Novel inhibitors of interleukin receptor- associated kinase

Abstract

This patent document provides novel compounds as inhibitors of interleukin- 1 receptor-associated kinases such as IRAKI and IRAK4. Also disclosed are methods of treating diseases associated with abnormal expression or activities of kinases of IRAK family.

Description

161118.08601Novel Inhibitors of Interleukin Receptor- Associated Kinase CROSS-REFERENCE TO RELATED APPLICATIONSTECHNICAL FIELD

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 720,841, filed on November 15, 2024, the disclosure of which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] This invention relates to the development of a novel interleukin receptor-associated kinase-1 (IRAKI) and / or -4 (IRAK4) protein degraders for the treatment of solid and liquid tumors, inflammatory disorders and other diseases associated with IRAK-1 and / or IRAK-4.BACKGROUND

[0003] Interleukin receptor-associated kinase-4 (IRAK4) is a key functional member of the IRAK family of intracellular serine-threonine kinases consisting of IRAKI, IRAK2, IRAK3, and IRAK4. IRAK4 is a downstream signaling mediator of the pro-inflammatory IL-1 family of receptors and of the pathogen sensing and innate signaling toll-like receptors (TLRs). The TLRs are activated by endogenous pathogens associated with necrotic cell death and tissue damage, the critical hallmarks of chronic inflammatory processes. Aberrant expression of IRAK4 orchestrates chronic inflammatory diseases, such as rheumatoid arthritis and lupus. Aberrant signaling of the IRAK4 pathway due to activating mutations in the MyD88 adaptor protein has also been implicated in malignancies. The proximal location of IRAK4 to immune signaling receptors (TLRs and IL-1R) has generated significant interest in therapeutic targeting of IRAK4 for mounting control against autoimmune and inflammatory diseases. Therapeutic agents targeting IRAK4 have been proposed for controlling high-risk malignancies such as pancreatic cancer, colitis-induced tumorigenesis and chemoresistance in colorectal cancer. A need exists for the development of novel therapeutic agents for the treatment of diseases associated with IRAK, particularly IRAKI and IRAK4.SUMMARY

[0004] The compounds described in this patent document address this specific need. The compounds or pharmaceutically acceptable salts thereof are inhibitors of IRAK including IRAKI and IRAK4.161118.08601

[0005] An aspect of this patent document provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula I,WhereinR1is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo-Ci-ealkyl, O-(halo)Ci-ealkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6 or 10 membered aryl, and 5-10 membered heteroaryl;R2is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo-Ci-ealkyl, O-(halo)Ci-ealkyl;R3is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo-Ci-ealkyl, O-(halo)Ci-ealkyl;R4is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo-Ci-ealkyl, O-(halo)Ci-ealkyl;m is 0, 1, 2, 3 or 4;n is 0, 1, 2, or 3;o is 0, 1, or 2;p is 0, 1, or 2;Ring AisZ\— or, wherein Z is SO2, SO, or C=O;X1, X2, and X3are each independently N or CH, provided that at least one of them is N;X4-X5Ring B is, wherein X4and X5are each independently N, O, S or CH, provided that at least one of them is a heteroatom; andL is NHC(O), NHSO2.161118.08601

[0006] Another aspect of this patent document discloses a pharmaceutical composition comprising the compound described herein or the pharmaceutically acceptable salt, isomer, or prodrug thereof.

[0007] Another aspect of this disclosure provides a method of treating a disease associated with abnormal expression or activities of IRAK in a subject. The method includes administering to the subject in need a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salt or isomer thereof, or a pharmaceutical composition thereof. In some embodiments, the method further includes administering to the subject a secondary agent. In some embodiments, the disease or disorder is selected from inflammatory disorder, organ fibrosis, pain, and cancer.

[0008] Another aspect provides a method of inhibiting IRAK. The method includes contacting the kinase with an effective amount of the compound or the pharmaceutically acceptable salt thereof disclosed herein. In some embodiments, the IRAK is selected from the group consisting of IRAK- 1, IRAK-2 and IRAK-4. In some embodiments, the contacting takes place in vivo.

[0009] A method of inhibiting angiogenesis in a subject, comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition disclosed herein to the subject in need thereof.DESCRIPTIONS OF THE DRAWINGS

[0010] Figure 1 shows that compound La inhibits NF-kB activity in THP1- AML cells-based reporter assay. At 800nM -50% NF-kB reporter activity was found to be decreased.

[0011] Figure 2 shows activities of example compounds of Formula A.

[0012] Figure 3 shows activities of example compounds of Formula A.DETAILED DESCRIPTION

[0013] Various embodiments of this patent document disclose compounds for targeting interleukin receptor-associated kinase including for IRAKI, IRAK 2 and IRAK4. These compounds have utility in the treatment of diseases or disorders associated with aberrant161118.08601expression or signaling of kinases of IRAK family. Nonlimiting examples of the diseases or disorders include cancer, autoimmune disease, infection, and inflammation.

[0014] While the following text may reference or exemplify specific embodiments of a compound or a method of treating a disease or condition, it is not intended to limit the scope of the compound or method to such particular reference or examples. Various modifications may be made by those skilled in the art, in view of practical and economic considerations, such as the substitutions of the compound and the amount or administration of the compound for treating or preventing a disease or condition.

[0015] The articles "a" and "an" as used herein refers to "one or more" or "at least one," unless otherwise indicated. That is, reference to any element or component of an embodiment by the indefinite article "a" or "an" does not exclude the possibility that more than one element or component is present.

[0016] The term “pharmaceutical composition” refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or additional carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a pharmaceutical composition exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. In some embodiments, pharmaceutically acceptable salts of the compounds disclosed herein are provided.

[0017] The term "subject" encompasses any animal, but preferably a mammal, e.g., human, non-human primate, a dog, a cat, a horse, a cow, or a rodent. More preferably, the subject is a human.

[0018] The term “carrier” refers to a chemical compound that facilitates the incorporation of a compound into cells or tissues.

[0019] The term “diluent” refers to chemical compounds diluted in water that will dissolve the composition of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound. As used herein, an “excipient” refers to an inert substance that is added to a composition to provide,161118.08601without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability, etc., to the composition. A “diluent” is a type of excipient.

[0020] The term “physiologically acceptable” or “pharmaceutically acceptable” refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0021] The term “therapeutically effective amount” refers to an amount of a compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0022] The term "alkyl" refers to monovalent saturated alkane radical groups particularly having up to about 18 carbon atoms, more particularly as a lower alkyl, from 1 to 8 carbon atoms and still more particularly, from 1 to 6 carbon atoms. The hydrocarbon chain may be either straight-chained or branched. The term " Ci-io alkyl" or " C1-C10 alkyl" refers to alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Similarly, the term " Ci-4alkyl" refers to alkyl groups having 1, 2, 3, or 4 carbon atoms. Non-limiting examples of alkyls include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like.

[0023] The term “Ci-4 alkoxy” includes an alkyloxy group having 1, 2, 3 or 4 carbons.

[0024] The term “carbocycle” or "cycloalkyl" refers to 3 to 10 membered cyclic hydrocarbyl groups having only carbon atoms as ring atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems, which optionally can be substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ring structures such as adamantanyl, and the like.

[0025] The term “haloalkyl”, “halo-alkyl” or “(halo)alkyl” refers to a Ci-ioalkyl, straight chain or branched, in which one or more hydrogen has been replaced by a halogen. Non-limiting examples of haloalkyls include CHF2, CFH2, CF3, CF2CH3, CH2CF3, and CH2CH2F. In some embodiments, the alkyl in haloalkyl has 1, 2, 3 or 4 carbons. Likewise, the term “haloalkylene” refers to an alkylene, straight or branched, in which one or more161118.08601hydrogen has been replaced by a halogen. Non-limiting examples of haloalkylenes include CHF, CF2, and CH2CF2.

[0026] The term “heterocycle” or "heterocycloalkyl" refers to 3 to 10 membered substituted or non-substituted non-aromatic cyclic groups where one or more carbon ring atoms are replaced with hetero atoms or groups containing heteroatoms (e.g. NH, NC1-4 alkyl O, and S). Nonlimiting examples include pyrrolidine, piperidine, piperazine, N-methyl-piperazine, and morpholine. Optional substituents include C1-6 alkyl, Ci-4 alkoxy, halogen, haloalkyl, sulfonamido, and amido.

[0027] The term “aryl” is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and all ring atoms of the aromatic ring are carbon atoms. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acephenanthrene, anthracene, azulene, benzene, fluoranthene, fluorene, hexalen, hexaphene, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, astacene, octaphene, octylene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, and the like. Particularly, an aryl group comprises from 6 to 10 or 6 to 14 carbon atoms.

[0028] The term "hetero" when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloheteroalkyl.

[0029] The term "halogen" refers to F, Cl, Br, or I.

[0030] The term “heteroaryl” refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 147t electrons shared in a cyclic array, wherein at least one ring atom contributing to the shared TI electrons in the cyclic array is a heteroatom. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phenanthridine, phenanthroline, phenazine, phthalazine, phthalimide, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole,161118.08601xanthene, and the like. Preferably, the heteroaryl group is between 5-15 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.

[0031] The term "treating" or "treatment" of any disease or condition refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In some embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In some embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In some embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder, or even preventing the same. “Prophylactic treatment” is to be construed as any mode of treatment that is used to prevent progression of the disease or is used for precautionary purpose for persons at risk of developing the condition.

[0032] The term “pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Non-limiting examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, 2-naphthalenesulfonic acid, 3 -phenylpropionic acid, 4,4'-methylenebis(3-hydroxy- 2-ene- 1 -carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene- 1 -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphor sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, / ?-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, / ?-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium161118.08601hydroxide. Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and 7V-methylglucamine. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0033] An aspect of this patent document provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula A(R4)PWhereinR1is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, O-(halo)Ci-ealkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6 or 10 membered aryl, and 5-10 membered heteroaryl;R2is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl;R3is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl;R4is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl;m is 0, 1, 2, 3 or 4;n is 0, 1, 2, or 3;o is 0, 1, or 2;p is 0, 1, or 2;161118.08601Ring Ais, wherein Z is SO2, SO, or C=0;X1, X2, and X3are each independently N or CH, provided that at least one of them is N;X4-X5Ring B is, wherein X4and X5are each independently N, O, S or CH, provided that at least one of them is a heteroatom;E is a bond, Ci-4alkylene or -C(=O)-; andL is NHC(O), NHSO2.

[0034] In some embodiments, the compound is represented by Formula I,(R4)PBWhereinR1is selected from halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, O-(halo)Ci-ealkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6 or 10 membered aryl, and 5-10 membered heteroaryl;R2is selected from halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl;R3is selected from halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl;R4is selected from halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl;161118.08601m is 0, 1, 2, 3 or 4;n is 0, 1, 2, or 3;o is 0, 1, or 2;p is 0, 1, or 2;Ring A isor, wherein Z is SO2, SO, or C=O;X1, X2, and X3are each independently N or CH, provided that at least one of them is N;5Ring B is, wherein X4and X5are each independently NH, N, O, S or CH, provided that at least one of them includes a heteroatom;L is NHC(O), NHSO2.

[0035] In each of the embodiments disclosed herein, when one or more chiral centers are present, each chiral center is independently R or S in configuration.

[0036] In some embodiments, A isIn some embodiments, A is \ / In some embodiments, A isIn some embodiments, A isIn some embodiments, Z is SO2.

[0037] In some embodiments, ring B is selected from the group consisting ofEach of these rings can be optionally substituted. An unsubstituted ring atom can be NH or CH. When a ring atom is substituted, NH or CH will be replaced with N-R4or C-R4. In some embodiments, the optionally substituted HNAring is161118.08601

[0038] In some embodiments, ring C is an unsubstituted phenyl. In some embodiments, ring C is substituted with one or more substituents. Nonlimiting examples of substituted ring C include the following. Either end of the ring can be bonded to L while the remaining end is bonded to E or ring A.

[0039] In some embodiments, ring D is a pyridyl. In some embodiments, X1is N, X2and X3are CH. Nonlimiting examples of ring D in connection with L and ring B include the following.

[0040] In some embodiments, R1is selected from halogen, Ci-ealkyl, OCi-ealkyl, halo-Ci-ealkyl, and O-(halo)Ci-ealkyl, wherein m is 0, 1 or 2. In some embodiments, R1is selected from halogen, OCi-ealkyl, Ci-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl, wherein R1is positioned ortho to L, wherein m is 1 or 2.

[0041] In some embodiments, R2is selected from halogen, Ci-ealkyl, OCi-ealkyl, halo-Ci-ealkyl, and O-(halo)Ci-ealkyl, wherein n is 0, 1 or 2. In some embodiments, n is 0.161118.08601

[0042] In some embodiments, R3is selected from the group consisting of halogen, Ci-ealkyl, and OCi-ealkyl, wherein o is 0 or 1. In some embodiments, o is 0.

[0043] In some embodiments, R4is selected from halogen, Ci-ealkyl, and OCi-ealkyl, wherein p is 0 or 1. In some embodiments, p is 0.

[0044] In some embodiments, L is NHC(O). In some embodiments, the nitrogen of L is connected to the phenyl ring C.

[0045] In some embodiments, E is a bond. In some embodiments, E is Ci-4alkylene (e.g. methylene, ethylene, or propylene). In some embodiments, E is -C(=O)-.

[0046] Nonlimiting examples of the combination of ring A and E include the following. Each of these structures can be further substituted as described above.

[0047] In some embodiments, the compound is represented by Formula IIWherein each R1is independently selected from halogen, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl, wherein m’ is 0, 1 or 2; each R2is independently selected from halogen, Ci-ealkyl, OCi-ealkyl, halo-Ci-ealkyl, and O-(halo)Ci-ealkyl, wherein n is 0, 1 or 2; each R4is independently selected from halogen, Ci-ealkyl, and OCi-ealkyl, wherein p is 0 or 1.161118.08601

[0048] In some embodiments of Formula II, m’ is 0 or 1, n is 0 or 1, and p is 0 or 1. In some embodiments of Formula II, each R1is independently selected from halogen, Ci-ealkyl, OCi-ealkyl, and halo-Ci-ealkyl. In some embodiments of Formula II, the R1ortho to L (NHC(O)) is Ci-ealkyl, OCi-ealkyl, or halo-Ci-ealkyl.

[0049] In some embodiments, the compound is represented by Formula IIIWherein each R1is independently selected from halogen, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl, wherein m’ is 0, 1 or 2.

[0050] In some embodiments of Formula III, m’ is 0 or 1. In some embodiments of Formula II, the R1ortho to L (NHC(O)) is Ci-ealkyl, OCi-ealkyl, or halo-Ci-ealkyl. In some embodiments of Formula III, m’ is 0. In some embodiments of Formula III, m’ is 1.

[0051] In some embodiments, the compound is represented by Formula IVWherein R1is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, O-(halo)Ci-ealkyl, 3-6 membered cycloalkyl.

[0052] In some embodiments of Formula IV, R1is selected from Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, O-(halo)Ci-ealkyl, and 3-6 membered cycloalkyl. In some embodiments of Formula IV, R1is Ci-ealkyl, OCi-ealkyl, or halo- Ci-ealkyl.

[0053] In some embodiments, the compound is represented by Formula V161118.08601Wherein each R1is independently selected from halogen, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl, wherein m’ is 0, 1 or 2.

[0054] In some embodiments, the compound is represented by Formula VWherein each R1is independently selected from halogen, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl, wherein m’ is 0, 1 or 2. In some embodiments, E is methylene, ethylene or propylene. In some embodiments, E is -C(=O)-.

[0055] In some embodiments, the compound is represented by Formula VWherein each R1is independently selected from halogen, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-(halo)Ci-ealkyl, wherein m’ is 0, 1 or 2. In some embodiments, E is methylene, ethylene or propylene. In some embodiments, E is -C(=O)-.

[0056] In some embodiments, the compound of Formula I s selected from161118.08601

[0057] Another aspect of the present disclosure provides a pharmaceutical composition containing a therapeutically effective amount of the above-described compound and a pharmaceutically acceptable carrier.

[0058] The pharmaceutical composition may also contain one or more physiologically acceptable surface-active agents, additional carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof; and a composition disclosed herein. Acceptable additional carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s161118.08601Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, microcrystalline cellulose, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium metasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methylacetate-methacrylate copolymer as a derivative of polyvinyl may be used as suspension agents; and plasticizers such as ester phthalates and the like may be used as suspension agents.

[0059] The pharmaceutical compounds described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredient(s), as in combination therapy, or suitable carriers or excipient(s). In some embodiments, a dosage form includes those forms in which the compound is administered per se. In addition, a dosage form may include a pharmaceutical composition. In any case, the dosage form may comprise a sufficient amount of the compound to treat a disease as part of a particular administration protocol, as would be understood by those of skill in the art. Techniques for formulation and administration of the compounds of the instant application may be found in “Remington’s Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0060] The pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or tableting processes.

[0061] Pharmaceutical compositions may be formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.161118.08601Any of the well-known techniques, diluents, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington’s Pharmaceutical Sciences, above.

[0062] Another aspect of this disclosure provides a method of inhibiting an IRAK kinase. The method includes contacting the kinase with an effective amount of the compound or the pharmaceutically acceptable salt thereof disclosed herein. In some embodiments, the IRAK is IRAK-1, IRAK-2 or IRAK-4. In some embodiments, the contacting takes place in vivo. In some embodiments, the contacting takes place in vitro.

[0063] Another aspect of this disclosure provides a method of inhibiting angiogenesis in a subject. The method includes administering to the subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof disclosed herein. Angiogenesis, the rapid proliferation of epithelial cells resulting in formation of new blood vessels, supports the progression and survival of tumors. As a secondary effect, angiogenesis may damage the various organs and tissues, eyes, skin, heart, blood vessels, lung, GI tract and genitourinary tract. Methods and techniques to assess angiogenesis are known to those of ordinary skill in the art.

[0064] Another aspect of this disclosure provides a method of treating a disease or disorder associated with abnormal expression or activities of IRAK in a subject. The method includes administering to the subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof disclosed herein. In some embodiments, the IRAK is IRAK-1, IRAK-2 or IRAK-4. Nonlimiting examples of the disease or disorder associated with abnormal expression or activities of IRAK includes cancer, autoimmune disease, inflammatory disorder, organ fibrosis, pain.

[0065] In some embodiments, the disease or disorder associated with abnormal expression or activities of IRAK is an autoimmune disease. Autoimmune diseases associated with type 1 interferon include, but are not limited to Systemic lupus erythematosus, Psoriasis, insulin-dependent diabetes mellitus (IDDM), dermatomyositis and Sjogren's syndrome (SS).

[0066] In some embodiments, the disease or disorder is inflammation, which may be inflammation of any tissue and organs of the body, including for example musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation, as exemplified below.161118.08601

[0067] Further nonlimiting examples of disease or disorder associated with abnormal expression or activities of IRAK include peritonitis, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, graft vs. host disease, osteoporosis, multiple myeloma-related bone disorder, leukemias and related disorders, myelodysplastic syndrome, acute myelogenous leukemia, chlonal hematopoesis, anemia of chronic diseases, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, infectious hepatitis, juvenile diabetes, lichen planus, acute dermatomyositis, eczema, primary cirrhosis, uveitis, Behcet's disease, atopic skin disease, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis, nephrotic syndrome, burns, bronchitis, tendinitis, bursitis, periarteritis nodosa, thyroiditis, Hodgkin's disease, rheumatic fever, sarcoidosis, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, allergic rhinitis, endotoxin shock syndrome, and atherosclerosis, psoriatic arthritis, vasculitis, Polymyalgia, Rheumatica, Wegener's granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection and ataxia telangiectasia.

[0068] In some embodiments, the disease or disorder associated with abnormal expression or activities of IRAK is organ fibrosis, which include for example renal fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, Crohn’s disease, liver fibrosis, heart fibrosis, scleroderma, and progressive massive fibrosis.

[0069] In some embodiments, the disease or disorder associated with abnormal expression or activities of IRAK is pain disorder, which may include, for example, inflammatory pain (including infection-induced inflammatory pain including but not limited to pain induced from the flu, SARS, or a cold), post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia,161118.08601diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

[0070] In some embodiments, the pain disorder comprises neuropathic or nociceptive pain. Neuropathic pain is pain caused by damage or disease that affects the somatosensory nervous system. Neuropathic pain is typically characterized by abnormal sensations (dysethesia) or pain from normally non-painful stimuli (allodynia). Neuropathic pain may result from a disorder of the peripheral system or a disorder of the central nervous system, e.g, the brain or spinal cord. Central neuropathic pain is found in cases of spinal cord injury, multiple sclerosis, and stroke. Peripheral neuropathic pain can be found in patients with diabetes (diabetic neuropathy), herpes zoster infection, HIV infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune-mediated disorders, and physical trauma to the nerve trunk. Neuropathic pain may occur in cases of cancer either due to direct compression of a tumor on peripheral nerves, or as a side effect of chemotherapy (chemotherapy-induced peripheral neuropathy), radiation or surgery.

[0071] In some embodiments, the disease or disorder associated with abnormal expression or activities of IRAK is carcinoma which include for example acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous161118.08601carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian carcinoma, scirrhous carcinoma, carcinoma scrota, signet-ring cell carcinoma, carcinoma simplex, small cell carcinoma, solandoid carcinoma, pancreatic, breast, melanoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, carcinoma vilosum. In some embodiments, the cancers to be treated are a refractory or a responding cancer.

[0072] In some embodiments, the cancer is immunogenic. Examples of immunogenic cancers include malignant melanoma and renal cell carcinoma, mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acute lymphoblastic leukemia, Burkitt Lymphoma, myeloma, immunocytoma, acute promyelocyte leukemia, chronic myeloid / acute lymphoblastic leukemia, acute leukemia, B-cell acute lymphoblastic leukemia, anaplastic large cell leukemia, myelodysplasia syndrom e / acute myeloid leukemia, nonHodgkin's lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia(AML), common (pre-B)acute lymphocytic leukemia, malignant melanoma, T-cell lymphoma, leukemia, B-cell lymphoma, epithelial malignancies, lymphoid malignancies, gynecologic carcinoma, biliary adenocarcinomas and ductal adenocarcinomas of the pancreas.

[0073] In some embodiments, the disease or disorder associated with abnormal expression or activities of IRAK is sarcomas. Sarcomas are mesenchymal neoplasms that arise in bone and soft tissues. Different types of sarcomas are recognized and these include: liposarcomas (including myxoid liposarcomas and pleomorphic liposarcomas), leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors (including Ewing's sarcoma of bone, extraskeletal or non-bone) and primitive neuroectodermal tumors (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor,161118.08601gastrointestinal stromal tumor (GIST) and osteosarcoma (also known as osteogenic sarcoma) skeletal and extra- skeletal, and chondrosarcoma.

[0074] In some embodiments, the disease or disorder associated with abnormal expression or activities of IRAK is a hematologic (heme) malignancy. Nonlimiting examples include acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) (including polycythemia vera, essential thrombocythemia, and primary myelofibrosis), multiple myeloma, Waldenstrom macroglobulinemia, Hodgkin lymphoma, non-Hodgkin lymphomas (such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, marginal zone lymphoma, and T-cell lymphomas), and chronic myelomonocytic leukemia (CMML).

[0075] In some embodiments, the disease or disorder associated with abnormal expression or activities of IRAK is selected from Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), and MYD88 L265P-positive Activated B-cell-like Diffuse Large B-cell Lymphoma (ABC-DLBCL), Waldenstrom’s macroglobulinemia (WM), breast cancer, and ovarian cancer. In some embodiments, the breast cancer is lq21.3+ amplified breast cancer. In some embodiments, the breast cancer is selected from triple-negative breast cancer (TNBC), particularly the basal-like subtype, HER2-enriched breast cancer, luminal A, luminal B, estrogen receptor–positive (ER+) breast cancers, and recurrent and metastatic breast cancers.

[0076] A related aspect provides a method of suppressing tumor cell growth in a subject in need thereof. The method includes administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof to the subject.

[0077] Another aspect of the patent document provides a method for sensitizing a tumor to treatment with an additional therapeutic agent comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof. In some embodiments, the compound described herein, or a pharmaceutically acceptable salt thereof provides a synergistic effect when used in combination with a second agent.161118.08601

[0078] Another aspect of the patent document provides a method ILlb-induced activation of NF-KB in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0079] Another aspect of the patent document provides a method for stem cell mobilization and stem cell engraftment in a subject upon. The method includes administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, alone or in combinations with a second agent.

[0080] In any method disclosed herein, the compound of Formula I or a salt thereof can be used with a second or additional agent or therapy, at the same time, sequentially or in a suitable interval. Nonlimiting examples of such therapy or agent include radiation therapy, surgery, conventional chemotherapy, one or more checkpoint inhibitors. For example, the compounds described herein can be administered before, after, or simultaneously with chemotherapeutic and / or cytotoxic agents. Simultaneous administration can take place in the form of one fixed combination with two or more active ingredients, or by simultaneously administering two or more compounds that are formulated independently. The chemotherapeutic and / or cytotoxic agents which may be administered include, but are not limited to, alkylating agents (e.g., chlorambucil, cyclophosphamide, ccnu, melphalan, procarbazine, thiotepa, bcnu, and busulfan), antimetabolites (e.g., 6- mercaptopurine and 5-fluorouracil), anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone), antitumor antibiotics (e.g., bleomycin), monoclonal antibodies (e.g., alemtuzumab, bevacizumab, cetuximab, gemtuzumab, ibritumomab, panitumumab, rituximab, tositumomab, and trastuzumab), platinums (e.g., cisplatin, oxaliplatin, and carboplatin), plant alkaloids (e.g., vincristine), topoisomerase I or II inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide), vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine, and vindesine), taxanes (e.g., paclitaxel and docetaxel), epipodophyllotoxins (e.g., etoposide and teniposide), nucleoside analogs, and angiogenesis inhibitors (e.g., Avastin (beracizumab), a humanized monoclonal antibody specific for VEGF-A). Examples of glutathione antagonists include but are not limited to buthionine sulfoximine, cyclophosphamide, ifosphamide, actinomycin-d and N-(4-hydroxyphenyl) retinamide (4-HPR). Examples of angiogenesis inhibitors include but are not limited to 2-methoxyestradiol(2-ME), AG3340, Angiostatin, antithrombin-III, Anti- VEGF antibody,161118.08601Batimastat, bevacizumab (Avastin), BMS-275291, CAI, Canstatin, combretastatin, Combretastatin-A4 phosphate, CC-5013, captopril, celecoxib, Dalteparin, EMD121974, Endostatin, Erlotinib, Gefitinib, Genistein, Halofuginone, ID 1, ID3, IM862, Imatinib mesylate, Inducible protein- 10, Interferon- alpha, Interleukin- 12, Lavendustin-a, LY317615, or AE-941, Marimastat, Mapsin, Medroxyprogesterone acetate, Meth- 1, Meth-2, Neovastat, Osteopontin cleaved product, PEX, Pigment epithelium growth factor (PEGF), platelet growth factor 4, prolactin fragment, proliferin-related protein(PRP), PTK787 / ZK222584, recombinant human platelet factor-4(rPF4), restin, squalamine, SU5416, SU6668, Suramin, Taxol, Tecogalan, Thalidomide, Tetrathiomolybdate (TM), Thrombospondin, TNP-470, Troponin I, Vasostatin, VEGF1, VEGF-TRAP and ZD6474. In some embodiment the angiogenesis inhibitor is a VRGF antagonist. The VEGF antagonist may be a VEGF binding molecule. VEGF binding molecule include VEGF antibodies, or antigen binding fragment (s) thereof. One example of a VEGF antagonist is NeXstar.

[0081] In some embodiments, the compound described herein is administered in combination with one or more immune checkpoint inhibitors, kinase inhibitors, tubulin inhibitors, or topoisomerase inhibitors.

[0082] Nonlimiting examples of immune checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Illustrative immune checkpoint targets for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, y5, and memory CD8+ (aP) T cells), CD160 (also referred to as BY55), CGEN- 15049, CHK 1 and CHK2 kinases, A2aR and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Immune checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN- 15049. Illustrative immune checkpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS-936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody),161118.08601MSB0010718C (anti-PDLl antibody) and Yervoy / ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

[0083] In some embodiments, the compound or salt thereof described herein is used in combination with antibodies that can act as agonists of PD-1 and which thereby modulate immune responses regulated by PD-1. In one embodiment, the anti-PD-1 antibodies can be antigen-binding fragments. Anti-PD-1 antibodies disclosed herein are able to bind to human PD-1 and agonize the activity of PD-1, thereby inhibiting the function of immune cells expressing PD-1. In some embodiments, the compounds of the present disclosure may be used in combination with one or more PD-1 inhibitors selected from pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, nivolumab, AMP-224, or AMP-514. In some embodiments, the compounds of the present disclosure may be used in combination with one or more PD-L1 inhibitors selected from atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, or BMS-986189.

[0084] In some embodiments, the compound or salt thereof described herein is used in combination is used in combination with one or more therapeutic agents that inhibit CTLA-4. Suitable anti-CTLA4 antagonist agents for use herein, include, without limitation, anti-CTLA4 antibodies, human anti-CTLA4 antibodies, mouse anti-CTLA4 antibodies, mammalian anti-CTLA4 antibodies, humanized anti-CTLA4 antibodies, monoclonal anti-CTLA4 antibodies, polyclonal anti-CTLA4 antibodies, chimeric anti-CTLA4 antibodies, MDX-010 (ipilimumab), tremelimumab, anti-CD28 antibodies, anti-CTLA4 adnectins, anti-CTLA4 domain antibodies, single chain anti-CTLA4 fragments, heavy chain anti-CTLA4 fragments, light chain anti-CTLA4 fragments, inhibitors of CTLA4 that agonize the co- stimulatory pathway, the antibodies disclosed in PCT Publication No. WO 2001 / 014424, the antibodies disclosed in PCT Publication No. WO 2004 / 035607, the antibodies disclosed in U. S. Publication No.2005 / 0201994, and the antibodies disclosed in granted European Patent No. EP 1212422 Bl. Additional CTLA-4 antibodies are described in U. S. Pat. Nos. 5,811,097, 5,855,887, 6,051,227, and 6,984,720; in PCT Publication Nos. WO 01 / 14424 and WO 00 / 37504; and in U. S. Publication Nos. 2002 / 0039581 and 2002 / 086014. Other anti-CTLA-4 antibodies that can be used in a method of the present invention include, for example, those disclosed in: WO 98 / 42752; U. S. Pat. Nos. 6,682,736 and 6,207,156; Hurwitz et al., Proc. Natl. Acad. Sci. USA, 95(17):10067-10071 (1998); Camacho et al., J. Clin. Oncology, 22(145): Abstract No. 2505161118.08601(2004) (antibody CP-675206); Mokyr et al., Cancer Res., 58:5301-5304 (1998), and U. S. Pat. Nos. 5,977,318, 6,682,736, 7,109,003, and 7,132,281. Additional anti-CTLA4 antagonists include, but are not limited to, the following: any inhibitor that is capable of disrupting the ability of CD28 antigen to bind to its cognate ligand, to inhibit the ability of CTLA4 to bind to its cognate ligand, to augment T cell responses via the co-stimulatory pathway, to disrupt the ability of B7 to bind to CD28 and / or CTLA4, to disrupt the ability of B7 to activate the costimulatory pathway, to disrupt the ability of CD80 to bind to CD28 and / or CTLA4, to disrupt the ability of CD80 to activate the co-stimulatory pathway, to disrupt the ability of CD86 to bind to CD28 and / or CTLA4, to disrupt the ability of CD86 to activate the co-stimulatory pathway, and to disrupt the costimulatory pathway, in general from being activated. This necessarily includes small molecule inhibitors of CD28, CD80, CD86, CTLA4, among other members of the co-stimulatory pathway; antibodies directed to CD28, CD80, CD86, CTLA4, among other members of the co-stimulatory pathway; antisense molecules directed against CD28, CD80, CD86, CTLA4, among other members of the co- stimulatory pathway; adnectins directed against CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway, RNAi inhibitors (both single and double stranded) of CD28, CD80, CD86, CTLA4, among other members of the co-stimulatory pathway, among other anti-CTLA4 antagonists.

[0085] In some embodiments, the compound or salt thereof described herein is used in combination is used in combination with one or more therapeutic agents that inhibit TIM-3. Blocking the activation of TIM-3 by a ligand, results in an increase in Thl cell activation. Furthermore, TIM-3 has been identified as an important inhibitory receptor expressed by exhausted CD8+ T cells. TIM-3 has also been reported as a key regulator of nucleic acid mediated antitumor immunity. In one example, TIM-3 has been shown to be upregulated on tumor-associated dendritic cells (TADCs).

[0086] Additional examples of chemotherapeutic agents that can be combined with the compounds disclosed herein include, but are not limited to, DNA damaging agents and these include topoisomerase inhibitors (e.g. etoposide, camptothecin, topotecan, irinotecan, teniposide, mitoxantrone), anti -microtubule agents (e.g. vincristine, vinblastine), antimetabolite agents (e.g. cytarabine, methotrexate, hydroxyurea, 5-fluorouracil, flouridine, 6-thioguanine, 6-mercaptompurine, fludarabine, pentostatin, chlorodeoxyadenosine), DNA alkylating agents (e.g. cisplatin, mecholorethamine, cyclophosphamide, ifosphamide,161118.08601melphalan, chlorambucil, busulfan, thiotepa, carmustine, lomustine, carboplatin, dacarbazine, procarbazine) and DNA strand break inducing agents( e.g. bleomycin, doxorubicin, daunorubicin, idarubicin, mitomycin C).

[0087] Further examples of chemotherapeutic agents that can be used in combiantion with the compounds described herein include synthetic, semisynthetic and naturally derived agents. Important chemotherapeutic agents include, but are not limited to, Avicine, Aclarubicin, Acodazole, Acronine, Adozelesin, Adriamycin, aldesleukin, Alitretinoin, AUopurinol sodium, Altretamine, Ambomycin, Ametantrone acetate, Aminoglutethimide, Amsacrine, Anastrazole, Annonaceous Acetogenins, Anthramycin, Asimicin, Asparaginase, asperlin, Azacitidine, azetepa, Azotomycin, batimastat, benzodepa, bexarotene, Bicalutamide, Bisantrene, Bisnafide, Bizelesin, Bleomycin, Brequinar, Bropirimine, Bullatacin, Busulfan, Cabergoline, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedefingol, chlorambucil, celecoxib, cirolemycin, cisplatin, cladribine, crisnatol, cyclophosphamide, cytarabine, dacarbazine, DACA, dactinomycin, Daunorubicin, daunomycin, Decitabine, denileukin, Dexormaplatin, Dezaguanine, Diaziquone, Docetaxel, Doxorubicin, Droloxifene, Dromostalone, Duazomycin, Edatrexate, Eflornithine, Elsamitrucin, Estramustine, Etanidazole, Etoposide, Etoprine, Fadrozole, Fazarabine, Fenretinide, Floxuridine, Fludarabine, Fluorouracil, Flurocitabine, 5-FdUMP, Fosquidone, Fosteuecine, FK-317, FK-973, FR-66979, FR-900482, Gemcitabine, Gemtuzumab, Ozogamicin, Gold Aul 98, Goserelin, Guanacone, Hydroxyurea, Idarubicin, Ilmofosine, Interferon alpha and analogs, Iproplatin, irinotecan, Lanreotide, Letrozole, Leuprolide, Liarozole, Lometrexol, Lomustine, Losoxantrone, masoprocol, Maytansine, Mechlorethamine, Megestrol, Melengestrol, Melphalan, Menogaril, Metoprine, maturedepa, mitindomide, Mitocarcin, Mitogillin, Mitomalacin, Mitomycin, Mitomycin C, Mitosper, Mitotane, Mitoxantrone, Mycophenolic acid, Nocodazole, Nogalamycin, Oprelvekin, ormaplatin, Oxisuran, Paclitaxel, pamidronate, pegaspargase, Peliomycin, Pentamustine, Peplomycin, Perfosfamide, Pipobroman, Piposulfan, Piroxantrone, Plicamycin, Plomestane, Porfimer, Porfiromycin, Prednimustine, procarbazine, Puromycin, Pyrazofurin, Riboprine, Rituximab, Rogletimide, Rolliniastatin, safingol, Samarium, Semustine, Simtrazene, Sparfosate, Sparsomycin, spirogermanium, Spiromustine, Spiroplatin, Squamocin, Squamotacin, streptonigrin, streptozocin, SrC12, Sulphofenur, Talisomycin, Taxane, Toxoid, Tecoglan, Tegafur, teloxantrone, Temoporfin, teniposide, Teroxirone, Testolactone, Thiamiprine,161118.08601Thiotepa, Thymitaq, Tiazofurin, Tirapazamine, Tomudex, Top-53, Topotecan, Toremixifme, Trastuzumab, Trestolone, triciribine, Triciribine, Trimetrexate, trimetrexate glucuronate, Triptorelin, Tubulozole, uracil mustard, Uredepa, valrubicin, vapreotide, Vinblastine, Vincristine, Vindesine, Vinepidine, Vinglycinate, Vinleurosine, Vinorelbine, Vinrosidine, Vinzolidine, Vorozole, Zeniplatin, Zinostatin, Zorubicin, 2-cholrodeoxyrubicine, 2'-deoxyformycin, 9-aminocamptothecin, raltitrexed, N-propargyl-5,8-didezafolic acid, 2-cholo-2'arabinofluoro-2' deoxyadenosine, 2-cholo- 2'-deoxyadenosine, anisomycin, Trichostatin, hPRL-G129R, CEP-751, Linomide, Sulfur mustard, nitrogen mustard, N-methyl-N-nitrosourea, fotemustine, Streptozotocin, dacarbazine, mitozolomide, temozolomide, AZQ, ormaplatin, CI-973, DWA21 14R, JM216, JM335, Bisplatinum, Tomudex, azacitidine, cytrabincine, gemcitabine, 6-mercaptopurine, Hypoxanthine, Teniposide, CPT-1 1, Doxorubicin, Daunorubicin, Epirubicin, darubicin, losoxantrone, amsacrine, pyrazoloacridine, all trans retinol, 14- hydroxy-retro-retinol, all-trans retinoic acid, N-(4-hydroxyphenyl) retinamide, 13- cisretinoic acid, 3 -methyl TTNEB, 9-cisretenoic acid, fludarabine, and 2-Cda.

[0088] Further examples of chemotherapeutic agents that can be used in combination with the compounds described herein include 20-epil,25-dihydroxyvitamin-D3, 5-ethynyl uracil, abiraterone, aclarubicin, acylfulvene, adecylpenol, adozelesin, aldesleukin, ALL-TK antagonists, altretamine, ambumastine, amidox, amifostine, amino levulinic acid, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonists D, antarelix, anti-dorsalizing morphogenetic protein- 1, antiandrogen, antiestrogen, antineoplastone, antisense oligonucleotides, aphidicolin, apoptosis gene modulators, apoptosis regulators, apurinic acid, ara-cdp-dl-PTBA, arginine aminase, asulacrine, atamestine, atrimustine, axinamastine 1 and axinamastine 2, axinamastine 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, BCR / ABL antagonist, benzochlorins, benzoylsaurosporine, beta lactam derivatives, beta-alethine. Perillyl alcohol, phenozenomyein, phenyl acetate, phosphatase inhibitors, picibanil, pilocarbine and salts or analogs thereof, pirarubucin, piritrexim, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, phenyl ethyl isothiocyanate and analogs thereof, platinum compounds, platinum triamine complex, podophylotoxin, porfimer sodium, porphyromycin, propyl bis acridones, prostaglnadins J2, protease inhibitors, protein A based immune modulators, PKC inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine neucleoside phosphorylase inhibitors, purpurins, pyrazoloacridines, pyridoxylated haemoglobn polyoxyethylene conjugate, raf antagonists,161118.08601raltitrexed, ramosetron, ras farnesyl protein tranaferase inhibitors, rasinhibitors, ras-GAP inhibitors, ratelliptine demethylated, Rhenium Re 186 etidronate, rhizoxine, ribozyme, RII retinide, rogletimide, rosagliatazone and analogs and derivatives thereof, rohitukine, romurtide, roquinimex, rubiginone Bl, ruboxyl, safingol, saintopin, SarCNU, sarcophytol A, sargrmostim, sdi 1 mimetics, semustine, senescence derived inhibitor 1, sense oligonucleotide, signal transduction inhibitors, signal transduction modulators, single chain antigen binding protein, sizofiran, sobuzoxane, sodium borocaptate, sodium phenyl acetate, solverol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, spiromustin, splenopentine, spongistatin 1, squalamine, stem cell inhibitor, stem cell division inhibitor, stipiamide, stromelysin, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, siramin, swainsonine, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tacogalan sodium, tegafur, tellurapyrilium, telomerase inhibitors, temoporfin, tmeozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalidomide, thiocoraline, thrombopoetin and mimetics thereof, thymalfasin, thymopoetin receptor agonist, thymotrinan, thyroid stimulating harmone, tin ethyl etiopurpin, tirapazamine, titanocene and salts thereof, topotecan, topsentin, toremifene, totipotent stem cell factors, translation inhibitors, tretinoin, triacetyluridine, tricribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector system, erythrocyte gene therapy, velaresol, veramine, verdins, verteporfin, vinorelbine, vinxaltine, vitaxin, vorozol, zanoterone, zeniplatin, zilascorb and zinostatin.

[0089] Further chemotherapeutic agents that can be combined with the compounds described herein include: antiproliferative agents (e.g., piritrexim isothiocyanate), antiprostatic hypertrophy agents(sitogluside), Benign prostatic hyperplasia therapy agents (e.g., tomsulosine, RBX2258), prostate growth inhibitory agents (pentom one) and radioactive agents: Fibrinogen 11 25, fludeoxyglucose F18, Flurodopa F18, Insulin 1125, lobenguane 1123, lodipamide sodium 1131, lodoantipyrine 1131, lodocholesterol 1131, lodopyracet 1125, lofetamine HCL 1123, lomethin 1131, lomethin 1131, Iothalamate sodium 1125, Iothalamate 1131, lotyrosine 1131, Liothyronine 1125, Merosproprol Hgl 97, Methyl ioodobenzoguanine (MIBG-I131 or MIBGI 123), selenomethionine Se75, Technetium Tc99m furifosmin, technetium Tc99m gluceptate, Tc99m Biscisate, Tc99m disofenin, TC99m gluceptate, Tc99m lidofenin, Tc99m mebrofenin, Tc99m medronate and sodium salts thereof, Tc99m mertiatide,161118.08601Tc99m oxidronate, Tc99m pentetate and salts thereof, Tc99m sestambi, Tc99m siboroxime, Tc99m succimer, Tc99m sulfur colloid, Tc 99m teboroxime, Tc 99m Tetrofosmin, Tc99m Tiatide, Thyroxine 1125, Thyroxine 1131, Tolpovidone 1131, Triolein 1125 and Treoline 1125, and Treoline 131, MIBG-I123 and MIBG 1131.

[0090] The compositions or pharmaceutical compositions described herein may be administered to the subject by any suitable means. Non-limiting examples of methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrasternally, or the like, including infusion pump delivery; as well as (d) administration topically; as deemed appropriate by those of skill in the art for bringing the active compound into contact with living tissue.

[0091] Pharmaceutical compositions suitable for administration include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. In some embodiments, a therapeutically effective amount of a compound is an amount effective to treat a viral infection, for example, in a mammalian subject (e.g., a human). The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication, and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0092] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific161118.08601use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.

[0093] In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be about 10 microgram / kg to about 100 mg / kg body weight, preferably about 100 microgram / kg to about 10 mg / kg body weight. Alternatively, dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.

[0094] The exact formulation, route of administration and dosage for the pharmaceutical compositions can be chosen by the individual physician in view of the patient’s condition, (see e.g., Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”, which is hereby incorporated herein by reference in its entirety, with particular reference to Ch. 1, p.1). In some embodiments, the dose range of the composition administered to the patient can be from about 0.5 to about 1000 mg / kg of the patient’s body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In instances where human dosages for compounds have been established for at least some conditions, those same dosages, or dosages that are about 0.1% to about 500%, more preferably about 25% to about 250% of the established human dosage may be used. Where no human dosage is established, as will be the case for newly discovered pharmaceutical compositions, a suitable human dosage can be inferred from EDso or IDso values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0095] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in161118.08601the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0096] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of about 0.1 mg to 2000 mg of the active ingredient, preferably about 1 mg to about 500 mg, e.g. 5 to 200 mg. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of the active ingredient of about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 60 mg, e.g. about 1 to about 40 mg is used. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free acid. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively, the compositions may be administered by continuous intravenous infusion, preferably at a dose of up to about 1000 mg per day. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range to effectively and aggressively treat particularly aggressive diseases or infections. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0097] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the antibiotic effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0098] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0099] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.161118.08601

[0100] The amount of composition administered may be dependent on the subject being treated, on the subject’s weight, the severity of the infection, the manner of administration and the judgment of the prescribing physician.

[0101] Compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of the compound may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition. Similarly, acceptable animal models may be used to establish efficacy of chemicals to treat such conditions. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, and route of administration, and regime. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0102] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. 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. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U. S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0103] In some embodiments, in the pharmaceutical industry, it is standard practice to provide substantially pure material when formulating pharmaceutical compositions. Therefore, in some embodiments, “substantially pure” refers to the amount of purity required for formulating pharmaceuticals, which may include, for example, a small amount of other161118.08601material that will not affect the suitability for pharmaceutical use. In some embodiments, the substantially pure compound contains at least about 96% of the compound by weight, such as at least about 97%, 98%, 99%, or 100% of the compound.

[0104] Examples

[0105] Example 1. Compound synthesis

[0106] Synthesis of Intermediate 1

[0107] Step 1: Synthesis of ethyl 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinate (3)

[0108] A stirred solution of ethyl 6-bromopicolinate (1, 3.0 g, 13 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2, 3.9 g, 14 mmol) and cesium carbonate (8.55 g, 26.3 mmol) in 1,4-dioxane (30 mL) at room temperature was degassed with argon for 5 min. Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.0 g, 1.3 mmol) was added, the vessel was sealed, and the mixture was heated at 100 °C for 16 h. After this time, water (50 mL) was added and the mixture was extracted with ethyl acetate (3 x 70 mL). The combined organic extracts were dried over sodium sulfate, filtrated and concentrated under reduced pressure. The residue obtained was chromatographed (silica gel; 0-20% ethyl acetate in hexanes) to afford ethyl 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinate (3, 3.1 g, 79%) as a brown liquid.

[0109] Step 2: Synthesis of 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinic acid (Intermediate 1)

[0110] To a stirred solution of ethyl 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinate (3, 3.0 g, 10 mmol) in 2:1 ethanol / water (30 mL) was added sodium hydroxide (0.800 g, 19.9 mmol) at room temperature, and the mixture was stirred for 3 h. After this time, water (50 mL) was added and the mixture was washed with tert-butyl methyl ether (50 mL) to remove nonpolar impurities. The aqueous layer was adjusted to pH 5-6 with aq. citric acid and161118.08601extracted with dichloromethane (5 x 70 mL). The combined organic extracts were dried over sodium sulfate, filtrated and concentrated under reduced pressure to afford 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinic acid (Intermediate 1, 1.8 g, 62%) as a brown semisolid.

[0111] Synthesis of compound I-a and Compound I-cR = OMeor R = CF3

[0112] Step 1: General procedure for the synthesis of 6

[0113] Method A: A stirred solution of the corresponding bromo nitrobenzene 4 (1.0 eq), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 5 (1.5 eq), and potassium phosphate tribasic (3.0 eq) in 1,4-di oxane (20 vol) at room temperature was degassed with argon for 5 min. Bis(di- / c / 7-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.1 eq) was added and the mixture was heated at 100 °C for 16 h. After this time, water (10 vol) was added and the mixture was extracted with ethyl acetate (3 x 10 vol). The combined organic extracts were dried over sodium sulfate, filtrated and concentrated under reduced pressure. The residue obtained was chromatographed (silica gel; 0-10% ethyl acetate in hexanes) to afford compound 6.

[0114] Step 2: General procedure for the synthesis of 7

[0115] Method B: To a stirred solution of the corresponding thiopyran compound 6 (1.0 eq) in dichloromethane (20 vol) was added 3 -chloroperbenzoic acid (3.0 eq) at 0° C and the mixture was stirred at room temperature for 16 h. After this time, sat. sodium bicarbonate161118.08601solution (20 vol) was added and the mixture was extracted with di chloromethane (2 x 30 vol). The combined organic extracts were washed with brine (20 vol), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude compound 7, which was used in the next step without purification.

[0116] Step 3: General procedure for the synthesis of 8

[0117] Method C: To a stirred solution of the corresponding nitro compound 7 (1.0 eq) in ethanol (20 vol) was added 10% palladium on carbon (50% wet, 0.5 eq). The reaction mixture was stirred under 1 atm of hydrogen for 16 h at room temperature. After this time, the catalyst was removed by filtration through diatomaceous earth, and the filter cake was washed with ethanol (30 vol). The filtrate was concentrated under reduced pressure to afford crude compound 8, which was used in the next step without purification.

[0118] Step 4: General procedures for synthesis of 9

[0119] Method D: To a stirred solution of amine 8 (1.0 eq), 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinic acid (Intermediate 1, 1.0 eq), and triethylamine (2.5 eq) in dichloromethane (10 vol) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 2.5 eq) at 0° C and the mixture was stirred at room temperature for 16 h. After this time, sat. sodium bicarbonate solution (20 vol) was added and the mixture was extracted with dichloromethane (2 x 30 vol). The combined organic extracts were washed with brine (20 vol), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was chromatographed (silica gel; 0-80% ethyl acetate in hexanes) to afford compound 9.

[0120] Method E: To a stirred solution of the corresponding amine 8 (1.0 eq), 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinic acid (Intermediate 1, 1.0 eq) and pyridine (5.0 eq) in dichloromethane (10 vol) was added phosphorus(V) oxychloride (3.0 eq) at 0° C and the mixture was stirred at room temperature for 1 h. After this time, sat. sodium bicarbonate solution (20 vol) was added and the mixture was extracted with dichloromethane (2x30 vol). The combined organic extracts were washed with brine (20 vol), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was chromatographed (silica gel; 0-80% ethyl acetate in hexanes) to afford compound 9.

[0121] Step 5: General procedures for the synthesis of compound I-a and Compound I-c161118.08601

[0122] Method F: To a stirred solution of amide 9 (1.0 eq) in 1,4-dioxane (10 vol) was added 4 M HC1 in 1,4-dioxane (5.0 eq) at 0° C and the resultant mixture was stirred at room temperature for 2 h. After this time, the volatiles were removed under reduced pressure. The residue obtained was purified by mass-triggered preparative HPLC to afford pure compound as a mixture of tautomers.

[0123] Method G: To a stirred solution of amide 9 (1.0 eq) in 1,4-dioxane (10 vol) was added 4 M HC1 in 1,4-dioxane (5.0 eq) at 0° C and the resultant mixture was stirred at room temperature for 2 h. After this time, the precipitated solid was collected by filtration, washed with diethyl ether (2 x 10 vol) and dried under vacuum to afford the desired product as the hydrochloride salt.

[0124] Synthesis of compound I-a

[0125] Step 1: Synthesis of 4-(3-methoxy-4-nitrophenyl)-3,6-dihydro-2H-thiopyran. Prepared according to Method A.

[0126] Step 2: Synthesis of 4-(3-methoxy-4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide. Prepared according to Method B.

[0127] Step 3: Synthesis of 4-(4-amino-3-methoxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide. Prepared according to Method C.NH2

[0128] Step 4: Synthesis of N-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-methoxyphenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinamide. Prepared according to Method D.161118.08601

[0129] Step 5: Synthesis of N-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-methoxyphenyl)-6-(1H-pyrazol-5-yl)picolinamide. Prepared according to Method F.

[0130] Synthesis of Compound I-c

[0131] Step 1: Synthesis of 4-(4-nitro-3-(trifluoromethyl)phenyl)-3,6-dihydro-2H-thiopyran. Prepared according to Method A.

[0132] Step 2: Synthesis of 4-(4-nitro-3-(trifluoromethyl)phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide. Prepared according to Method B.

[0133] Step 3: Synthesis of 4-(4-amino-3-(trifluoromethyl)phenyl)tetrahydro-2H-thiopyran 1,1-dioxide. Prepared according to Method C.

[0134] Step 4: Synthesis of N-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(trifluoromethyl)-phenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinamide. Prepared according to Method E.161118.08601

[0135] Step 5: Synthesis of N-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(trifluoromethyl)-phenyl)-6-(1H-pyrazol-5-yl)picolinamide hydrochloride (Compound I-c). Prepared according to Method G.

[0136] Synthesis of Compound I-b and Compound I-d

[0137] Step 1: General procedure for the synthesis of 10

[0138] Method H: To a stirred solution of compound 7 (1.0 eq) in tetrahydrofuran / methanol / water (3:2:1) (20 vol), were added zinc dust (15.0 eq) and ammonium chloride (15.0 eq) at room temperature. The mixture was stirred for 5 h. After this time, water (10 vol) was added and the mixture was extracted with dichloromethane (3 x 30 vol). The combined organic layers were dried over sodium sulfate, filtered and concentrated161118.08601under reduced pressure to afford crude amine compound 10, which was used in the next step without purification.

[0139] Step 3: General procedure for the synthesis of Compound I-b and Compound I-d

[0140] Method I: To a stirred solution of amide 11 (1.0 eq) in 1,4-dioxane (10 vol) was added 4 M HC1 in 1,4-dioxane (5.0 eq) at 0° C and the resultant mixture was stirred at room temperature for 2 h. After this time, the volatiles were removed under reduced pressure. The residue obtained was purified by mass-triggered preparative HPLC to afford pure product. This material was dissolved in 1,4-dioxane (10 vol), 4 M HC1 in 1,4-dioxane (2.0 eq) was added, and the mixture was stirred for 2 h. The precipitated solid was collected by filtration, washed with diethyl ether (2 x 10 vol) and dried under vacuum to afford pure compound as the hydrochloride salt.

[0141] Synthesis of COMPOUND I-b

[0142] Step 1: Synthesis of 4-(4-amino-3-methoxyphenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide. Prepared according to Method H.

[0143] Step 2: Synthesis of N-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methoxyphenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinamide. Prepared according to Method D.

[0144] Step 3: Synthesis of N-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methoxy-phenyl)-6-(1H-pyrazol-5-yl)picolinamide hydrochloride (Compound I-b). Prepared according to Method I.161118.08601

[0145] Synthesis of Compound I-d

[0146] Step 1: Synthesis of 4-(4-amino-3-(trifluoromethyl)phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide. Prepared according to Method H.

[0147] Step 2: Synthesis of N-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-(trifluoro-methyl)phenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinamide. Prepared according to Method E.

[0148] Step 3: Synthesis of N-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-(trifluoro-methyl)phenyl)-6-(1H-pyrazol-5-yl)picolinamide hydrochloride (Compound I-d). Prepared according to Method I.

[0149] Synthesis of Compound I-e161118.08601

[0150] Step 5: General procedure for the synthesis of 17

[0151] Method J: To a stirred solution amine 16 (1.0 eq), 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinic acid (Intermediate 1, 1.0 eq) and triethylamine (2.5 eq) in dichloromethane (10 vol) was added propanephosphonic acid anhydride (T3P, 2.5 eq) at 0° C and the mixture was stirred at room temperature for 16 h. After this time, sat. sodium bicarbonate solution (20 vol) was added and the mixture was extracted with dichloromethane (2x30 vol). The combined organic extracts were washed with brine (20 vol), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was chromatographed (silica gel; 0-80% ethyl acetate in hexanes) to afford compound 17.

[0152] Step 1: Synthesis of 4-(3-ethoxy-4-nitrophenyl)-3,6-dihydro-2J / -thiopyran (13) Prepared according to Method A.

[0153] Step 2: Synthesis of 4-(3-ethoxy-4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (14). Prepared according to Method B.

[0154] Step 3: Synthesis of 4-(4-amino-3-ethoxyphenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (15). Prepared according to Method C.

[0155] Step 4: Synthesis of 4-(4-amino-3-ethoxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide (16)161118.08601

[0156] To a stirred solution of 4-(4-amino-3-ethoxyphenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (15, 0.330 g, 1.23 mmol) in ethanol (20 mL) was added 20% palladium hydroxide (50% wet, 0.1 g), and the mixture was stirred under 1 atm of hydrogen at room temperature for 16 h. After this time, the catalyst was removed by filtration, and the filter cake was washed with ethanol (30 mL). The filtrate was concentrated under reduced pressure to afford 4-(4-amino-3-ethoxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide (16, 0.300 g) as a brown liquid which was used in the next step without purification. MS (ESI) m / z 270 [M + H]+.

[0157] Step 5: Synthesis of N-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-ethoxyphenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinamide (17). Prepared according to Method J.

[0158] Step 6: Synthesis of N-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-ethoxyphenyl)-6-(1H-pyrazol-5-yl)picolinamide hydrochloride (Compound I-e). Prepared according to Method F.

[0159] Synthesis of Compound I-f

[0160] Step 1: Synthesis of 4-bromo-l-nitro-2-propoxybenzene (19)

[0161] To a stirred suspension of sodium hydride (60% dispersion in mineral oil) (0.363 g, 9.09 mmol) in A'A -di methyl form am ide (25 mL) was added propan-l-ol (0.546 g, 9.09 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stir for 30 min. After cooling back to 0 °C, 4-bromo-2-fluoro-1-nitrobenzene (18, 2.0 g, 9.1 mmol) was added. The mixture was allowed to warm to room temperature and stir for 16 h. After this time, sat.161118.08601ammonium chloride (50 mL) was added slowly dropwise, and the mixture was extracted with ethyl acetate (2 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was chromatographed (silica gel; 0-10% ethyl acetate in hexanes) to afford 4-bromo-l-nitro-2-propoxybenzene (19, 1.2 g, 50%) as a yellow liquid.

[0162] Step 2: Synthesis of 4-(4-nitro-3-propoxyphenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (21). Prepared according to Method A.

[0163] Step 3: Synthesis of 4-(4-amino-3-propoxyphenyl)tetrahydro-2J / -thiopyran 1,1-dioxide (22)

[0164] To a stirred solution of 4-(4-nitro-3-propoxyphenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (21, 0.700 g, 2.25 mmol) in ethanol (30 mL) were added 10% palladium on carbon (50% wet, 0.1 g) and 20% palladium hydroxide (50% wet, 0.1 g). The reaction mixture was stirred under 1 atm of hydrogen for 16 h. After this time, the catalyst was removed by filtration, and the filter cake was washed with ethanol (50 mL). The filtrate was concentrated under reduced pressure to afford 4-(4-amino-3-propoxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide (22, 0.600 g) as a brown liquid which was used in the next step without purification. MS (ESI) m / z 284 [M + H]+.

[0165] Step 4: Synthesis of N-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-propoxyphenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinamide (23). Prepared according to Method J.

[0166] Step 5: Synthesis of N-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-propoxyphenyl)-6-(1H-pyrazol-5-yl)picolinamide hydrochloride (Compound I-f) Prepared according to Method I.

[0167] Example 2

[0168] Compounds of Formula I have been screened against IRAK-1, IRAK-2, and IRAK-4. In comparison with other kinase inhibitors reported in literature, a representative compound of Formula I exhibited excellent activities.

[0169] The kinase profiling assay for UR241-2 involved testing in 10-dose IC50 mode with a 3-fold serial dilution, starting at 20 pM. The control compound, staurosporine, was tested in 10-dose IC50 mode with a 4-fold serial dilution, starting at 20 pM. Reactions were161118.08601carried out with 1 μM ATP, and the % enzyme activity was calculated relative to DMSO controls. Curve fits were performed where the enzyme activities at the highest concentration of compounds were less than 65%. An IC50 value of less than 1.0 nM was estimated based on the best available curve fitting.

[0170] Table 2. Kinase inhibition IC50 of Compound I-a in comparison with UR241-2, CA4948 and staurosporine.Comparison of kinase inhibitory IC50 against clinically leading inhibitor CA4948 and a nonspecific kinase inhibitor control staurosporineKinase UR241-2 EDI-238382 CA4948 Staurosporine Comparator comparator IRAK1 1.3nM <0.5 1nM 4.5pM 33.61nM IRAK2 585.6nM 1.06pM No activity 0.799nMIRAK4 1.88nM 1.8 InM 17.98nM 7.86nM

[0171] As shown in Figure 1, Compound I-a (EDI-238382) inhibits NF-kB activity in THP1- AML cells-based reporter assay. At 800nM -50% NF-kB reporter activity was found to be decreased.

[0172] The Selectivity Profile of Compound I-a (EDI-238382) is summarized below. EDI-238382 IRAK1 / 4 Kinase inhibition:• IRAK4 IC50 = 1.8 nM• IRAKI IC50 < 0.5 nM375 kinases screened at 50 and 500 nM• 360 kinases <50% inhibition at 50 nM (>25 fold selective)• Only 22 kinases >80% inhibition at 500 nM• Cell-based assays (NanoBRET) show strong IRAK-4 inhibition maintained with reduced inhibition of off-target kinases44 safety targets (enzymes, ion channels, receptors) screened at 10 uMNo hERG inhibition161118.08601• Only two off targets hit (vasopressin antagonism, PDE4D2 inhibition)Strong overall selectivity data for EDI-238382

[0173] The ADME profile of Compound I-a is summarized below.

[0174] Table 3. ADME profiling of Compound I-athermodynamic solubility 1.8 uM pH 7.4 PBS (1% DMSO)24 hplasma protein binding (h) 98.8% 105% recovery at 4hplasma protein binding (m) 96.8% 71% recovery at 4hCaco-2 permeability Papp2.9 (A→B) Moderate efflux(x 10'6cm / sec) 11.2 (B→A) Efflux ratio 3.9Plasma stability (h) t1 / 2407 minPlasma stability (m) t1 / 2182 minMicrosomal Cli (h) 3.2 uL / min / mg t1 / 2214 minMicrosomal Cli (m) 51.4 uL / min / mg t1 / 213.5 minCYP450 ICsos 2C19 IC50 = 5.3 uM All others IC50 > 30 uM (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2J2 IC50 = 1.9 uM2D6, 2E1, 2J2, 3A4, 3A5, 19A)2C9 IC50 = 4.9 uM

[0175] Compound I-a is stable in human liver microsome. It is also more stable than UR241-2 in mouse liver microsome. The half-life of Compound I-a in mice is significantly longer than that of UR241-2.

[0176] All references cited herein are incorporated herein by reference in their entireties. It will be appreciated by persons skilled in the art that the present invention is not161118.08601limited to what has been particularly shown and described. Rather, the scope of the present invention is defined by the claims which follow. It should further be understood that the above description is only representative of illustrative examples of embodiments. The description has not attempted to exhaustively enumerate all possible variations. The alternate embodiments may not have been presented for a specific portion of the invention, and may result from a different combination of described portions, or that other un-described alternate embodiments may be available for a portion, is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those un-described embodiments are within the literal scope of the following claims, and others are equivalent.

Claims

161118.08601WE CLAIM1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented as Formula A,WhereinR1is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo-Ci-ealkyl, O-halo-Ci-ealkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6 or 10 membered aryl, and 5-10 membered heteroaryl;R2is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-halo-Ci-ealkyl;R3is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-halo-Ci-ealkyl;R4is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi-ealkyl, halo- Ci-ealkyl, and O-halo-Ci-ealkyl;m is 0, 1, 2, 3 or 4;n is 0, 1, 2, or 3;o is 0, 1, or 2;p is 0, 1, or 2;Ring Ais X1, X2, and X3are each independently N or CH, provided that at least one of them is N;47178014722.3161118.08601 X4-X5Ring B is', wherein X4and X5are each independently NH, N, O, S or CH, provided that at least one of them is a heteroatom;E is a bond, Ci-4alkylene or -C(=O)-; andL is NHC(O) or NHSO2.

2. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein ring A isor3. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-2,wherein ringA is4. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein Z is SO2.

5. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-4,wherein ring B is selected from the group consisting of6. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-5,wherein ring Bis7. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein X1is N, X2and X3are CH.

8. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein R1is selected from the group consisting of halogen, Ci-ealkyl, OCi-ealkyl, halo-Ci- ealkyl, and O-halo-Ci-ealkyl, wherein m is 0, 1 or 2.

9. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein R1is selected from the group consisting of halogen, OCi-ealkyl, Ci-ealkyl, halo- Ci- ealkyl, and O-(halo)Ci-ealkyl, wherein R1is positioned ortho to L, wherein m is 1.161118.08601 10. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein R2is selected from the group consisting of halogen, Ci-ealkyl, OCi-ealkyl, halo- Ci- ealkyl, and O-(halo)Ci-ealkyl, wherein n is 0, 1 or 2.

11. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-10, wherein R3is selected from the group consisting of halogen, Ci-ealkyl, and OCi-ealkyl, wherein o is 0 or 1.

12. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-11, wherein R4is selected from the group consisting of halogen, Ci-ealkyl, and OCi-ealkyl, wherein p is 0 or 1.

13. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-12, wherein L is NHC(O), wherein the nitrogen of L is connected to the phenyl ring C.

14. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-13, wherein E is a bond.

15. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-14, wherein L is NHC(O), wherein the compound is represented as Formula (IV):Wherein R1is selected from the group consisting of halogen, nitro, cyano, Ci-ealkyl, OCi- ealkyl, halo-Ci-ealkyl, O-halo-Ci-ealkyl, and 3-6 membered cycloalkyl16. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein R1is selected from the group consisting of Ci-ealkyl, OCi-ealkyl, halo-Ci-ealkyl, O- halo-Ci-ealkyl, and 3-6 membered cycloalkyl.

17. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the compound is selected from the group consisting of161118.0860118. A pharmaceutical composition comprising a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-17 and a pharmaceutically acceptable carrier.

19. A method of treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-16 or the pharmaceutical composition of claim 17, wherein the disease or disorder is selected from the group consisting of inflammatory disorder, organ fibrosis, pain, and cancer.161118.08601 20. The method of claim 19, wherein the disease or disorder is selected from the group consisting of Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), and MYD88 L265P-positive Activated B- cell— like Diffuse Large B-cell Lymphoma (ABC-DLBCL), Waldenstrom’s macroglobulinemia (WM), breast cancer, and ovarian cancer.

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