, or about 0.7 mg / kg to about 2.5 mg / kg per day. Dosages may be higher or lower depending on, among other factors, the activity of the disclosed compound, its bioavailability, the mode of administration, and the various factors discussed above.

[0219] Dosage amount and dosing interval can be tailored to the individual to provide plasma levels of the disclosed compounds that are sufficient to maintain therapeutic or prophylactic effects.For example, the compounds can be administered once a day, multiple times a day, once a week, multiple times a week (e.g., every other day), once a month, multiple times a month, or once a year, depending on, among other things, the mode of administration, the particular indication being treated, and the judgment of the prescribing physician.Those skilled in the art will be able to optimize effective local dosages without undue experimentation.

[0220] A composition comprising one or more of the disclosed compounds typically comprises from greater than 0 up to 99% total weight percent of the disclosed compound or compounds, and / or other therapeutic agents. More typically, a composition comprising one or more of the disclosed compounds comprises from about 1 to about 20 total weight percent of the disclosed compounds and other therapeutic agents, and from about 80 to about 99 weight percent of pharma- ceutically acceptable excipients. A typical daily administration can range from 100 to 300 mg / day, e.g., 100, 150, 200, 250, or 300 mg / day. Administration can be once or more than once a day, e.g., 100 mg or 150 mg twice a day. Thus, a pharmaceutical dosage form comprising a compound disclosed herein can contain 50 to 300 mg of the disclosed compound, e.g., 50, 100, 150, 200, 250, 300 mg of the disclosed compound.

[0221] Preferably, the disclosed compounds, combinations of the disclosed compounds, or compositions thereof will provide therapeutic or prophylactic benefits without causing substantial toxicity. The toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxic effects and therapeutic (or prophylactic) effects is the therapeutic index. Disclosed compounds that exhibit high therapeutic indices are preferred. EXAMPLES

[0222] VII. Examples Example 1 3-(Dimethylamino)-1-(pyrimidin-2-yl)prop-2-en-1-one (D-2) A solution of 1-(pyrimidin-2-yl)ethan-1-one (D-1, 5 g, 40.95 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (11 mL, 81.9 mmol) was stirred at 90° C. overnight. The reaction was complete as monitored by LCMS. The volatiles were removed in vacuo and the crude product was used in the next reaction without further purification. 1H NMR(400MHz,chloroform-d) δ 8.89 (d,J = 4.9 Hz,2H),8.00 (d,J = 10.3 Hz,1H),7.35 (dd,J = 4.9,4.9 Hz,1H),6.39 (d,J = 10.3 Hz,1H),3.20 (s,3H),3.00 (s,3H);LRMS (M+H) m / z 178.2.

[0223] Example 2 2-(1H-pyrazol-3-yl)pyrimidine (D-3) TIFF2025513716000018.tif42165Hydrazine monohydrate solution (64-65% in water, 2.8 mL, ca. 0.9 equiv.) was added to a solution of 3-(dimethylamino)-1-(pyrimidin-2-yl)prop-2-en-1-one (D-2, 41 mmol) in EtOH (15 mL) while cooling in an ice bath. After refluxing for 3 h, the reaction was complete as monitored by LCMS. Volatiles were removed in vacuo and the crude product was used in the next reaction without further purification. 1 H NMR(400MHz,chloroform-d) δ 11.20 (br s,1H),8.79 (d,J = 4.9 Hz,2H),7.71 (d,J = 2.0 Hz,1H),7.22 (dd,J = 4.9,4.9 Hz,1H),7.08 (d,J = 2.0 Hz,1H);LRMS(M+H) m / z 147.1.

[0224] Example 3 2-(4-nitro-1H-pyrazol-3-yl)pyrimidine (D-4) TIFF2025513716000019.tif4816590% fuming nitric acid (3.8 mL, 81.9 mmol) was added dropwise to a suspension of 2-(1H-pyrazol-3-yl)pyrimidine (D-3, ca. 41 mmol) in concentrated H2SO4 (10 mL) while cooling in an ice bath. After complete addition of nitric acid, the mixture was stirred at 70 °C overnight. The reaction was complete as monitored by LCMS. After cooling to room temperature, the mixture was carefully poured into ice water. The pH was adjusted to 8 with aqueous NaOH, and the product was extracted with EtOAc (100 mL × 5). The combined organic layers were dried (Na2SO4), filtered, and the solvent was removed in vacuum. After silica gel chromatography purification, compound 2-(4-nitro-1H-pyrazol-3-yl)pyrimidine (D-4) was obtained as an off-white solid in 5.6 g (71.5% yield for three steps); 1 H NMR (400 MHz, chloroform-d) δ 11.26 (br s, 1H), 8.90 (d, J = 4.9 Hz, 2H), 8.28 (s, 1H), 7.40 (dd, J = 4.9, 4.9 Hz, 1H); LRMS (M+H) m / z 192.1.

[0225] Alternative procedure: To a suspension of 2-(1H-pyrazol-3-yl)pyrimidine (D-3, 32.6 g, 223 mmol) in concentrated H2SO4 (200 mL), fuming nitric acid (100 mL) was added dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was carefully poured onto ice and 27N aqueous NaOH was added to adjust the pH to 6. The solid was collected by filtration, washed with water and dried in vacuum. Compound 2-(4-nitro-1H-pyrazol-3-yl)pyrimidine was obtained as an off-white solid in 29.2 g (69% yield).

[0226] Example 4 8-Ethoxy-1,4-dioxaspiro[4.5]decane (B-2) TIFF2025513716000020.tif32165 A solution of 1,4-dioxaspiro[4.5]decanol B-1 (158 g, 1.0 mol, 1.0 equiv) in tetrahydrofuran (500 mL) was added to a suspension of hexane-washed sodium hydride (48 g of a 60% suspension in mineral oil, 1.2 mol, 1.2 equiv) in tetrahydrofuran (500 mL) at 0° C. The reaction was stirred at 0° C. for 15 min and at room temperature for 4 h, then cooled to 0° C. and iodoethane (104.5 mL, 1.3 mol, 1.3 equiv) was added. The reaction was stirred at 0° C. for 10 min and at room temperature for 14 h. The reaction was quenched by careful addition of NH4Cl (ca. 100 mL). The reaction was concentrated to remove tetrahydrofuran and the concentrate was partitioned between EtOAc (800 mL) and water (600 mL). The aqueous phase was extracted with EtOAc (300 mL). The combined organics were washed with NaHCO3 (500 mL) and brine (500 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (177 g, 95%) as an orange oil which was used without purification. 1 H nmr(400MHz,CD3Cl) δ 3.90,3.89 (4H,2d AB series,J 2.5 Hz,OCH2CH2O),3.44 (2H,q,J 7.0 Hz,OCH2CH3),3.35 (1H,tt,J 7.5,3.0 Hz,H-8),1.82-1.74 (4H,m,4H's H-6,H-7,H-9,H-10),1.70-1.63 (2H,m,2H's H-6,H-7,H-9,H-10),1.54-1.47 (2H,m,2H's H-6,H-7,H-9,H-10),1.15 (3H,t,J 7.0 Hz,OCH2CH3).

[0227] Example 5 4-Ethoxycyclohexan-1-one (B-3) TIFF2025513716000021.tif32165 Hydrochloric acid (450 mL of a 3 M solution) was added to a solution of dioxalane B-2 (177 g, 952 mmol) in tetrahydrofuran (450 mL). The reaction was stirred vigorously at 60° C. for 20 h. NMR analysis suggested 75% completion. Additional hydrochloric acid (100 mL of a 4 M solution) was added and the reaction was stirred at 60° C. for a further 24 h before being cooled and concentrated to remove tetrahydrofuran. The organics were extracted with EtOAc (3×400 mL). The combined organics were washed with brine (400 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (142.2 g, theoretical yield 135.1 g) as an orange oil; 1 H nmr (400 MHz, CD3Cl) δ 3.71 (1H, m, cyclohexane H-4), 3.55 (2H, q, J 7.0 Hz, OCH2CH3), 2.58 (2H, ddd, J 15.5, 10.5, 6.0 Hz, 2H cyclohexane H-2, H-6), 2.25 (2H, m, 2H cyclohexane H-2, H-6), 2.10-2.02 (2H, m, 2H cyclohexane H-3, H-5), 1.98-1.90 (2H, m, 2H cyclohexane H-3, H-5), 1.24 (3H, t, J 7.0 Hz, OCH2CH3).

[0228] Example 6 (1s,4s)-4-Ethoxycyclohexan-1-ol (B-4) TIFF2025513716000022.tif32165 A solution of ketone B-3 (146.2 g, 1.0 equiv) in tetrahydrofuran (300 mL) was cooled to -78°C. Lithium aluminum hydride (400 mL of a 1 M solution in tetrahydrofuran, 400 mmol, 0.4 equiv) was added dropwise over 90 min. The reaction was stirred at -78°C for an additional 30 min and the reaction was quenched by first adding NaOH (1 M, 300 mL) dropwise at -78°C before being removed from the cold bath. A gel was obtained. The reaction was diluted with EtOAc (400 mL) and stirred before being decanted to remove the gel. The decanted organics were washed with Rochelle's salt (400 mL) and the aqueous phase was back extracted with EtOAc (200 mL). The combined organics were washed with Rochelle's salt (300 mL) and brine (400 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (131.1 g) as an orange oil without purification. 1 H nmr (400 MHz, CD3Cl) δ 3.74 (1H main, m, cyclohexane H-1), 3.68 (1H minor, m, cyclohexane H-1), 3.48 (2H minor, J 7.0 Hz, OCH2CH3), 3.47 (2H minor, J 7.0 Hz, OCH2CH3), 3.37 (1H main, tt, J 6.5, 3.0 Hz, H-4), 3.25 (1H minor, m, H-4), 1.99 (1H, m, 1H H-2, H-3, H-5, H-6), 1.81 (2H, m, 2H H-2, H-3, H-5, H-6), 1.73-1.51 (5H, m, 5H H-2, H-3, H-5, H-6), 1.19 (3H Main,t,J 7.0 Hz,OCH2CH3),1.19 (3H sub,J 7.0 Hz,OCH2CH3).

[0229] Example 7 (1r,4r)-4-Ethoxycyclohexyl 4-nitrobenzenesulfonate (B-5) TIFF2025513716000023.tif27165To a solution of 4-ethoxycyclohexan-1-ol B-4 (112.9 g, 782.9 mmol, 1.0 equiv. as approximately 2:1 ratio of 1s,4s and 1r,4s diastereomers) in dichloromethane (800 mL) was added 1,4-diazabicyclo[2.2.2]octane (105.4 g, 939.5 mmol, 1.2 equiv.) at 0° C. 4-Nitrobenzenesulfonyl chloride (190.8 g, 861.2 mmol, 1.1 equiv.) was added in portions over 1 h at 0° C. and the reaction was allowed to warm to room temperature over 16 h. The reaction was diluted with CH2Cl2 (400 mL) and washed with NaHCO3 (1 L), water (1 L), and brine (1 L). The organics were dried (Na2SO4) and concentrated under reduced pressure. The resulting solid was triturated from ethyl acetate and hexane to give 160.8 g of 4-ethoxycyclohexyl 4-nitrobenzenesulfonate (as a mixture of 1r,4r and 1s,4s) as an off-white solid; 1 H nmr(400MHz,CD3Cl) δ 8.39 (2H,d,J 9.0 Hz,2H C6H4NO2),8.11 (2H,d,J 9.0 Hz,2H C6H4NO2),4.75 (1H main,tt,J 7.5,3.5 Hz,H-1),4.70 (1H sub,m,H-1),3.45 (2H sub,J 7.0 Hz,OCH2CH3),3.44 (2H main,J 7.0 Hz,OCH2CH3),3.34 (1H,tt,J 6.5,3.0 Hz,H-4),1.99-1.88 (3H,m,3H H-2,H-3,H-5,H-6),1.80-1.71 (1H,m,1H H-2,H-3,H-5,H-6), 1.67-1.56 (3H,m,3H H-2,H-3,H-5,H-6), 1.48-1.40 (1H,m,1H H-2,H-3,H-5,H-6), 1.17 (3H major,t,J 7.0 Hz,OCH2CH3), 1.16 (3H minor,J 7.0 Hz,OCH2CH3).

[0230] Example 8 2-(1-(trans-4-ethoxycyclohexyl)-4-nitro-1H-pyrazol-3-yl)pyrimidine (E-1) TIFF2025513716000024.tif63165Under a nitrogen atmosphere, and cooling with an ice bath, NaH (60% dispersion in mineral oil, 1.68 g, 42 mmol) was added in small portions to a suspension of 2-(4-nitro-1H-pyrazol-3-yl)pyrimidine (D-4, 5.73 g, 30 mmol) in 1,4-dioxane (150 mL, 0.2 M). After removing the ice bath, the suspension was stirred at 25 °C. After 3 h, compound 4-ethoxycyclohexyl 4-nitrobenzenesulfonate (B-5, 11.86 g, 36 mmol, cis / trans ratio ≥ 2) was added and the reaction mixture was stirred at gentle reflux at 100 °C. After 19 h, another ca. 0.4 equivalents (5 g) of B-5 was added and the reaction was continued. The progress of the reaction was monitored by LC-MS, and it was stopped on the fourth day. After cooling to room temperature, the reaction was quenched with saturated aqueous NaHCO3 (100 mL) and most of the dioxane was removed by rotary evaporation under reduced pressure. The product was extracted with EtOAc (150 mL), which was further washed with brine. The organic layer was dried (Na2SO4), filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by silica gel chromatography followed by trituration from hexane-EtOAc (8 mL-2 mL, 35°C, overnight, then collected as a precipitate at room temperature). Compound 2-(1-(trans-4-ethoxycyclohexyl)-4-nitro-1H-pyrazol-3-yl)pyrimidine (E-1) was obtained in 1.98 g (21% yield) as an off-white solid; 1H NMR(400MHz,chloroform-d) δ 8.89 (d,J = 4.9 Hz,2H),8.24 (s,1H),7.37 (dd,J = 4.9,4.9 Hz,1H),4.27 (tt,J = 11.8,3.9 Hz,1H),3.55 (q,J = 7.0 Hz,1H),3.35 (tt,J = 10.7,4.2 Hz,1H),2.35 - 2.29 (m,2H),2.26 - 2.20 (m,2H),1.94 - 1.83 (m,2H),1.50 - 1.40 (m,2H),1.22 (t,J = 7.0 Hz,3H);LRMS(M+H) m / z 318.3.

[0231] Example 9 1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-amine TIFF2025513716000025.tif63165 In a Parr flask, under 15 psi of hydrogen, a solution of 2-(1-(trans-4-ethoxycyclohexyl)-4-nitro-1H-pyrazol-3-yl)pyrimidine (E-1, 974.2 mg, 3.07 mmol) and Pd-BaSO4 (5% Pd on BaSO4, 450 mg) in MeOH (30 mL) was shaken at room temperature for 4 hours. The reaction was complete as monitored by LC-MS. Under a nitrogen atmosphere, the reaction mixture was passed through a Celite pad, which was further washed with MeOH. The filtrate was collected and the solvent was removed in vacuo. Compound 1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-amine was obtained as a pale yellow solid (used in the next reaction without further purification). 1H NMR(400MHz,chloroform-d) δ 8.75 (d,J = 4.9 Hz,2H),7.09 - 7.06 (m,2H),4.56 (br s,2H),4.20 (tt,J = 12.1,3.7 Hz,1H),3.54 (q,J = 7.0 Hz,2H),3.33 LRMS(M+H) m / z 288.3.

[0232] Example 10 N-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide (I-1) TIFF2025513716000026.tif581652-(1H-pyrazol-4-yl)thiazole-4-carboxylic acid (599.2 mg, 3.07 mmol) was added to a solution of 1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-amine (3.07 mmol) in DMF (12 mL) while cooling in an ice bath, followed by HATU (1.28 g, 3.38 mmol) after 30 min. After another hour, N-ethyl-N-isopropylpropan-2-amine (DIPEA, 1.6 mL, 9.2 mmol) was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 16 h. The reaction was quenched by dropwise addition of saturated aqueous NaHCO3 (300 mL), and after 1 h, the precipitate was collected by filtration, washed with H2O, and then dried in vacuum. A yellow solid (about 1.17 g) was obtained and dissolved in CHCl2-MeOH (10:1). The solution was then passed through a silica gel pad to remove darker impurities. Compound N-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide (I-1) was obtained as a pale yellow solid in 1.10 g (77% yield);1 H NMR(400MHz,chloroform-d) δ 12.04 (s,1H),11.10 (v br s,1H),8.90 (d,J = 4.9 Hz,2H),8.49 (s,1H),8.16 (s,2H),8.10 (s,1H),7.23 (dd,J = 4.9,4.9 Hz,1H),4.34 (tt,J = 12.0,3.9 Hz,1H),3.56 (q,J = 7.0 Hz,2H),3.37 (tt,J = 10.8,4.2 Hz,1H),2.33 - 2.29 (m,2H),2.25 - 2.20 (m,2H),2.00 - 1.89 (m,2H),1.51 - 1.41 (m,2H),1.22 (t,J = 7.0 Hz,3H); 13 C NMR (101 MHz, chloroform-d) δ 161.47, 160.21, 158.35, 157.15, 150.29, 136.25, 132.67, 122.71, 121.86, 119.89, 118.68, 117.15, 76.33, 63.62, 61.83, 31.09, 31.01, 15.65; LRMS (M+H) m / z 465.4.

[0233] The compounds were used without further purification to make tartrate salts / co-crystals and for prodrug synthesis. Additionally, if necessary, the compounds were further purified by silica gel chromatography or RP-HPLC.

[0234] Example 11 Alternative synthesis of I-1 A. 2-Bromo-N-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide (E-2) TIFF2025513716000027.tif631652-Bromothiazole-4-carboxylic acid (298 mg, 1.43 mmol) and HATU (572 mg, 1.50 mmol) in CHCl (20 mL) were stirred at room temperature for 15 min. N-Ethyl-N-isopropylpropan-2-amine (0.623 mL, 3.58 mmol) was added while cooling in an ice bath, followed by a solution of 1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-amine (452 ​​mg, 1.576 mmol) in CHCl (5 mL). The reaction mixture was stirred at room temperature for 17 h, after which LC-MS showed the reaction was complete. The reaction was quenched by adding saturated aqueous NaHCO and stirring was continued for 30 min. The two layers were separated, and the organic layer was washed again with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. After silica gel chromatography, 581.1 mg (85% yield) of the compound 2-bromo-N-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide (E-2) was obtained as a white solid; 1 H NMR(400MHz,chloroform-d) δ 8.89 (d,J = 4.9 Hz,2H),8.42 (s,1H),8.12 (s,1H),7.22 (dd,J = 4.9,4.9 Hz,1H),4.33 (tt,J = 12.0,3.9 Hz,1H),3.56 (q,J = 7.0 Hz,2H),3.36 (tt,J = 10.8,4.2 Hz,1H),2.32 - 2.28 (m,2H),2.24 - 2.20 (m,2H),1.99 - 1.89 (m,2H),1.50 - 1.41 (m,2H),1.22 (t,J = 7.0 Hz,3H);LRMS(M+H) m / z 477.3,479.3.

[0235] BN-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide (I-1) A suspension of 2-bromo-N-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide (E-2, 477.4 mg, 1 mmol), (1H-pyrazol-4-yl)boronic acid (279.8 mg, 2.5 mmol), Na2CO3 (318 mg, 3 mmol), and tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.02 mmol) in 1,4-dioxane-HO (4 mL-1 mL) was degassed and then backfilled with nitrogen three times. The mixture was heated at 90 °C under nitrogen atmosphere for 21.5 h, after which LC-MS indicated the reaction was complete. Most of the dioxane was removed by rotary evaporation under reduced pressure, and the crude product was mixed with water and saturated aqueous NaHCO3 until a free-flowing solid appeared. The solid was collected by filtration, washed with H2O, and then stirred in hexane-EtOAc-EtOH (1 mL-3 mL-0.5 mL) at 35°C over the weekend. The solid product was collected by filtration, washed with ice-cold hexane-EtOAc (ca. 1:1), and dried in vacuum. Compound N-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide (I-1) was obtained in 287.1 mg (62% yield) as a light beige solid; 1H NMR(400MHz,chloroform-d) δ 12.04 (s,1H),11.10 (v br s,1H),8.90 (d,J = 4.9 Hz,2H),8.49 (s,1H),8.16 (s,2H),8.10 (s,1H),7.23 (dd,J = 4.9,4.9 Hz,1H),4.34 (tt,J = 12.0,3.9 Hz,1H),3.56 (q,J = 7.0 Hz,2H),3.37 (tt,J = 10.8,4.2 Hz,1H),2.33 - 2.29 (m,2H),2.25 - 2.20 (m,2H),2.00 - 1.89 (m,2H),1.51 - 1.41 (m,2H),1.22 (t,J = 7.0 Hz,3H);LRMS(M+H) m / z 465.4.

[0236] Example 12 N-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (2R,3R)-2,3-dihydroxysuccinic acid (I-4; Tartrate salt of I-1 / cocrystal) TIFF2025513716000029.tif58165N-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide (I-1, 1.10 g, 2.37 mmol) and (L)-tartaric acid (177.9 mg, 1.19 mmol) in CHCl 2- The MeOH (12 mL-1 mL) solution was stirred at 35° C. for 18 h. Another 12 mL of CH2Cl2 was added and stirring was continued for another 5 h. After cooling to room temperature, the precipitate was collected by filtration, washed with ice-cold CH2Cl2, and dried in vacuum. The product was obtained as a pale yellow solid, 702.7 mg; 1H NMR(400MHz,DMSO-d6) δ 13.41 (br s,1H),12.68 (br s,2H),11.93 (s,1H),8.98 (d,J = 4.9 Hz,2H),8.52 (v br s,1H),8.50 (s,1H),8.31 (s,1H),8.13 (v br s,1H),7.49 (dd,J = 4.9,4.9 Hz,1H),5.08 (br s,2H),4.39 - 4.31 (m,3H),3.50 (q,J = 7.0 Hz,2H),3.41 - 3.31 (m,overlapping with H2O,1H),2.13 - 2.06 (m,4H),1.96 - 1.86 (m,2H),1.41 - 1.32 (m,2H),1.12 (t,J = 7.0 Hz,3H); 13 C NMR(101MHz,DMSO-d6) δ 173.14,161.27,160.61,157.55,157.31,149.07,135.61,132.61,123.08,121.86,1 20.21,119.46,115.64,75.64,72.13,62.58,60.34,30.60,30.50,15.67;LRMS(M+H) m / z 465.5.

[0237] For the filtrate: After removing the solvent, the material was dissolved in CHCl. 2- Redissolved in MeOH (12 mL-1 mL) and additional (L)-tartaric acid (177.9 mg, 1.19 mmol) was added. After a similar reaction and work-up procedure, another crop of product was obtained as a pale yellow solid, 280.9 mg, identical to the first crop. 1 H NMR.

[0238] Total: 983.6mg, 68% yield.

[0239] Example 13 Di-tert-butyl((4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate tert-butyl((4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)hydrogen phosphate TIFF2025513716000030.tif53165Cs2CO3 (495 mg, 1.52 mmol) was added to a solution of N-(1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide (I-1, 470.6 mg, 1.01 mmol) in DMF (5 mL) at room temperature. After 10 min, di-tert-butyl(chloromethyl)phosphate (524 mg, 2.03 mmol) was added. After 22 h, the main peak on LC-MS was the desired product (m / z 687.7 (M+H)) with less than 5% of compound I-1 remaining. The reaction was quenched by dropwise addition of water (60 mL) while cooling in an ice bath and stirring was continued at room temperature. After 3 h, the product was extracted with CH2Cl2 (50 mL x 2). The combined organic layers were dried (Na2SO4), filtered, and the solvent was removed in vacuo. A light brown oil was obtained, mainly mono- t Appeared to be Bu product: 635 mg; 1H NMR(400MHz,chloroform-d) δ 11.97 (s,1H),8.88 (d,J = 4.9 Hz,2H),8.01 - 8.00 (m,3H),7.97 (s,1H),7.25 (dd,J = 4.9,4.9 Hz,1H),5.96 (d,J = 12.1 Hz,2H),4.32 (tt,J = 11.8,3.9 Hz,1H),3.57 (q,J = 7.0 Hz,2H),3.37 (tt,J = 10.7,4.2 Hz,1H),2.33 - 2.30 (m,2H),2.25 - 2.21 (m,2H),1.99 - 1.89 (m,2H),1.45 (s,partially overlapping,9H),1.51 - 1.36 (m,partially overlapping,2H),1.23 (t,J = 7.0 Hz,3H); 31 P NMR (162 MHz, chloroform-d) δ -5.03; LRMS (M+H) m / z 631.6.

[0240] The aqueous layer was adjusted to pH 2 with 1N HCl (aq) and the precipitate was collected which was further washed with H2O to give 55.3 mg of a bright yellow solid which was mostly acid by LCMS.

[0241] From a different reaction using a similar work-up procedure, di- t The Bu product was obtained: 1H NMR(400MHz,chloroform-d) δ 12.08 (s,1H),8.96 (d,J = 4.9 Hz,2H),8.47 (s,1H),8.35 (s,1H),8.09 (s,1H),8.08 (s,1H),7.25 (dd,J = 4.9,4.9 Hz,1H),5.96 (d,J = 13.2 Hz,2H),4.34 (tt,J = 11.6,3.8 Hz,1H),3.56 (q,J = 7.0 Hz,2H),3.37 (tt,J = 10.4,4.5 Hz,1H),2.33 - 2.30 (m,2H),2.24-2.20 (m,2H),2.00 - 1.89 (m,4H),1.50-1.41(m,partially overlapping,2H),1.44 (s,partially overlapping,18H),1.22 (t,J = 7.0 Hz,3H);LRMS(M+H) m / z 687.7).

[0242] Example 14 (4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate (I-2) TIFF2025513716000031.tif53165 Trifluoroacetic acid (TFA) (0.613 mL, 8 mmol) was added to a solution of tert-butyl ((4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)hydrogen phosphate (635 mg, 1 mmol) in CHCl (7 mL) while cooling in an ice bath and stirring was continued at room temperature. After 2 h, LC-MS indicated the reaction was complete. The volatiles were removed in vacuo to give a light brown oil. The crude product was suspended in acetone-H0 (10:1, 12 mL) at 35 °C for 15 h. The solid was collected by filtration, washed with acetone, and then further suspended in CHCl (5 mL) at room temperature for 1 h. The precipitate was collected by filtration, washed with CHCl, and dried in vacuum. Compound (4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate (I-2) was obtained in 277.6 mg (52% yield) as a pale yellow solid; 1 H NMR(400MHz,DMSO-d6) δ 11.97 (s,1H),11.62 (v br s,1H),9.02 (d,J = 4.9 Hz,2H),8.63 (d,J = 0.8 Hz,1H),8.49 (s,1H),8.36 (s,1H),8.20 (d,J = 0.8 Hz,1H),7.46 (dd,J = 4.9,4.9 Hz,1H),5.92 (d,J = 11.2 Hz,2H),4.35 (tt,J = 11.5,3.7 Hz,1H),3.50 (q,J = 7.0 Hz,2H),3.37 (tt,J = 10.7,3.8Hz,1H),2.13 - 2.07 (m,4H),1.96 - 1.85 (m,2H),1.41 - 1.31 (m,2H),1.12 (t,J = 7.0 Hz,3H); 31 P NMR(162 MHz,DMSO-d6) δ -2.17;LRMS(M+H) m / z 575.5.

[0243] Example 15 Sodium (4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate (I-3) TIFF2025513716000032.tif581651N NaOH solution (0.9 mL, 0.9 mmol) was added dropwise to a suspension of (4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate (I-2, 258.5 mg, 0.45 mmol) in CH3CN (2 mL) and HO (2 mL) while cooling in an ice bath until pH = 8 was obtained. Stirring was continued at room temperature for another 10 min and the solvent was removed by lyophilization. The compound sodium (4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate (I-3) was obtained as a cream-colored solid in 278 mg (99% yield); 1 H NMR (400MHz, deuterium oxide) δ 8.63 (d,J = 5.0 Hz,2H),8.23 (s,1H),8.10 (s,1H),7.81 (s,1H),7.74 (s,1H),7.27 (dd,J = 5.0,5.0 Hz,1H),5.74 (d,J = 6.8 Hz,2H),4.21 (br t,J = 12.1 Hz,1H),3.73 (q,J = 7.1 Hz,2H),3.69 - 3.59 (m,1H),2.31 - 2.23 (m,4H),1.93 - 1.84 (m,2H),1.53 - 1.44 (m,2H),1.25 (t,J = 7.1 Hz,3H); 31 P NMR (162MHz, deuterium oxide) δ 2.10; LRMS (M+H) m / z 575.4.

[0244] Example 16 1,3-Dihydroxy-2-(hydroxymethyl)propan-2-aminium (4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate (I-5) To a suspension of (4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate (I-2, 25 mg, 0.0435 mmol) in i-PrOH-HO (0.2 mL-0.2 mL) was added 2-amino-2-(hydroxymethyl)propane-1,3-diol (5.4 mg, 0.044 mmol) and the thin suspension was stirred at 30 °C overnight. After cooling to room temperature, additional i-PrOH (0.2 mL, then up to 0.5 mL) was added and the mixture remained cloudy with no free-flowing precipitate. After removing most of the organic solvent by rotary evaporation under reduced pressure, the mixture was resuspended in i-PrOH-ACN-H2O until a white solid appeared. After filtration, the collected (hygroscopic) solid was dissolved in water and the solvent was removed in vacuo. The title compound 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium (4-(4-((1-(trans-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate (I-5) was obtained as an off-white solid in 15.2 mg (50% yield); 11H NMR (400 MHz, deuterium oxide) δ 8.45 (d, J = 4.9 Hz, 2H), 8.01 (s, 1H), 7.92 (s, 1H), 7.60 (s, 1H), 7.51 (s, 1H), 7.13 (dd, J = 4.9, 4.9 Hz, 1H), 5.68 (d, J = 7.9 Hz, 2H), 4.11 (br t, J = 12.2 Hz, 1H), 3.72 - 3.67 (m, 8H), 3.58 (tt, J = 11.1, 3.9 Hz, 1H), 2.28 - 2.25 (m, 2H), 2.20 - 2.17 (m, 2H), 1.86 - 1.77 (m, 2H), 1.49 - 1.40 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H); 31 31P NMR (162 MHz, deuterium oxide) δ 0.18; LRMS (M+H) m / z 576.1.

[0245] Example 17 LPS-induced IL23p19 assay in THP-1 cells (primed with IFNγ) Materials and equipment THP-1 cells (ATCC, Cat#TIB-202), dimethyl sulfoxide (DMSO) (Sigma-Aldrich, Cat#D2650), RPMI1640 (Cellgro, Cat#10-040-CM), fetal bovine serum (Sigma, Cat#F4135), bovine serum albumin (BSA) (Sigma-Aldrich, Cat#A7906), LPS (serotype K-235, Sigma, product number L2143), IFNγ (Peprotech, Cat#300-02), capture antibody: human IL-23p19 ELISA (e-Bioscience, Cat#14-7238-85), detection antibody: Primary Mouse Biotinylated Anti-Human IL-12 (p40 / p70) (e-Bioscience, Cat#13-7129-85), Secondary HRP-conjugated Streptavidin (R&D Systems, Cat#DY998), 1x PBST Wash Buffer (PBS-Tween Tablets) (VWR International, Cat#80058-558), ELISA Blocking Buffer (PBS with 1% BSA), ELISA Dilution Buffer (PBS with 1% BSA), 384-well flat bottom, MaxiSorp black immunoplates (Thermo Scientific, Cat#12-565-346), 384-well flat bottom, white tissue culture plates (Thermo Scientific, Cat#12-565-343), Super Signal ELISA Pico Chemiluminescent Substrate (Thermo Scientific, Cat#37070), Cell Titer Glo reagent (Promega, Cat# G7573), positive control, IKK2VI inhibitor (Calbiochem, Cat# 401483), AquaMax 4000 plate washer (Molecular Devices), luminometer, Wallac Victor2 1420 Multilabel Counter.

[0246] method THP-1 cell stimulation: On day 1, 50K / well THP-1 cells were seeded in 384-well plates and primed with IFNγ (50ng / mL) in RPMI medium with 10% FBS for approximately 18 hours. On day 2, compounds were serially diluted in 3-fold dilutions starting from 5mM in DMSO and then diluted 1:125 in RPMI medium with 10% FBS. 50μL / well of 2x compound was added in duplicate to 50μL / well of THP-1 cells (primed with IFNγ) in 384-well tissue culture plates. Cells were pre-incubated with compound for 1 hour at 37°C, 5% CO2, followed by the addition of 10μL / well of 11×LPS to a final concentration of 1μg / mL LPS. On day 3, after stimulation for 18 hours at 37°C, 5% CO2, the assay plates were centrifuged and 70μL / well of supernatant was collected. IL-23p19 protein in 70 μL / well of supernatant was measured by sandwich ELISA and 25 μL / well of Cell Titer Glo reagent was added to the remaining cells to measure compound toxicity.

[0247] Human IL-23p19 Sandwich ELISA: Maxisorp immuno ELISA plates were pre-coated with 25 μL / well of anti-IL-23p19 capture antibody in PBS (2.5ug / mL) overnight at room temperature. After washing with 1×PBST, the plates were blocked with 100 μL / well of 1% BSA in PBS for 2 hours at room temperature. The plates were washed 3 times with 1×PBST and 70 μL / well of supernatant was added. The plates were incubated for 2 hours at room temperature with shaking and washed 3 times with 1×PBST. 25 μL / well of biotin-labeled anti-IL-12 (p40 / p70) detection antibody in 1% BSA in PBS (100ng / mL) was added and the plates were incubated for 2 hours at room temperature with shaking. After washing 3 times with 1×PBST, 25 μL / well of streptavidin-HRP (1:200) in 1% BSA in PBS was added and the plates were incubated for 20 minutes at room temperature with shaking. Plates were washed 3 times with 1x PBST and 25 μL / well of Super Signal ELISA Pico Chemiluminescent Substrate was added. Plates were read in a luminometer and chemiluminescence values ​​were curve fitted and EC 50 The data was input into Athena (Rigel) for calculation and database storage. The results are shown in Table 1.

[0248] Example 18 Compound screening using DC cells material Human PBMC cells (whole cells, Cat No. PB002) RPMI growth medium containing 10% FBS IFNγ (Peprotech, Cat No. 300-02) GMCSF (Peprotech, Cat No. 300-03) and IL4 (Peprotech Cat No. 200-04) White clear bottom 96-well plate (Fisher, Cat No. 07-200-587, Corning #3903) LPS (made stock at 2.5mg / ml in PBS) from Sigma Aldrich (Cat No. L2018-5MG) Cell Titer Glo Reagent (Promega, Cat No. G7573) Positive control, IKK2VI inhibitor (Calbiochem, Cat No. 401483)

[0249] protocol 1. Differentiation of PBMCs into DC cells: Human PBMC cells (400 million) obtained from a supplier were transferred to a T-175 flask containing 15 ml of RPMI medium (10% FBS) and incubated for 2 hours at 37° C. After 2 hours, the medium containing the suspended cells was carefully aspirated, 12 ml of fresh RPMI medium (10% FBS) containing GMCSF (100 ng / ml) and IL4 (20 ng / ml) was added, and the flask was maintained in a 37° C. incubator for 7 days.

[0250] After 3 days, fresh GMCSF (100ng / ml) and IL4 (20ng / ml) were added to the flask and incubation was continued. After 7 days, fully differentiated cells were harvested by spinning down (1200rpm / 5min) and the medium was aspirated. Cells were suspended in fresh RPMI medium (10%FBS) containing 50ng / ml IFNγ (1000U / ml) and then seeded (50K / well in 100μl) onto white clear bottom 96 well plates and left in a 37℃ incubator for 24 hours.

[0251] 2. Addition of compounds: After 24 h of incubation, 100 μl of RPMI medium containing 2x concentrated test compounds per well was added to the above cell culture medium (to a final concentration of 1x) and the plates were preincubated at 37°C for 1 h before LPS stimulation.

[0252] After 1 hour of compound pre-incubation, 10 μl / well of a 20-fold concentrated LPS solution in RPMI medium was added to a final concentration of 1 μg / ml. The mixture was shaken and the plates were incubated at 37° C. for an additional 18 hours.

[0253] 155μl of supernatant was carefully collected from each well (without the tip touching the bottom of the well) and 50μl of Cell Titer Glo reagent was added to the remaining 50μl / well of the cell culture plate. The mixture was incubated on a shaker for 1-2 minutes and the luminescence intensity of the plate was read to determine the cytotoxicity of the compound. Using the cell culture supernatant collected above, IL23 ELISA (65μl supernatant) and IL10 ELISA (90μl supernatant) were performed as follows.

[0254] Example 19 Human IL-23 (p19 / p40) ELISA Protocol (e-Biosciences) material: 96-well high-binding opaque white plates (Pierce, Cat No. 15042); 1x PBS; 1x TBST washing buffer; Blocking solution: 0.5% casein in PBS (BDH, Cat No. 440203H); Diluent: 1% BSA in PBS (10% BSA, Fisher, Cat No. 37525); Capture antibody: rat anti-human IL-23(p19) (e-Biosciences, Cat. No. 14-7238-85); Detection antibody: primary mouse biotinylated anti-human IL-12 (p40 / p70) (e-biosciences, Cat No. 13-7129-85); secondary HRP-conjugated streptavidin (R&D Systems, Cat No. DY998); rHuman-IL-23 (e-biosciences, Cat No. 34-8239) (recommended starting concentration = 5ng / ml in RPMI cell culture medium); cell culture supernatant (65 μl, from THP-1 cells primed with IFNγ (50 ng / ml–1000 U / ml) and stimulated with 0.01% SAC); SuperSignal ELISA Pico Chemiluminescent substrate [Pierce, Cat No. 37069].

[0255] Plate Coating: To 10.5 ml of PBS, 50 μl of anti-IL23 (p19) was added, followed by capture antibody (2.5 μg / ml). The mixture was mixed well and 100 μl of coating solution was added to each well of a 96-well white plate from Pierce. The wells were covered and incubated overnight at 4°C.

[0256] Blocking the plates: Anti-IL23(p19) antibody-coated plates were washed twice with TBST (using a plate washer) and blocked with 200 μl of 0.5% casein for 1.5-2 h at room temperature with shaking.

[0257] Supernatant addition and detection: Plates were washed twice with TBST and supernatants were transferred (65 μl / well) to the above preblock / IL23(p19) antibody coated 96-well plates and incubated for 1.5 hours at room temperature with shaking.

[0258] Plates were washed 4 times with TBST (plate washer) and 100 μl / well of detection antibody solution was added, prepared from 2 μl of biotin-labeled anti-IL-12 (p40 / p70) antibody in 11 ml of 1% BSA / PBS solution (1-5000 dilution). Plates were incubated for 1 hour at room temperature with shaking.

[0259] The plate was washed again four times with TBST, 100 μl of HRP-labeled streptavidin (R&D Systems) solution (10 μl / 10 ml 1% BSA solution) was added, and the plate was incubated for a further 45 minutes at room temperature with shaking.

[0260] After 45 minutes, plates were washed 4 times with TBST and 100ul / well of Pierce Super Signal ELISA Pico Chemiluminescent Substrate (3.5mL A+3.5mL B+3.5mL MQ water) was added. Plates were shaken for 1-2 minutes and then read on a plate reader.

[0261] Example 20 IRAK4 ADP-GLO assay material IRAK4 kinase enzyme (Signalchem, I12-10G-20), 0.1M DTT (Signalchem, D86-09B), MBP Substrate (Signalchem, M42-51N), ADP Glo (Promega, V9101), 1M MgCl2 (Teknova, M03304), 1M Tris-HCl pH 7.4 (Teknova, T1074), BSA (Sigma (A3059), distilled H2O

[0262] Device Wallac Victor2 1420 Multilabel Counter

[0263] method ADP-Glo™ Reagent was thawed at ambient temperature. Kinase Detection Reagent was prepared and secured by mixing Kinase Detection Buffer with lyophilized Kinase Detection Substrate.

[0264] A 5x stock volume of reaction kinase buffer was made with final concentrations of 100 mM MgCl2, 200 mM Tris-HCl, and 0.5 mg / ml BSA in distilled H2O, final pH 7.4. A 2x working stock volume of reaction kinase buffer was made containing a final concentration of 100 μM DTT.

[0265] IRAK4 enzyme components were thawed on ice. IRAK4 was prepared at 5.0 ng / μl in 1x kinase reaction buffer (diluted from 2x buffer). A working stock ATP assay solution of 250 μM was prepared in 1x kinase reaction buffer (diluted from 2x buffer).

[0266] Compounds were diluted in DMSO from 250 μM in 8-point 4-fold serial dilutions. Then diluted 1:5 in 2x reaction buffer in a 96-well plate. 1.0 μl was transferred in duplicate to a 384-well plate. 2 μl of diluted active IRAK4 was added (not added to column 1), 2x reaction buffer was added to column 1.1 μl, and a stock solution of MBP substrate at 1 mg / ml was added. Note: MBP can be combined with an equal volume of ATP mix and then added at 2 μl / well. Final reaction volume was 5 μl.

[0267] The plates were centrifuged and the reaction mixtures were incubated at room temperature for 60 min or at 30° C. for 30 min.

[0268] The reaction was terminated by adding 5 μl of ADP-Glo™ Reagent to deplete residual ATP, the 384-well plate was centrifuged and the reaction mixture was then incubated for an additional 40 minutes at ambient temperature.

[0269] 10 μl of kinase detection reagent was added, the plate was centrifuged and the reaction mixture was then incubated for a further 30 minutes at ambient temperature.

[0270] The 384-well reaction plate was read using a WALLAC plate reader (Luminescence 0.1s).

[0271] Example 21 IRAK1 ADAPTA assay material Barcoded Corning, low volume, white 384-well plates (Corning Cat. #4512) ● Test compounds: Test compounds are screened at 1% DMSO in the wells (final), 3-fold serial dilutions to 10 μM for 10-point titrations. ● Substrate / kinase mix: Prepare a 2x IRAK1 / Histone H3(1-20) peptide mix in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. ●ATP Solutions: All ATP solutions are diluted in water to a 4x working concentration. • The apparent ATP Km is previously determined using a radiometric assay unless substrate is not available, in which case the Adapta assay is performed. Detection mixture: The detection mixture is prepared in TR-FRET dilution buffer. The detection mixture consists of EDTA (30 mM), Eu-anti-ADP antibody (6 nM), and ADP tracer. The detection mixture is prepared according to the EC of the tracer for ATP between 5 and 150 μM. 60 Contains concentration.

[0272] IRAK1 method 1. 100nL - 100x test compound in 100% DMSO 2.2.4 μL - 30 mM HEPES 3. 2.5 μL-4x ATP solution 4.5 μL - 2x substrate / kinase mixture The final 10 μL kinase reaction consisted of 3.17-42 ng of IRAK1 and 100 μM histone H3 (1-20) peptide in 32.5 mM HEPES, pH 7.5, 0.005% BRIJ-35, 5 mM MgCl2, 0.5 mM EGTA. 5.30-second plate vibration 6. Centrifuge at 1000xg for 1 minute. 7. Kinase reaction incubation for 60 minutes at room temperature 8.5 μL - Detection Mixture 9.30 second plate vibration 10. Centrifuge at 1000xg for 1 minute. 11. Detection Mixture Equilibration for 60 Minutes at Room Temperature 12. Read with a Fluorescent Plate Reader and Analyze Data

[0273] Example 22 IRAK4 Z'-LYTE assay material Barcoded Corning, low volume NBS, black 384-well plate (Corning Cat.#4514) ● Test compounds: Test compounds are screened in 1% DMSO (final) in the wells. For 10-point titrations, 3-fold serial dilutions are performed from 10□M. ● Peptide / Kinase Mixture: Prepare 2x IRAK4 / Ser / Thr 07 mix in 50mM HEPES pH 7.5, 0.01% BRIJ-35, 10mM MnCl2, 1mM EGTA, 2mM DTT, 0.02% NaN3. ATP Solutions: All ATP solutions are diluted to 4x working concentration in kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA). Apparent ATP Km is previously determined using the Z'-LYTE® assay. • Development Reagent Solution: Development Reagent is diluted 1:45000 in Development Buffer.

[0274] Common methods 1. 100nL - 100x test compound in 100% DMSO 2.2.4 μL - Kinase Buffer 3.5 μL - 2x peptide / kinase mixture 4. 2.5 μL-4x ATP solution The final 10 μL kinase reaction consisted of 3.45-63.6 ng of IRAK4 and 2 μM Ser / Thr 07 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 5 mM MgCl2, 5 mM MnCl2, 1 mM EGTA, 1 mM DTT, 0.01% NaN3. 5.30-second plate vibration 6. Kinase reaction incubation at room temperature for 60 minutes 7.5μL - Development reagent solution 8.30 seconds of plate vibration 9. Development Reaction Incubation for 60 Minutes at Room Temperature 10. Read with a Fluorescent Plate Reader and Analyze Data

[0275] The results of the assay are shown in Table 1.

[0276] Table 1. In vitro results TIFF2025513716000034.tif56165

[0277] Example 23 Plasma protein binding for I-1 Experimental procedures Brain and plasma drug binding was performed by equilibrium dialysis using a Rapid Equilibrium Dialysis (RED) device. Briefly, 300 μL of plasma or brain homogenate (1 brain / 3 buffer) containing drug (5 μM) was equilibrated (4-18 h) against 500 μL of buffered saline. After incubation, the concentrations of drug in plasma / brain homogenate and buffer were determined by LC-MS / MS.

[0278] Recovery Value Recovery is calculated by measuring the total amount of drug in 50 μL of plasma and 50 μL of buffer after incubation and comparing it to the amount of drug in 50 μL of plasma sample that was not incubated. For protein binding assays, drug was added to plasma, which was added to one side of the dialyzer and buffer to the other. After filing the plasma chamber of the equilibration device, a 50 μL aliquot of plasma was mixed with 50 μL of buffer and then quenched with a stop reagent. Drug recovery = (drug buffer + drug plasma) / (initial drug in plasma)

[0279] Lower recoveries may result from hydrolysis of the drug in plasma (i.e., amide hydrolysis) resulting in loss due to binding to the device.

[0280] Free drug Higher free drug in the plasma and brain allows more drug to interact with the target. TIFF2025513716000035.tif63165In terms of free drug, compound I-1 was released approximately 6-fold more than comparator-1 in rat, dog, monkey, and human proteins.

[0281] Recovery in mice was low due to hydrolysis, which was comparable to other similar studies in mice.

[0282] Table 2: Plasma protein binding results The result for TIFF2025513716000036.tif54165* appears to be greater than 100% due to experimental error.

[0283] Two runs of rat brain homogenate binding by I-1 compared to Comp-1. Approximately 10-fold more I-1 is free in rat brain than Comp-1. Comparison-1 0.102% and 0.114% I-1 1.06% and 1.43%

[0284] Example 24 Whole Blood Assay Compound I-1 exhibited similar biochemical potency as Comparative-1 in in vitro assays (see Example 23 for the structure of Comparative-1), but I-1 was significantly more potent in cells and in assays performed in the presence of whole blood.

[0285] Table 3. In vitro assays TIFF2025513716000037.tif30165

[0286] Table 4. Free fraction in whole blood assay TIFF2025513716000038.tif24165

[0287] The greater potency of I-1 in whole blood assays is driven by the plasma free fraction, and the free fraction percentages are consistent across species.

[0288] To evaluate the effect of compound I-1 on TLR and IL-1R dependent cytokine release, multiple cell types were isolated and stimulated in the presence of compound I-1 or comparative-1. The results are provided in Table 5.

[0289] Table 5. Cell assays TIFF2025513716000039.tif44165

[0290] The results obtained in the above cellular assays demonstrate that compound I-1 is a potent inhibitor of TLR- and IL-1R-dependent cytokine production in multiple cell types (Table 5). Compound I-1 inhibits TLR4-induced IL-23 and TNF-α production by human THP-1 cells. In human primary dendritic cells (DCs), compound I-1 blocks TLR4-induced IL-23 production, TLR7- and TLR2-induced TNF-α production. Compound I-1 is also a potent inhibitor of TLR7-dependent cytokine production in human PBMCs and TLR4-dependent cytokine production in mouse macrophages. In addition, compound I-1 potently inhibits IL-1β-induced production of the cytokine IL-6 in primary human endothelial cells. Compound I-1 broadly inhibits TLR- and IL-1R-dependent inflammatory cytokine production in multiple primary human cell types through inhibition of IRAK1 / 4 kinase activity. Furthermore, compound I-1 is a more potent inhibitor of TLR- and IL-1R-dependent signaling in multiple cell types.

[0291] Assay Protocol: TLR4 and TLR2 induced cytokines in THP-1 cells.

[0292] material Dimethyl sulfoxide (DMSO) (Sigma-Aldrich, Cat#D2650) Fetal bovine serum (Sigma, Cat#F4135) ●RPMI1640 (Cellgro, Cat#10-040-CM) THP-1 (ATCC, Cat#TIB-202) ●Recombinant human IFN-γ (Peprotech, Cat#AF-300-02) Lipopolysaccharides (LPS) from Escherichia coli K-235 (Sigma-Aldrich, Cat#L2018) ●LTA (InvivoGen, Cat No.tlrl-pslta) Anti-human IL-23p19 (eBioscience, Cat#14-7238-85) ● Biotin anti-human IL-12 (p40 / 70) (eBioscience, Cat#13-7129-85) ● Bovine serum albumin (BSA) (Sigma-Aldrich, Cat#A7906) ●1×PBST wash buffer (PBS-Tween tablets) (VWR International, Cat#80058-558) ●ELISA blocking buffer (PBS containing 2% BSA) ●ELISA dilution buffer (0.2%BSA in PBST) ●Human TNF-α DuoSet ELISA kit (R&D Systems, Cat#DY210) CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Cat#G7571) ●96-well flat bottom, white transparent bottom, tissue culture plate (Costar 3903) ● 96-well flat bottom, MaxiSorp black immunoplate (Thermo Scientific, Cat#12-566-24) ●Super Signal ELISA Pico Chemiluminescent Substrate (Thermo Scientific, Cat#37070)

[0293] Device ●Scan Washer 400 plate washer (Molecular Devices) Luminometer, Wallac Victor2 1420 Multilabel Counter

[0294] method THP-1 cells (100μL / well 100K) were primed with 25ng / mL IFN-γ for 18 hours at 37°C, 5% CO2. Compounds were serially diluted in 4-fold dilutions starting from 2.5mM in DMSO and then diluted 1:125 in RPMI1640 complete medium containing 10% FBS. 100μL / well 2x compound was mixed with 100μL / well IFN-γ primed THP-1 in a 96-well flat bottom white tissue culture plate. Cells were pre-incubated with compound for 1 hour at 37°C, 5% CO2, followed by the addition of 10μL / well 21×LPS to give a final concentration of 1μg / mL in LPS. Cells were stimulated with LPS for 18 hours at 37°C, 5% CO2. After centrifugation, 100μL / well of supernatant was extracted using a multichannel pipette. IL-23p19 or TNF-α protein in the supernatant was measured by sandwich ELISA. Cell viability assays were performed using the remaining IFN-γ primed THP-1 cell pellets to determine compound cytotoxicity. Plates were read in a luminometer and chemiluminescence values ​​were curve fitted to determine EC 50 The data was input into Athena (Rigel) for calculation and database storage.

[0295] THP1 cells primed with IFN-γ as described above were stimulated with LTA for an additional 18 hours at 37°C, 5% CO2 (10 μl per well of 20-fold concentrated LTA solution in RPMI medium to give a final concentration of 4 μg / ml). Supernatants (155 μL / well) were harvested and TNF-α was measured. TNF-α was quantified by ELISA using the Human TNF-α DuoSet ELISA kit according to the kit protocol.

[0296] Human IL-23p19 Sandwich ELISA: Maxisorp immuno ELISA plates were pre-coated with 100 μL / well of anti-IL-23p19 capture antibody in PBS (2.4 μg / mL) overnight at room temperature. After washing with 1×PBST, the plates were blocked with 300 μL / well of 1% BSA in PBS for 2 h at room temperature. The plates were washed 3 times with 1×PBST and 100 μL / well of supernatant was added. The plates were incubated for 2 h at room temperature with shaking. The plates were washed 3 times with 1×PBST and 100 μL / well of biotin anti-human IL-12 (p40 / 70) detection antibody (10 ng / mL) was added in PBS containing 0.1% BSA. The plates were incubated for 2 h at room temperature with shaking. The plates were washed 3 times with 1×PBST and 100 μL / well of streptavidin-HRP (1:200) in PBS containing 0.1% BSA was added. Plates were incubated at room temperature for 20 minutes with shaking. Plates were washed 3 times with 1x PBST and 100 μL / well of Super Signal ELISA Pico Chemiluminescent Substrate was added. Plates were read in a luminometer and chemiluminescence values ​​were curve fitted and EC 50 The data was input into Athena (Rigel) for calculation and database storage.

[0297] Assay protocol: TLR7-induced TNF-α in human peripheral blood mononuclear cells (PBMCs).

[0298] material Corning™ Costar™ 96-well, cell culture-treated, U-bottom microplates (Fisher, Cat#07-200-95) ● Human PBMC (whole cells, Cat#PB002) Resiquimod (InvivoGen, Cat No. tlrl-r848) ●Human TNF-α DuoSet ELISA kit (R&D Systems, Cat#DY210) ●Recombinant human IFN-β (Peprotech, Cat#300-02BC) ●RPMI containing 10% FBS Axygen 96-well, 1.1 mL, sterile (VWR International, Cat# 47734-788)

[0299] method Human peripheral blood mononuclear cells (PBMCs) were seeded at 100,000 cells per well in 100 μL RPMI containing 10% FCS and primed with 8 ng / ml IFN-β overnight at 37° C., 5% CO2. Compounds were serially diluted from 2 mM in 3-fold dilutions in DMSO and then diluted 1:100 in RPMI1640 complete medium containing 10% FBS (2× stock). PBMCs were pre-incubated with test compounds for 1 h at 37° C., 5% CO2 by adding 100 μL RPMI medium (0.5% final DMSO concentration) containing 2× concentrated test compounds per well.

[0300] Resiquimod Stimulation: PBMCs were stimulated with resiquimod for an additional 18 hours at 37°C, 5% CO2 (10 μl per well of a 21-fold concentrated resiquimod solution in RPMI medium to give a final concentration of 0.1 μg / ml). 100 μL of supernatant per well was collected to measure TNF-α. TNF-α was quantified using the DuoSet ELISA kit according to the manufacturer's protocol.

[0301] Assay protocol: TLR-induced cytokines in human primary monocyte-derived dendritic cells (DCs).

[0302] material Dimethyl sulfoxide (DMSO) (Sigma-Aldrich, Cat#D2650) Fetal bovine serum (Sigma, Cat#F4135) ●Human PBMC cells (whole cells, Cat No. PB002) ●RPMI growth medium containing 10% FBS ●IFN-γ (Peprotech, Cat No.300-02) ●GMCSF (Peprotech, Cat No. 300-03) and IL4 (Peprotech Cat No. 200-04) ●White clear bottom 96-well plate (Fisher, Cat No. 07-200-587, Corning #3903) LPS (prepared as a 2.5mg / ml stock in PBS) from Sigma Aldrich (Cat No. L2018-5MG) Lipopolysaccharides (LPS) from Escherichia coli K-235 (Sigma-Aldrich, Cat#L2018) Gardiquimod, a new imidazoquinoline compound (InvivoGen, Cat# tlrl-gdqs) Anti-human IL-23p19 (eBioscience, Cat#14-7238-85) ● Biotin anti-human IL-12 (p40 / 70) (eBioscience, Cat#13-7129-85) ● Bovine serum albumin (BSA) (Sigma-Aldrich, Cat#A7906) ●1×PBST wash buffer (PBS-Tween tablets) (VWR International, Cat#80058-558) ●ELISA blocking buffer (PBS containing 2% BSA) ●ELISA dilution buffer (0.2%BSA in PBST) ●Human TNF-α DuoSet ELISA kit (R&D Systems, Cat#DY210) Cell Titer Glo Reagent (Promega, Cat No. G7573) Positive control, IKK2VI inhibitor (Calbiochem, Cat No. 401483)

[0303] Device ●Scan Washer 400 plate washer (Molecular Devices) Luminometer, Wallac Victor2 1420 Multilabel Counter

[0304] method Dendritic cell differentiation and IFNγ-priming: Human peripheral blood mononuclear cells (PBMCs) (400 million) were allowed to adhere in a T-175 flask containing 15 ml of RPMI medium (10% FBS) at 37° C., 5% CO 2 for 2 hours to capture monocytes.

[0305] After 2 hours, the medium containing the floating cells was carefully removed, and 12 ml of fresh RPMI medium (10% FBS) containing GM-CSF (100 ng / ml) and IL-4 (20 ng / ml) was added to the adherent monocytes. The monocytes were differentiated for 7 days at 37°C, 5% CO2, and replenished with fresh GM-CSF and IL-4 after 3 days.

[0306] Differentiated dendritic cells (DCs) were harvested by centrifugation (1200 rpm / 5 min).DCs were primed with 50 ng / ml IFN-γ (1000 U / ml) at 50K / well in 100 μL / well of fresh RPMI medium (10% FBS) in white clear-bottom 96-well plates at 37° C., 5% CO2 for 24 h.

[0307] Compound preincubation: Compounds were serially diluted in DMSO starting at 2.5 mM in 4-fold dilutions, then diluted 1:125 in RPMI 1640 complete medium containing 10% FBS. Primed DCs were pre-incubated with test compounds for 1 h at 37° C., 5% CO2 by adding 100 μL of RPMI medium (0.5% final DMSO concentration) containing 2-fold concentrated test compounds per well.

[0308] LPS stimulation: DCs were stimulated with LPS (10 μL per well of a 20-fold concentrated LPS solution in RPMI medium to give a final concentration of 1 μg / ml) for an additional 18 h at 37° C. and 5% CO 2 .

[0309] Supernatants (155 μL / well) were collected and IL-23 was measured by ELISA (65 μL-supernatant). Cell Titer Glo reagent (50 μL / well) was added to the remaining 50 μL / well of the cell culture plate, incubated on a shaker for 1-2 min, and the luminescence intensity of the plate was read to determine the cytotoxicity of the compounds. The chemiluminescence values ​​were curve-fitted and EC 50 The data was input into Athena (Rigel) for calculation and database storage.

[0310] Gardiquimod Stimulation: DCs were stimulated with gardiquimod for an additional 18 hours at 37°C, 5% CO2 (10 μL per well of a 20-fold concentrated gardiquimod solution in RPMI medium to give a final concentration of 4 μg / ml). Supernatants (155 μL / well) were collected to measure TNF-α. TNF-α was quantified by ELISA according to the kit protocol.

[0311] Whole Blood Assays: To evaluate the effect of whole blood on the efficacy of Compound I-1 and Comparative-1, the compounds were evaluated for their inhibitory potential on TLR-dependent cytokine release in human blood. Fresh peripheral blood drawn from healthy volunteers was incubated with test compounds and stimulated overnight with LPS or galdiquimod. Serum was isolated after centrifugation, and TNF-α and IL-6 were measured by ELISA. The results are shown in Table 6.

[0312] Assay protocol: LPS induced TNF-α in human blood.

[0313] material ●RPMI1640 (Cellgro, Cat#10-040-CM) Fetal bovine serum (Sigma, Cat#F4135) Lipopolysaccharides from Escherichia coli K-235 (Sigma-Aldrich Chemicals, Cat#L2018-5MG) ●BD Vacutainer Sodium Heparin Tubes (BD Cat# 4191982) ●96-well polystyrene plate (Fisher Cat# 12-565-500) Dimethyl sulfoxide (DMSO) (Sigma-Aldrich, Cat# D2650) ●Human Cytokine MAGNETIC Panel: Magnetic (EMD Millipore Corp. Cat#HCYTOMAG-60K-02)

[0314] Device Luminex Flexmap 3d

[0315] method Whole blood from healthy volunteers was collected into Vacutainers containing sodium heparin, and 40 μL of blood was plated into each well. Compounds were serially diluted from 2 mM in 3-fold dilutions in DMSO, then diluted 1:100 in medium containing 10% FBS. 50 μL of 2x compound was added per well in duplicate to each well and incubated for 1 hour. 10 μL of LPS was added to each well at a final concentration of 0.5 ng / ml, and cells were allowed to incubate overnight.

[0316] 100 μL of PBS was added to each well and centrifuged at 1000 RPM for 10 minutes. 25 μL of the supernatant was taken and TNF-α was measured on a Luminex Flexmap 3d.

[0317] Assay Protocol: Gardiquimod induced IL-6 in human blood induced TNF-α in human blood.

[0318] material ●RPMI1640 (Cellgro, Cat#10-040-CM) Fetal bovine serum (Sigma, Cat#F4135) Gardiquimod (InvivoGen, Cat#tlrl-gdqs) ●BD Vacutainer Sodium Heparin Tubes (BD Cat# 4191982) ●96-well polystyrene plate (Fisher Cat# 12-565-500) Dimethyl sulfoxide (DMSO) (Sigma-Aldrich, Cat# D2650) ●Human Cytokine MAGNETIC Panel: Il6 Magnetic (EMD Millipore Corp. Cat# HCYTOMAG-60K-02)

[0319] Device Luminex Flexmap 3d

[0320] method Whole blood from healthy volunteers was collected in Vacutainers containing sodium heparin, and 40 μL of blood was seeded into each well. Compounds were serially diluted from 2 mM in 3-fold dilutions in DMSO, then diluted 1:100 in medium containing 10% FBS. 50 μL of 2x compound per well was added in duplicate to each well and incubated for 1 hour. 10 μL of gardiquimod was added to each well at a final concentration of 4 μg / ml, and cells were incubated overnight.

[0321] 100 μL of PBS was added to each well and centrifuged at 1000 RPM for 10 minutes, 25 μL of supernatant was taken and IL-6 was measured by Luminex Flexmap 3d.

[0322] Table 6. Human whole blood assay TIFF2025513716000040.tif33165

[0323] Compound I-1, when tested in the presence of whole human blood, exhibits greater potency in blocking inflammatory signaling in cell-based assays and loses less potency than comparator-1.

[0324] Example 25 Prodrug Compound I-3

[0325] Table 7. Bioavailability of compound I-3 TIFF2025513716000041.tif38165

[0326] The bioavailability of compound I-3 was measured as the amount of parent compound I-1 detected, thereby demonstrating that compound I-3 functions as a prodrug of I-1 in vivo.

[0327] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are merely preferred examples of the technology and should not be construed as limiting the scope of the technology. Rather, the scope of the technology is defined by the following claims. We therefore claim as our technology all that comes within the scope and spirit of those claims.

Claims

1. Equation I Compounds having the structure of, or pharmaceutically acceptable salts or solvates thereof: During the ceremony, R １ However, it is H, aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkylphospholamidate, or alkyl phosphate. R ２ However, C １－６ It is alkyl.

2. R １ However, H, alkyl, or -alkyl OP(O)(OR) ２ In the formula, each OR is -OH, -O alkyl, -O aryl, -O heteroaryl, -O aralkyl, or -O － M ＋ And in the formula, M ＋ The compound according to claim 1, wherein the counterion is a single positively charged counterion.

3. The compound according to claim 1, wherein R 1 is H, or -alkyl OP(O)(OR) 2, where each OR is -OH, -O alkyl, -O aryl, -O heteroaryl, -O aralkyl, or -O-M+, where M+ is a single positively charged counterion.

4. The compound according to claim 1, wherein R 1 is -alkylOP(O)(OR) 2, where each OR is -OH, -O alkyl, -O aryl, -O heteroaryl, -O aralkyl, or -O-M+, where M+ is a single positively charged counterion.

5. R １ is -CH(CH ３ )(OP)(OR) ２ or -CH ２ (OP)(OR) ２ The compound according to any one of claims 1 to 4.

6. R ２ However, C １－４ A compound according to any one of claims 1 to 4, wherein it is alkyl.

7. Formula II A compound according to any one of claims 1 to 4, having the structure thereof, or a pharmaceutically acceptable salt or solvate thereof.

8. R １ The compound according to any one of claims 1 to 4, wherein H is present.

9. R １ However, C １－６ A compound according to any one of claims 1 to 4, wherein it is alkyl.

10. R １ However, -CH ２ OP(O)(OR) ２ The compound according to any one of claims 1 to 4.

11. R １ However, -CH ２ OP(O)(OH) ２ The compound according to claim 10.

12. R １ However, -CH ２ OP(O)(OC １－６ Alkyl) ２ The compound according to claim 10.

13. R １ However, -CH ２ OP(O)(O － M ＋ ) ２ The compound according to claim 10.

14. R １ However, -CH ２ OP(O)(O － Na ＋ ) ２ The compound according to claim 10.

15. The compound according to any one of claims 1 to 4, which is in the form of a free base.

16. The compound according to any one of claims 1 to 4, which is a salt cocrystal.

17. The compound according to claim 16, wherein the salt cocrystal is a tartrate cocrystal or a Tris salt cocrystal.

18. I-1: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidine-2-yl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide, I-2: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidine-2-yl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl dihydrogen phosphate, I-3: Sodium (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidine-2-yl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylphosphate, I-4: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidine-2-yl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide tartrate, I-5: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidine-2-yl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl hydrogen phosphate 1,3-dihydroxy-2-(hydroxymethyl)propane-2-aminium (Tris salt), I-6: 1-(4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidine-2-yl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl dihydrogen phosphate, I-7: Sodium 1-(4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidine-2-yl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate, or I-8: 1-(4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidine-2-yl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl hydrogen phosphate 1,3-dihydroxy-2-(hydroxymethyl)propane-2-aminium (Tris salt) A compound according to claim 1, selected from the following.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. A pharmaceutical composition for use in a method for inhibiting the IRAK enzyme, wherein the pharmaceutical composition comprises an effective amount of the compound described in any one of claims 1 to 4 and 18, and the method comprises contacting the enzyme with the pharmaceutical composition.

21. The pharmaceutical composition according to claim 20, wherein contact is provided with the compound.

22. A pharmaceutical composition for use in a method for treating a disease or condition indicated by an IRAK inhibitor, wherein the pharmaceutical composition comprises an effective amount of any one of claims 1 to 4 and 18.

23. The pharmaceutical composition according to claim 22, wherein the disease or condition includes autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, allergic disorders, multiple organ failure, renal diseases, platelet aggregation, proliferative disorders, hyperproliferative disorders, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injury, respiratory diseases, ischemic conditions, bacterial infections, viral infections, immunomodulatory disorders, sickle cell disease, chemical or radiation-induced lung injury, hemorrhagic fever, or a combination thereof.

24. The pharmaceutical composition according to claim 22, wherein the disease or condition includes aplastic anemia, atopic dermatitis, pustular psoriasis, palmoplantar pustulosis, primary biliary cirrhosis, pyoderma, sclerosing cholangitis, systemic juvenile idiopathic arthritis, hidradenitis suppurativa, cytokine release syndrome, myelodysplastic syndrome (MDS), myelofibrosis, or polycythemia vera.

25. The pharmaceutical composition according to claim 22, wherein the disease is amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, pancreatitis, Kaposi's sarcoma, myelodysplastic syndrome, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, or asthma.

26. The aforementioned immunomodulatory disorders include rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type 1 diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, and nickylosing disease. Bleeding, alopecia areata, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal exudates, pemphigus of the eye, Mohlen's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, dust asthma, chronic or refractory asthma, delayed-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, ischemic disease and thrombosis-induced vascular problems Injuries, ischemic bowel disease, inflammatory bowel disease, necrotizing pancolitis, burn-associated intestinal lesions, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia , agranulocytosis, pernicious anemia, megaloblastic anemia, erythrohyperplasia, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granuloma, Sjögren's syndrome, hyperlipidemia, eosinophilic fasciitis, lesions of the gingiva, periodontal tissue, alveolar bone, and cementum of teeth, glomerulonephritis, prevention of hair loss or provision of hair germination and / or hair growth (hair germination)Male pattern baldness or senile alopecia due to accelerated growth, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, ischemic reperfusion injury of organs occurring during preservation, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug-induced poisoning, lung cancer, emphysema, cataracts, iron deposition disease, retinitis pigmentosa, senile macular degeneration, vitreous scarring, corneal alkaline burns, dermatitis, erythema multiforme The pharmaceutical composition according to claim 23, which is multiform), linear IgA bullous dermatitis and cementodermitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma, and altitude sickness, diseases caused by histamine or leukotriene-C4 release, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute hepatic necrosis, necrosis caused by toxins, viral hepatitis, shock or anoxia, B virus hepatitis, non-A / non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, delayed hepatic failure, acute exacerbation of chronic hepatic failure, enhancement of chemotherapy effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, CRS, ARDS, AKI, or chronic bacterial infection.

27. The pharmaceutical composition according to claim 22, wherein the disease or condition is selected from myeloproliferative neoplasm (MPN), polycythemia vera, myelo / lymphoid neoplasm with PDGFRA rearrangement, myelo / lymphoid neoplasm with PDGFRB rearrangement, myelo / lymphoid neoplasm with FFFR1 rearrangement, myelo / lymphoid neoplasm with PCM1-JAK2, myelodysplastic / myeloproliferative neoplasm (MDS / MPN), myelosarcoma, myeloproliferation associated with Down syndrome, blastocyte plasmacytoid dendritic cell neoplasm, B lymphoblastic leukemia / lymphoma, and / or T lymphoblastic leukemia / lymphoma.

28. The pharmaceutical composition according to claim 27, wherein the disease is selected from chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), primary myelofibrosis (PMF), essential thrombocythemia, chronic eosinophilic leukemia, or a combination thereof.

29. The pharmaceutical composition according to claim 28, wherein the disease is chronic myeloid leukemia.

30. The pharmaceutical composition according to claim 27, wherein the disease is a myelodysplastic / myeloproliferative neoplasm selected from chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), MDS / MPN with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T), or a combination thereof.

31. The pharmaceutical composition according to claim 22, wherein the disease is selected from psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, specifically pustular psoriasis, type 1 diabetes mellitus, type 2 diabetes mellitus, inflammatory bowel disease, hyperimmune globulinemia and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gouty flare, pseudogout, Sappho syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, 1-1 receptor antagonist deficiency, Alzheimer's disease, and Parkinson's disease.

32. The pharmaceutical composition according to claim 22, wherein the disease is selected from hematological malignancies, leukemia, acute myeloid leukemia, DLBCL, ABC DLBCL, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome, myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma.

33. The pharmaceutical composition according to claim 22, wherein the disease is thrombosis.

34. The pharmaceutical composition according to claim 22, wherein the disease is selected from arterial thrombosis, venous thrombosis, deep vein thrombosis, portal vein thrombosis, jugular vein thrombosis, renal vein thrombosis, stroke, myocardial infarction, Budd-Chiari syndrome, Paget-Schroetter disease, cerebral venous sinus thrombosis, influenza-associated thrombosis, and COVID-19-associated thrombosis.

35. The pharmaceutical composition according to claim 22, wherein the disease is selected from influenza-related ARDS, influenza-related AKI, influenza-related thrombosis, influenza-related sepsis, and influenza-related septic shock.

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