Interleukin receptor-associated kinase (IRAK) protac degraders and medical use thereof

Abstract

The present disclosure relates to compounds and methods for degrading interleukin receptor-associated kinase 4 (IRAK4), the methods comprising administering to the subject a compound of Formula (I). In some embodiments, the disclosure provides compounds and methods for treating cancer.

Description

[0001] TITLE OF THE INVENTION

[0002] INTERLEUKIN RECEPTOR-ASSOCIATED KINASE (IRAK) PROTAC DEGRADERS AND MEDICAL USE THEREOF

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to, and benefit of, U.S. Provisional Application No. 63 / 631,012, filed April 8, 2024, which is hereby incorporated by reference in its entirety.

[0005] BACKGROUND OF THE INVENTION

[0006] 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 (Li, S., et al., 2002, Proceedings of the National Academies of Science USA, 99:5567). IRAK4 is a downstream signaling mediator of the pro-inflammatory interleukin-1 (IL- 1) family of receptors and of the pathogen sensing and innate signaling toll-like receptors (TLRs). TLRs are activated by endogenous signaling molecules 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, while aberrant IRAK4 pathway signaling due to mutations in the MyD88 adaptor protein have been implicated in malignancies.

[0007] The proximal location of IRAK4 to immune signaling receptors has generated significant interest in therapeutics targeting IRAK4 for control against autoimmune and inflammatory diseases. These agents have also been suggested to be useful in controlling high-risk malignancies such as pancreatic cancer and colitis-induced tumorigenesis and chemoresistance in colon cancer (Zhang, D., et al., 2017, 23(7): 1748-1759; Li, Q., et al., 2019, JCI Insight, 4(19):el30867).

[0008] According to the National Institutes of Health, up to 23.5 Americans (>7% of the population) suffer from one form or another of autoimmune disease, and the prevalence is rising (National Institutes of Health Autoimmune Diseases Coordinating Committee, 2005, Progress in Autoimmune Diseases Research). Autoimmune diseases can lead the body to produce antibodies that, instead of fighting infections, attack the body’s cells, tissues, and organs, and may occur almost anywhere in the body, or may affect more than one part of the body. Autoimmune diseases are also characterized by severe unmet medical needs.

[0009] Thus, there is a need in the art for improved compositions and methods for inhibiting IRAK4 and treating diseases associated with its direct, or indirect, aberrant signaling. This invention satisfies this unmet need.

[0010] SUMMARY OF THE INVENTION

[0011] In some embodiments, the present invention provides a compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof

[0012] Formula (I), wherein: A1is selected from the group consisting of arylene and heteroarlyene; RA1is represents mono to the maximum allowable substitution, or no substitution; each occurrence of RA1is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3; L represents a divalent linking group; and Ubiig is an E3 ubiquitin ligase ligand.

[0013] In some embodiments, the compound of Formula (I) is a compound of Formula (II), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0014] Formula (II), wherein: A1is selected from the group consisting of arylene and heteroarlyene; RA1represents mono to the maximum allowable substitution, or no substitution; each occurrence of RA1is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3; L1and L2each independently represent a divalent linking group; and Ubiig is an E3 ubiquitin ligase ligand. In some embodiments, A1is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl, wherein A1is optionally further substituted.

[0015] In some embodiments, the compound of Formula (I) is a compound of Formula (III) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0016] Formula (III), wherein: each of X1, X2, X3, and X4is selected from N and CR1; and each instance of R1is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, L1and L2are each independently selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof. In some embodiments, L1and L2are each independently selected from the group consisting of alkylene, heteroalkylene, cycloalkylene, heteroalkylene, ester, and amide. In some embodiments, L1and L2are each independently selected from the group consisting of: and combinations thereof, wherein: RNis selected from the group consisting of H,

[0017] D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10.

[0018] In some embodiments, the compound of Formula (I) is a compound of Formula (IV) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof: Formula (IV).

[0019] In some embodiments, L1is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof. In some embodiments, L1is selected from the group consisting combinations thereof, wherein: RNis selected from the group consisting of H, D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10.

[0020] In some embodiments, Ubiig is selected from the group consisting of:

[0021] , and stereoisomers thereof; wherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl; wherein R42represents mono to the maximum allowable substitution, or no substitution; and each occurrence of RA2is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3,

[0022] OCDs, and OCF3.

[0023] In some embodiments, the compound of Formula (I) is selected from the group consisting of:

[0024] stereoisomers, prodrugs, derivatives, and pharmaceutically acceptable salts and solvates thereof.

[0025] In some embodiments, the present invention provides a method of decreasing IRAK4 protein levels in a subject, comprising administering to the subject the compound of the present invention.

[0026] In some embodiments, the present invention provides a method of treating a disease or disorder associated with increased IRAK4 activity in a subject, comprising administering to the subject the compound of the present invention. In some embodiments, the disease or disorder associated with IRAK4 activity is selected from the group consisting of cancer, Parkinson’s disease, Alzheimer’s disease, fibrosis, inflammatory diseases and disorders, and autoimmune diseases and disorders.

[0027] In some embodiments, the inflammatory disease or disorder is selected from the group consisting of 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 hepatitisjuvenile 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, atherosclerosis, psoriatic arthritis, vasculitis, Polymyalgia, Rheumatica, Wegener’s granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, and ataxia telangiectasia.

[0028] In some embodiments, the fibrosis is one or more selected from the group consisting of renal fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, Crohn’s disease, liver fibrosis, heart fibrosis, scleroderma, or progressive massive fibrosis.

[0029] In some embodiments, the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, uterine cancer, 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, mucinous carcinoma, 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 liposarcomas, leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing’s tumors, 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, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, chondrosarcoma, mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acutelymphoblastic 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 syndrome / acute myeloid leukemia, non-Hodgkin’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, pancreatic biliary adenocarcinoma, and pancreatic ductal adenocarcinomas. In some embodiments, the cells of the cancer have a mutation in an fms-like tyrosine kinase 3 (FLT-3) gene. In some embodiments, the mutation in an FLT-3 gene is an internal tandem duplication (ITD) mutation.

[0030] In some embodiments, the compound of the present invention is administered in combination with one or more therapies selected from the group consisting of radiation therapy, surgery, chemotherapy, and checkpoint inhibitors. In some embodiments, the therapy comprises one or more selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinum agents, topoisomerase I inhibitors, topoisomerase II inhibitors, vinca alkaloids, taxanes, epipodophyllotoxins, nucleoside analogs, angiogenesis inhibitors, and

[0031] In some embodiments, the present invention provides a method of inhibiting angiogenesis in a subject, comprising administering to the subject the compound of the present invention.

[0032] In some embodiments, the present invention provides a method of sensitizing a tumor in a subject to treatment, comprising administering to the subject the compound of the present invention.

[0033] In some embodiments, the present invention provides a method of treating a pain disorder in a subject, comprising administering to the subject the compound of the present invention. In some embodiments, the pain disorder is one or more selected from the group consisting of inflammatory pain, post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

[0034] In some embodiments, the pain disorder comprises neuropathic or nociceptive pain. In some embodiments, the subject with a pain disorder comprising neuropathic pain has one or more selected from the group consisting of spinal cord injury, multiple sclerosis, stroke, diabetes, herpes zoster infection, HIV infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune-related disorders, and physical trauma to the nerve trunk. In some embodiments, the present invention provides a method of inducing IL- 1 p- induced activation of NF-KB in a subject, comprising administering to the subject the compound of the present invention.

[0035] In some embodiments, the present invention provides a method of inducing stem cell mobilization and engraftment in a subject, comprising administering to the subject the compound of the present invention.

[0036] BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The following detailed description of embodiments of the invention will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0038] Figure 1 depicts representative survival curves of patients with melanoma having high (n = 25) or low (n = 77) interleukin receptor-associated kinase 4 (IRAK4) expression, demonstrating IRAK4 overexpression predicts poor survival (p = 0.0064).

[0039] Figure 2 depicts representative survival curves of patients with breast cancer having high (n = 848) or low (n = 227) IRAK4 expression, demonstrating IRAK4 overexpression predicts poor survival (p = 0.028).

[0040] Figure 3 depicts representative survival curves of patients with lung cancer having high (n = 173) or low (n = 192) IRAK4 expression, demonstrating IRAK4 overexpression predicts poor survival (p = 0.014). The average 5-year survival for patients with high IRAK4 expression is 42%, while patients with low expression exhibit a 53% survival rate.

[0041] Figure 4 depicts representative survival curves of patients with melanoma having high (n = 122) or low (n = 31) IRAK4 expression, demonstrating IRAK4 overexpression predicts poor survival (p = 0.057). The average 5-year survival for patients with high IRAK4 expression is 7%, while patients with low expression exhibit an 18% survival rate.

[0042] Figure 5 depicts representative IRAK4 degradation data with PS 102 at 0.5 pM and 1.0 pM treatment relative to dimethyl sulfoxide (DMSO, negative control).

[0043] Figure 6 depicts representative IRAK4 degradation data with PSP-119 at 10 nM for 6 hours when IRAK4 expression is driven by exposure to IL-ip for 45 minutes. Figure 7 depicts representative images of a Western blot demonstrating that PSP-119 induces degradation of both long (IRAK4-L) and short (IRAK4-s) forms of IRAK4 in MV-4-11 leukemia cells with a mutation in the FLT-3 gene after 24 hours of treatment.

[0044] Figure 8 depicts representative images of a Western blot demonstrating that PSP-119 induces degradation of both IRAK4-L and IRAK4-S forms of IRAK4 in MOLM-13 leukemia cells carrying a mutation in the FLT-3 gene after 24 hours of treatment.

[0045] Figure 9 depicts representative results of an IRAK4 activity assay, demonstrating that the IC50 of PSP-119 is 2.33 nM.

[0046] Figure 10 depicts representative cell results demonstrating that PSP-119 treatment reduces the viability of leukemia cells carrying an FLT-3 mutation (MV-4-11 and MOLM-13), but does not decrease viability of THP-1 leukemia cells with wildtype FLT-3.

[0047] Figure 11 depicts representative results demonstrating that daily administration of PSP- 119 inhibits tumor growth in an NSG mouse tumor xenograph model. PSP-119 was administered intraperitoneally once daily at a dose of 10 mg / kg.

[0048] DETAILED DESCRIPTION

[0049] In one aspect, the disclosure is based in part on the unexpected finding of novel compounds which degrade interleukin receptor-associated kinase 4 (IRAK4). In some embodiments, these compounds are useful for treating diseases and / or disorders associated with IRAK4 overexpression. For example, in some embodiments, the compounds of the disclosure may treat cancer. In some embodiments, the compounds may treat autoimmune diseases.

[0050] Definitions

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0052] As used herein, each of the following terms has the meaning associated with it in this section.

[0053] The articles “a” and “an” are used herein to refer to one or to more than one ( / .< ., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0054] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0055] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0056] A disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.

[0057] The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human.

[0058] As used herein, the term “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0059] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs or symptoms of pathology disease or disorder, for the purpose of diminishing or eliminating those signs or symptoms.

[0060] As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder contemplated herein, a sign or symptom of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a disease or disorder contemplated herein, the signs or symptoms of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

[0061] As used herein, the terms “effective amount,” “pharmaceutically effective amount" and “therapeutically effective amount” refer to a sufficient amount of an agent to provide the desired biological or physiologic result. That result may be reduction and / or alleviation of a sign, a symptom, or a cause of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0062] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0063] As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, paratoluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like. Furthermore, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), and ammonium salts. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0064] As used herein, the term “potency” refers to the dose needed to produce half the maximal response (ED50).

[0065] As used herein, the term “efficacy” refers to the maximal effect (Emax) achieved within an assay. As used herein, “activity” includes physiological activity, binding affinity, and / or the enzymatic activity of a molecule.

[0066] As used herein, “IRAK4” refers to interleukin receptor-associated kinase 4.

[0067] As used herein, “associated” refers to coincidence with the development or manifestation of a disease, condition, or phenotype. Association may be due to, but is not limited to, genes responsible for housekeeping functions, those that are part of a pathway that is involved in a specific disease, condition, or phenotype and those that indirectly contribute to the manifestation of a disease, condition, or phenotype.

[0068] As used herein, the term “cancer” refers to any of various types of malignant neoplasms, most of which invade surrounding tissues, may metastasize to several sites and are likely to recur after attempted removal and to cause death of the patient unless adequately treated. As used herein, neoplasia comprises cancer. Representative cancers include, for example, squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias, including non-acute and acute leukemias, such as acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, T-lineage acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas, among others, which may be treated by one or more compounds of the present invention.

[0069] As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. Ci-6 means one to six carbon atoms) and including straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.

[0070] As used herein, the term “substituted alkyl” means alkyl as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, -NH2, amino, azido, -N(CH3)2, -C(=O)OH, trifluoromethyl, -C=N, -C(=O)O(Ci-C4)alkyl, -C(=0)NH2, -SO2NH2, -C(=NH)NH2, and -NO2. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3 -chloropropyl.

[0071] As used herein, the term “heteroalkyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(=O)-CH3, and -CH2-CH2-S(-O)2-CH3 Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-O-CH3 or -CH2-CH2-S-S-CH3.

[0072] As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.

[0073] As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0074] As used herein, the term “cycloalkyl” refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl group is saturated or partially unsaturated. In another embodiment, the cycloalkyl group is fused with an aromatic ring. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moi eties:

[0075] Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyls include adamantine and norbornane. The term cycloalkyl includes “unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon double bond or one carbon triple bond.

[0076] As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, S and N. In some embodiments, each heterocycloalkyl group has from 4 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms. In another embodiment, the heterocycloalkyl group is fused with an aromatic ring. In some embodiments, the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quatemized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A heterocycle may be aromatic or nonaromatic in nature. In some embodiments, the heterocycle is a heteroaryl.

[0077] An example of a 3-membered heterocycloalkyl group includes, and is not limited to, aziridine. Examples of 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam. Examples of 5-membered heterocycloalkyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine and piperazine. Other non-limiting examples of heterocycloalkyl groups are:

[0078] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2, 3 -dihydrofuran, 2, 5 -dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,

[0079] 2.3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine,

[0080] 1.3-dioxepane, 4,7-dihydro-l,3-dioxepin, and hexamethyleneoxide.

[0081] As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n + 2) delocalized it (pi) electrons, where n is an integer.

[0082] As used herein, the term “aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracyl, and naphthyl.

[0083] As used herein, the term “aryl-(Ci-C3)alkyl” means a functional group wherein a one- to three-carbon alkylene chain is attached to an aryl group, e.g., -CEEClfc-phenyl. In some embodiments, aryl-(Ci-C3)alkyl is aryl-CH2- or aryl-CH(CH3)-. The term “substituted aryl-(Ci-C3)alkyl” means an aryl-(Ci-C3)alkyl functional group in which the aryl group is substituted. Similarly, the term “heteroaryl-(Ci-C3)alkyl” means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CTECIE-pyridyl. The term “substituted heteroaryl-(Ci-C3)alkyl” means a heteroaryl-(Ci-C3)alkyl functional group in which the heteroaryl group is substituted.

[0084] As used herein, the term “heteroaryl” or “heteroaromatic” refers to a heterocycle having aromatic character. A polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include the following moieties:

[0085] Examples of heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

[0086] Examples of polycyclic heterocycles and heteroaryls include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly 1- and 5 -isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl. As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. The term “substituted” further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In some embodiments, the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two.

[0087] As used herein, the term “optionally substituted” means that the referenced group may be substituted or un substituted. In some embodiments, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

[0088] In some embodiments, the substituents are independently selected from the group consisting of oxo, halogen, -CN, -NHz, -OH, -NH(CH3), -N(CH3)2, alkyl (including straight chain, branched and / or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoro alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, S(=O)2alkyl, -C(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -C(=O)N[H or alkyl]?, - OC(=O)N[substituted or unsubstituted alkyl]2, -NHC(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -NHC(=O)alkyl, -N[substituted or unsubstituted alkyl]C(=O)[substituted or unsubstituted alkyl], -NHC(=O)[substituted or unsubstituted alkyl], -C(OH)[substituted or unsubstituted alkyl]2, and -C(NH2)[substituted or unsubstituted alkyl]2. In another embodiment, by way of example, an optional substituent is selected from oxo, fluorine, chlorine, bromine, iodine, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2CF3, -0CH3, -OCH2CH3, -OCH(CH3)2, -OCF3, - OCH2CF3, -S(=O)2-CH3, -C(=0)NH2, -C(=O)-NHCH3, -NHC(=O)NHCH3, -C(=O)CH3, -ON(O)2, and -C(=O)OH. In yet one embodiment, the substituents are independently selected from the group consisting of C1-6 alkyl, -OH, C1-6 alkoxy, halo, amino, acetamido, oxo and nitro. In yet another embodiment, the substituents are independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic. Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0089] Compounds

[0090] The compounds of the present disclosure may be synthesized using techniques well- known in the art of organic synthesis. The starting materials and intermediates required for the synthesis may be obtained from commercial sources or synthesized according to methods known to those skilled in the art.

[0091] In one aspect, the disclosure provides compounds of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0092] Formula (I), wherein:

[0093] A1is selected from the group consisting of arylene and heteroarlyene;

[0094] RA1is represents mono to the maximum allowable substitution, or no substitution; each occurrence of RA1is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3;

[0095] L represents a divalent linking group; and

[0096] Ubiig is an E3 ubiquitin ligase ligand.

[0097] In some embodiments, Ubiig is selected from the group consisting of

[0098] and stereoisomers thereof; wherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl; wherein RA2represents mono to the maximum allowable substitution, or no substitution; and each occurrence of RA2is independently selected from the group consisting of H,

[0099] D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, L is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0100] In some embodiments, L is selected from the group consisting of alkylene, heteroalkylene, cycloalkylene, heteroalkylene, carbonyl, ester, and amide.

[0101] In some embodiments, L is selected from the group consisting of:

[0102] O , and combinations thereof, wherein:

[0103] R is selected from the group consisting of H, D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10.

[0104] In some embodiments, A1arylene or heteroarylene. In some embodiments, A1is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl, wherein A1is optionally further substituted. In some embodiments, A1is a substituted phenyl group.

[0105] In some RA1represents mono to the maximum allowable substitution, or no substitution. In some embodiments, each occurrence of RA1is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0106] In some embodiments, the compound of Formula (I) is a compound of Formula (II) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof: wherein:

[0107] A1is selected from the group consisting of arylene and heteroarlyene;

[0108] RA1is represents mono to the maximum allowable substitution, or no substitution; each occurrence of RA1is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3;

[0109] L1and L2each independently represent a divalent linking group; and Ubiig is an E3 ubiquitin ligase ligand.

[0110] In some embodiments, Ubiig is selected from the group consisting of and stereoisomers thereof; wherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl; wherein RA2represents mono to the maximum allowable substitution, or no substitution; and each occurrence of RA2is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0111] In some embodiments, L1and L2are each independently selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0112] In some embodiments, L1and L2are each independently selected from the group consisting of alkylene, heteroalkylene, cycloalkylene, heteroalkylene, ester, and amide.

[0113] In some embodiments, L1and L2are each independently selected from the group wherein:

[0114] R is selected from the group consisting of H, D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10. In some embodiments, A1is arylene or heteroarylene. In some embodiments, A1is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl, wherein A1is optionally further substituted. In some embodiments, A1is a substituted phenyl group. In some RA1represents mono to the maximum allowable substitution, or no substitution.

[0115] In some embodiments, each occurrence of RA1is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0116] In some embodiments, the compound of Formula (I) is a compound of Formula (III) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0117] Formula (III) wherein: each of X1, X2, X3, and X4is selected from N and CR1; and each instance of R1is independently selected from the group consisting of H, D,

[0118] F, CH3, CD3. CF3, OCH3, OCD3, and OCF3.

[0119] In some embodiments, Ubiig is selected from the group consisting of

[0120]

[0121] , and stereoisomers thereof; wherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl; wherein RA2represents mono to the maximum allowable substitution, or no substitution; and each occurrence of RA2is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0122] In some embodiments, L1and L2are each independently selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0123] In some embodiments, L1and L2are each independently selected from the group consisting of alkylene, heteroalkylene, cycloalkylene, heteroalkylene, ester, and amide.

[0124] In some embodiments, L1and L2are each independently selected from the group wherein:

[0125] R is selected from the group consisting of H, D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10.

[0126] In some embodiments, each of X1, X2, X3, and X4is selected from the group consisting of N and CR1. In some embodiments, each of X1, X2, X3, and X4is CR1. In some embodiments, X1or X4are both CR1and X2and X3are both CH. In some embodiments, X2and X3are both CH and one of X1and X4is CH, and the other is CR1. In some embodiments, X2and X3are both CH and one of X1and X4is CH, and the other is CR1, wherein R1is selected from the group consisting of OCH3, OCD3, and OCF3.

[0127] In some embodiments, A1is an aromatic ring. In some embodiments, A1is a heteroaromatic ring.

[0128] In some embodiments, RA1and R42each represent mono to the maximum allowable substitution, or no substitution. In some embodiments, RA1and RA2each represent no substitution. In some embodiments, RA1and RA2each represent mono substitution. In some embodiments, RA1and RA2each represent the maximum allowable substitution. In some embodiments, RA1represents mono and RA2represents mono to the maximum allowable substitution or no substitution. In some embodiments, RA2represents mono substitution and RA1represents mono to the maximum allowable substitution or no substitution. In some embodiments, RA1and RA2each represent mono substitution.

[0129] In some embodiments, each occurrence of R41and R42is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, RA1represents mono substitution and is selected from the group consisting of D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, RA1is selected from the group consisting of OCH3, OCD3, and OCF3. In some embodiments, RA2represents mono substitution and is selected from the group consisting of D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3. In some embodiments, RA2is F.

[0130] In some embodiments, A1is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein A1is optionally further substituted. In some embodiments, A1is phenyl and A2is independently selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein A2is optionally further substituted. In some embodiments, A1is substituted phenyl. In some embodiments, A2is pyrimidinyl and A1is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein A1is optionally further substituted. In some embodiments, A2is substituted pyrimidinyl and A1is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each of A1and A2is optionally further substituted. In some embodiments, A1is substituted phenyl and A2is pyrimidinyl.

[0131] In some embodiments, the compound of Formula (I) is a compound of Formula (IV) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0132] Formula (IV).

[0133] In some embodiments, L1is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0134] In some embodiments, L1is selected from the group consisting of: V^ / , combinations thereof, wherein:

[0135] R is selected from the group consisting of H, D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10.

[0136] In some embodiments, the compound of Formula (I) is selected from the group consisting of:

[0137]

[0138] stereoisomers, prodrugs, derivatives, and pharmaceutically acceptable salts and solvates thereof.

[0139] The compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration. In some embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In some embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The compounds described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound of the invention, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In another embodiment, the compounds described herein exist in unsolvated form.

[0140] In some embodiments, the compounds of the invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0141] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In some embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In another embodiment, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0142] In some embodiments, sites on, for example, the aromatic ring portion of compounds of the invention are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize, or eliminate this metabolic pathway. In some embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.

[0143] Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,nC,13C,14C,36C1,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In some embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet another embodiment, substitution with positron emitting isotopes, such asnC,18F,1?0 and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent otherwise employed.

[0144] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0145] The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference in their entirety). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

[0146] Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources or are prepared using procedures described herein.

[0147] In some embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In another embodiment, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0148] In some embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t- butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.

[0149] In some embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidativelyremovable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates.

[0150] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.

[0151] Typically blocking / protecting groups may be selected from:

[0152]

[0153] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

[0154] Methods

[0155] In some embodiments, the disclosure provides methods of inhibiting IRAK4 activity in a subject in need thereof. In some embodiments, the method of inhibiting IRAK4 activity comprises inducing degradation of IRAK4. In some embodiments, the method comprises administering to the subject an effective amount of a composition comprising a compound of the disclosure. In some embodiments, the compound of the disclosure binds to IRAK4 and a ubiquitin ligase, thereby targeting IRAK4 for degradation. In some embodiments, the disclosure provides methods comprising administering to a subject a compound of the disclosure. In some embodiments, the subject has a disease or disorder associated with IRAK4 activity. In some embodiments, the disclosure provides methods of treating or preventing a disease or disorder associated with IRAK4 activity. As used herein, the term “disease or disorder associated with IRAK4 activity” refers to any disease, disorder, or condition which is caused or characterized by abnormal IRAK4 enzymatic activity or IRAK4 overexpression. Exemplary diseases or disorders associated with IRAK4 activity include, but are not limited to cancer, Parkinson’s disease, Alzheimer’s disease, fibrosis, inflammatory diseases and disorders, and autoimmune diseases and disorders.

[0156] In some embodiments, the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, uterine cancer, 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, mucinous carcinoma, 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 liposarcomas, leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors, 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, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, chondrosarcoma, mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acutelymphoblastic 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 syndrome / acute myeloid leukemia, non-Hodgkin'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, pancreatic biliary adenocarcinoma, and pancreatic ductal adenocarcinomas.

[0157] In some embodiments, the fibrosis is one or more selected from the group consisting of renal fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, Crohn’s disease, liver fibrosis, heart fibrosis, scleroderma, or progressive massive fibrosis.

[0158] In some embodiments, the inflammatory disease or disorder is selected from the group consisting of 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, atherosclerosis, psoriatic arthritis, vasculitis, Polymyalgia, Rheumatica, Wegener's granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, and ataxia telangiectasia.

[0159] In some embodiments, the disclosure provides methods of treating cancer in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the disclosure.

[0160] In some embodiments, the method further comprises administering to the subject at least one additional therapy. In some embodiments, the therapy is selected from the group consisting of a selected from the group consisting of radiation therapy, surgery, chemotherapy, checkpoint inhibitors, and combinations thereof.

[0161] In some embodiments, the therapy comprises one or more selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinum agents, topoisomerase I inhibitors, topoisomerase II inhibitors, vinca alkaloids, taxanes, nucleoside analogs, angiogenesis inhibitors, antineoplastic agents, and chemotherapeutic agents.

[0162] Examples of alkylating agents include, but are not limited to, chlorambucil, cyclophosphamide, lomustine, melphalan, procarbazine, thiotepa, thiotepa, dacarbazine, procarbazine, carmustine, and busulfan.

[0163] Examples of antimetabolites include, but are not limited to, 6-mercaptopurine, 5- fluorouracil, cytarabine, methotrexate, hydroxyurea, fluoridine, 6-thioguanine, fludarabine, pentostatin, and chlorodeoxyadenosine.

[0164] Examples of anthracyclines include, but are not limited to, daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone.

[0165] Examples of antitumor antibiotics include, but are not limited to, bleomycin. Examples of monoclonal antibodies include, but are not limited to, alemtuzumab, bevacizumab, cetuximab, gemtuzumab, ibritumomab, panitumumab, rituximab, tositumomab, and trastuzumab.

[0166] Examples of platinum agents include, but are not limited to, cisplatin, oxaliplatin, and carboplatin.

[0167] Examples of topoisomerase I and topoisomerase II inhibitors include, but are not limited to, camptothecin, irinotecan, topotecan, amacrine, etoposide, etoposide phosphate, and teniposide.

[0168] Examples of vinca alkaloids include, but are not limited to, vincristine, vinblastine, vinorelbine, and vindesine.

[0169] Examples of taxanes include, but are not limited to, paclitaxel and docetaxel.

[0170] Examples of angiogenesis inhibitors include, but are not limited to, beracizumab, 2- methoxyestradiol, AG3340, angiostatin, antithrombin-III, anti-VEGF antibodies, batimastat, BMS-275291, CAI, canstatin, combretastatin, combretastatin-A4 phosphate, CC5013, captopril, celecoxib, dalteparin, EMD121974, endostatin, erlotininb, gefitinib, genistein, halofuginone, ID1, IDS3, IM862, imatinib mesylate, inducible protein-10, interferon-a, interleukin- 12, lavendustin A, LY317615, AE-941, marimasat, mapsin, medroxyprogesterone acetate, METH-1, METH-2, neovastat, osteopontin cleavage product, PED, pigment epithelium growth factor, platelet growth factor 4, prolactin fragment, proliferin-related protein, PTK787 / ZK222584, recombinant human platelet factor 4, restin, squalamine, SU5416, SU6668, suramin, taxol, tecogalan, thalidomide, tetrathiomolybdate, thrombospondin, TNP-470, troponin 1, vasostatin, VEDG1, VEGF-TPvAP, and ZD6474.

[0171] 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, melphalan, chlorambucil, busulfan, thiotepa, carmustine, lomustine, carboplatin, dacarbazine, procarbazine) and DNA strand break inducing agents( e.g. , bleomycin, doxorubicin, daunorubicin, idarubicin, mitomycin C). Examples of 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, cedefmgol, chlorambucil, celecoxib, cirolemycin, cisplatin, cladribine, crisnatol, cyclophosphamide, cytarabine, dacarbazine, DACA, dactinomycin, daunorubicin, daunomycin, decitabine, denileukin, dexormaplatin, dezaguanine, diaziquone, docetaxel, doxorubicin, droloxifene, dromostalone, duazomycin, edatrexate, eflomithine, 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, gold Au198, goserelin, guanacone, hydroxyurea, idarubicin, ilmofosine, interferon- a 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, ozogamacin, 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, thiotepa, 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, mitozolomide, temozolomide, AZQ, CI-973, DWA21 14R, JM216, JM335, bisplatinum, cytrabincine, 6-mercaptopurine, hypoxanthine, CPT-11, epirubicin, darubicin, pyrazoloacridine, all-trans-retinol, 14- hydroxy -retro-retinol, all-trans retinoic acid, N-(4-hydroxyphenyl) retinamide, 13-cis-retinoic acid, 3 -methyl TTNEB, 9-cis-retenoic acid, 2-Cda, 20-epil,25-dihydroxyvitamin-D3, 5-ethynyl uracil, abiraterone, acylfulvene, adecylpenol, ALL-TK antagonists, ambumastine, amidox, amifostine, amino levulinic acid, anagrelide, andrographolide, 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, axinamastine 2, axinamastine 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, BCR / ABL antagonist, benzochlorins, benzoyl saurosporine, beta lactam derivatives, beta-alethine, pentomone, perillyl alcohol, phenozenomyein, phenyl acetate, phosphatase inhibitors, picibanil, pilocarbine and salts and analogs thereof, pirarubucin, piritrexim, piritrexim isothiocyanate, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, phenyl ethyl isothiocyanate and analogs thereof, platinum triamine complex, podophylotoxin, porfimer sodium, propyl bis acridones, prostaglandin J2, protease inhibitors, protein A based immune modulators, PKC inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyridoxylated hemoglobin polyoxyethylene conjugate, raf antagonists, raltitrexed, ramosetron, ras famesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, ratellitptine demethylated, RBX2258, Rhenium Re186etidronate, rhizoxine, ribozymes, RII retinide, rosagliatazone and analogs and derivatives thereof, rohitukine, romurtide, roquinimex, rubiginone Bl , ruboxyl, saintopin, SarCNU, sarcophytol A, sargrmostim, sdi 1 mimetics, senescence derived inhibitor 1 , sense oligonucleotides, signal transduction inhibitors, signal transduction modulators, single chain antigen binding protein, sitogluside, sizofiran, sobuzoxane, sodium borocaptate, sodium phenyl acetate, solverol, somatomedin binding protein, sonermin, spicamycin D, splenopentine, spongistatin 1, squalamine, stem cell inhibitors, stem cell division inhibitors, stipiamide, stromelysin, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, siramin, swainsonine, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tacogalan sodium, tellurapyrilium, telomerase inhibitors, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalidomide, thiocoraline, thrombopoetin and mimetics thereof, thymalfasin, thymopoetin receptor agonist, thymotrinan, thyroid stimulating harmone, tin ethyl etiopurpin, titanocene and salts thereof, tomsulosine, topsentin, toremifene, totipotent stem cell factors, translation inhibitors, tretinoin, triacetyluridine, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus derived growth inhibitory factor, urokinase receptor antagonists, variolin B, vector system, erythrocyte gene therapy, velaresol, veramine, verdins, verteporfin, vinorelbine, vinxaltine, vitaxin, zanoterone, zilascorb zinostatin,125I fibrinogen,18F fludeoxyglucose,18F fluorodopa,125I insulin,123I iobenguane,131I iodipamine sodium,131I iodoantipyrine,131I iodocholesterol,125I iodopyracet,123I iofetamine HC1,131I iomethin,125I iothalamate sodium,131I iothalamate,131I iotyrosine,125I liothyronine,197Hg merosproprol,131I methyl iodobenzoguanine,75Se selenomethionine, "mTc technetium furifosmin, "mTc technetium gluceptate, "mTc technetium biscisate, "mTc technetium disofenin, "mTc technetium lidofenin, "mTc technetium mebrofenin, "mTc technetium medronate and sodium salts thereof, "mTc technetium sestambi, "mTc technetium siboroxime, "mTc technetium succimer, "mTc technetium sulfur colloid, "mTc technetium teboroxime, "mTc technetium tetrofosmin, "raTc technetium tiatide,125I thyroxine,13’I thyroxine,131I tolpovidone,125I triolein, and131I triolein.

[0172] In some embodiments, the therapy comprises one or more immune checkpoint inhibitors. Immune checkpoint inhibitors include any agent that blocks or inhibits, in a statistically significant manner, the inhibitory pathways of the immune system. Immune checkpoint inhibitors include antibodies or antigen binding fragments thereof, other binding proteins, biologic therapeutics, and small molecules, that bind to and block or inhibit the activity of a target. Examples of immune checkpoint targets for blocking or inhibition include, but are not limited to, CTLA-4, PD-L1, PD-L2, PD-1, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4, CD160 (also referred to as BY55), CGEN-15049, CHK1 kinase, CHK2 kinase, A2aR, and various B-7 family ligands. Examples of B-7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Examples of immune checkpoint inhibitors include, but are not limited to, tremelimumab, anti-OX40, anti-B7-Hl, MEDI4736, MK-3475, nivolumab, CT-011, BY55, AMP224, BMS-936559, MPLDL3280A, MSB0010718C, ipilimumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0173] In some embodiments, the immune checkpoint inhibitor blocks the interaction between programmed cell death protein (PD-1) and its ligand PD-L1. Examples of such antibodies include, but are not limited to, those listed in Mullard, A. (2013, Nature Reviews: Drug Discovery, 12:489-492.)

[0174] In some embodiments, the immune checkpoint inhibitor targets CTLA-4. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody. Examples of anti- CTLA-4 antibodies suitable for use in the present invention include any known in the art, and are described in PCT Publication Nos. WO 1998 / 042752, WO 2000 / 037504, WO 2001 / 014424, and WO 2004 / 035607, U.S. Publication No. US 2005 / 0201994, European Patent No. EP 1212422, US. Pat. Nos. 5,811,097, 5,855,887, 5,977,318, 6,051,227, 6,207,720, 6,682,736, 6,984,720, 7,109,003, and 7,132,281, Hurwitz et al. (1998, Proceedings of the National Academy of Sciences USA, 95(17):10067-10071), Camacho et al. (2004, Journal of Clinical Oncology, 22(145):Abstract No. 2505), and Mokyr et al. (1998, Cancer Research, 58:5301-5304).

[0175] In some embodiments, the immune checkpoint inhibitor that targets CTLA-4 disrupts binding of CTLA-4 to its ligand or disrupt B7 binding to CD28 and / or CTLA-4. IN some embodiments, the immune checkpoint inhibitor that targets CTLA-4 inhibits binding of CD80 or CD86 to CD28 or CTLA-4. In some embodiments, the inhibitor is selected from the group consisting of small molecules, antibodies, antisense nucleic acid molecules, adnectins, and RNAi inhibitors.

[0176] In some embodiments, the immune checkpoint inhibitor targets TIM-3. In some embodiments, the immune checkpoint inhibitor blocks TIM-3 from binding to its ligand.

[0177] In some embodiments, the present invention provides methods of inhibiting angiogenesis in a cancer. In some embodiments, the method comprises administering to a subject a compound of the present invention. In some embodiments, the method comprises administering to a subject a compound of the present invention, wherein the subject has cancer. In some embodiments, the present invention provides methods of sensitizing a cancer or tumor. In some embodiments, the cancer or tumor is sensitized to one or more chemotherapeutic agents. In some embodiments, the method comprises administering to a subject a compound of the present invention. In some embodiments, the method comprises administering to a subject a compound of the present invention, wherein the subject has a cancer or tumor. In some embodiments, the cancer or tumor is resistant to one or more chemotherapeutic agents.

[0178] In some embodiments, the present invention provides methods of treating a pain disorder. In some embodiments, the method comprises administering to a subject a compound of the present invention. In some embodiments, the method comprises administering to a subject a compound of the present invention, wherein the subject has a pain disorder. In some embodiments, the pain disorder is one or more selected from the group consisting of inflammatory pain, post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic neuralgia, post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

[0179] In some embodiments, the pain disorder comprises neuropathic or nociceptive pain. In some embodiments, the pain disorder comprising neuropathic or nociceptive pain is associated a disease, disorder, infection, or injury. In some embodiments, the pain disorder comprising neuropathic or nociceptive pain is one or more selected from the group consisting of spinal cord injury, multiple sclerosis, stroke, diabetes, herpes zoster infection, human immunodeficiency virus (HIV) infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune-related disorders, and physical trauma to the nerve trunk.

[0180] In some embodiments, the present invention provides methods of including IL- ip- induced NF-KB. In some embodiments, the method comprises administering to the subject a compound of the present invention.

[0181] In some embodiments, the present invention provides methods of inducing stem cell mobilization and engraftment in a subject. In some embodiments, the method comprises administering to the subject a compound of the present invention. Administration / Dosage / Formulations

[0182] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either before or after the onset of a disease or infection. Further, several divided dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0183] Administration of the compositions of the present invention to a patient or subject, such as a mammal, (e.g., human), may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or infection in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the subject; the age, sex, and weight of the subject; and the ability of the therapeutic compound to treat a disease in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily. In another example, the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 mg / kg to about 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to assess the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0184] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without generating excessive side effects in the subject.

[0185] In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, or materials used in combination with the compound, the age, sex, weight, condition, general health, and prior medical history of the subject being treated, and like factors well, known in the medical arts. A medical professional, e g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start with a dosage of the compound of the invention in the pharmaceutical composition at a level that is lower than the level required to achieve the desired therapeutic effect, and then increase the dosage over time until the desired effect is achieved.

[0186] In particular embodiments, it is advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. “Dosage unit form” as used herein refers to a physically discrete unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical vehicle. The dosage unit forms of the invention can be selected based upon (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of a disease or infection in a patient.

[0187] In some embodiments, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In some embodiments, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

[0188] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), vegetable oils, and suitable mixtures thereof. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In some embodiments, it is useful to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In some embodiments, the pharmaceutically acceptable carrier is DMSO, alone or in combination with other carriers. The therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the subject, the current medical condition of the subject and the severity of the disease in the subject being treated. The skilled artisan is able to determine appropriate doses depending on these and other factors.

[0189] The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

[0190] Doses of the compound of the invention for administration may be in the range of from about 1 pg to about 10,000 mg, from about 20 pg to about 9,500 mg, from about 40 pg to about 9,000 mg, from about 75 pg to about 8,500 mg, from about 150 pg to about 7,500 mg, from about 200 pg to about 7,000 mg, from about 3050 pg to about 6,000 mg, from about 500 pg to about 5,000 mg, from about 750 pg to about 4,000 mg, from about 1 mg to about 3,000 mg, from about 10 mg to about 2,500 mg, from about 20 mg to about 2,000 mg, from about 25 mg to about 1,500 mg, from about 30 mg to about 1,000 mg, from about 40 mg to about 900 mg, from about 50 mg to about 800 mg, from about 60 mg to about 750 mg, from about 70 mg to about 600 mg, from about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0191] In some embodiments, the dose of a compound of the invention is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dosage of a second compound as described elsewhere herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0192] The compounds for use in the method of the invention may be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0193] In some embodiments, the compositions of the invention are administered to the subject from about one to about five times per day or more. In various embodiments, the compositions of the invention are administered to the subject, 1-7 times per day, 1-7 times every two days, 1-7 times every 3 days, 1-7 times every week, 1-7 times every two weeks, and 1-7 times per month. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from individual to individual depending on many factors including, but not limited to, age, the disease or disorder to be treated, the severity of the disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosing regime and the precise dosage and composition to be administered to any subject is determined by the medical professional taking all other factors about the subject into account.

[0194] In the case wherein the subject’s status does improve, upon the doctor’s discretion the administration of the inhibitor of the invention is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0195] Once improvement of the subject’s condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced to a level at which the improved disease is retained. In some embodiments, a subject may require intermittent treatment on a long-term basis, or upon any recurrence of the disease or disorder. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LDso and EDso. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the EDso with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0196] In some embodiments, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat or prevent a disease or infection in a patient.

[0197] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

[0198] Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intratumoral, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0199] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for parenteral administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

[0200] Oral Administration

[0201] For oral administration, suitable forms include tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gel caps. The compositions formulated for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated, or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0202] For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fillers (e g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups, or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a “granulation.” For example, solvent-using “wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.

[0203] Melt granulation involves the use of materials that are solid or semi-solid at room temperature (i.e., having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e., drug) by forming a solid dispersion or solid solution.

[0204] U.S. Patent No. 5,169,645 discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) melt.

[0205] The present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of G-protein receptor-related diseases or disorders. Using a wax / pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.

[0206] Parenteral Administration

[0207] For parenteral administration, the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions, or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used.

[0208] Controlled Release Formulations

[0209] In some embodiments, the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release, and pulsatile release formulations.

[0210] The term sustained release refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a day, a week, or a month or more and should be a release which is longer than the same amount of agent administered in bolus form. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

[0211] For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

[0212] In some embodiments of the invention, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0213] The term pulsatile release refers to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

[0214] The term immediate release refers to a drug formulation that provides for release of the drug immediately after drug administration.

[0215] As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

[0216] As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

[0217] Those skilled in the art recognize, or are able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

[0218] Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0219] EMBODIMENTS

[0220] Embodiment 1 is a compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0221] Formula (I), wherein:

[0222] A1is selected from the group consisting of arylene and heteroarlyene;

[0223] RA1is represents mono to the maximum allowable substitution, or no substitution; each occurrence of RA1is independently selected from the group consisting of H,

[0224] D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3;

[0225] L represents a divalent linking group; and Ubiig is an E3 ubiquitin ligase ligand.

[0226] Embodiment 2 is a compound of embodiment 1, wherein the compound of Formula (I) is a compound of Formula (II), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0227] Formula (II), wherein:

[0228] A1is selected from the group consisting of arylene and heteroarlyene;

[0229] RA1represents mono to the maximum allowable substitution, or no substitution; each occurrence of RA1is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3;

[0230] L1and L2each independently represent a divalent linking group; and Ubiig is an E3 ubiquitin ligase ligand.

[0231] Embodiment 3 is the compound of embodiment 1 or 2, wherein A1is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl, wherein A1is optionally further substituted.

[0232] Embodiment 4 is the compound of any one of embodiments 1-3, wherein the compound of Formula (I) is a compound of Formula (III) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0233] Formula (III), wherein: each of X1, X2, X3, and X4is selected from N and CR1; and each instance of R1is independently selected from the group consisting of H, D,

[0234] F, CH3, CD3. CF3, OCH3, OCD3, and OCF3.

[0235] Embodiment 5 is the compound of any one of embodiments 2-4, wherein L1and L2are each independently selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0236] Embodiment 6 is the compound of any one of embodiments 2-5, wherein L1and L2are each independently selected from the group consisting of alkylene, heteroalkylene, cycloalkylene, heteroalkylene, ester, and amide.

[0237] Embodiment 7 is the compound of any one of embodiments 2-6, wherein L1and L2are thereof, wherein:

[0238] R is selected from the group consisting of H, D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10.

[0239] Embodiment 8 is the compound of any one of embodiments 1-8 wherein the compound of Formula (I) is a compound of Formula (IV) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof: Embodiment 9 is the compound of any one of embodiments 2-8, wherein L1is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

[0240] Embodiment 10 is the compound of any one of embodiments 2-9, wherein L1is selected wherein:

[0241] R is selected from the group consisting of H, D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10.

[0242] Embodiment 11 is the compound of any one of embodiments 1-10, wherein Ubiig is

[0243]

[0244] , and stereoisomers thereof; wherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl; wherein RA2represents mono to the maximum allowable substitution, or no substitution; and each occurrence of RA2is independently selected from the group consisting of H,

[0245] D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0246] Embodiment 12 is the compound of any one of embodiments 1-11, wherein the compound of Formula (I) is selected from the group consisting of:

[0247]

[0248] , stereoisomers, prodrugs, derivatives, and pharmaceutically acceptable salts and solvates thereof.

[0249] Embodiment 13 is a method of decreasing IRAK4 protein levels in a subject, comprising administering to the subject the compound of any one of embodiments 1-12.

[0250] Embodiment 14 is a method of treating a disease or disorder associated with increased IRAK4 activity in a subject, comprising administering to the subject the compound of any one of embodiments 1-12.

[0251] Embodiment 15 is the method of embodiment 14, wherein the disease or disorder associated with IRAK 4 activity is selected from the group consisting of cancer, Parkinson’s disease, Alzheimer’s disease, fibrosis, inflammatory diseases and disorders, and autoimmune diseases and disorders.

[0252] Embodiment 16 is the method of embodiment 15, wherein the inflammatory disease or disorder is selected from the group consisting of 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, atherosclerosis, psoriatic arthritis, vasculitis, Polymyalgia, Rheumatica, Wegener’s granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, and ataxia telangiectasia.

[0253] Embodiment 17 is the method of embodiment 15, wherein the fibrosis is one or more selected from the group consisting of renal fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, Crohn’s disease, liver fibrosis, heart fibrosis, scleroderma, or progressive massive fibrosis.

[0254] Embodiment 18 is the method of embodiment 15, wherein the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, uterine cancer, 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, mucinous carcinoma, 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 liposarcomas, leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing’s tumors, 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, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, chondrosarcoma, mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acutelymphoblastic 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 syndrome / acute myeloid leukemia, non-Hodgkin’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, pancreatic biliary adenocarcinoma, and pancreatic ductal adenocarcinomas.

[0255] Embodiment 19 is the method of embodiment 18, wherein the cells of the cancer have a mutation in an fms-like tyrosine kinase 3 (FLT-3) gene. Embodiment 20 is the method of embodiment 19, wherein the mutation in an FLT-3 gene is an internal tandem duplication (ITD) mutation.

[0256] Embodiment 21 is the method of embodiment 18, wherein the compound of any one of embodiments 1-12 is administered in combination with one or more therapies selected from the group consisting of radiation therapy, surgery, chemotherapy, and checkpoint inhibitors.

[0257] Embodiment 22 is the method of embodiment 21, wherein the therapy comprises one or more selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinum agents, topoisomerase I inhibitors, topoisomerase II inhibitors, vinca alkaloids, taxanes, epipodophyllotoxins, nucleoside analogs, angiogenesis inhibitors, and

[0258] Embodiment 23 is a method of inhibiting angiogenesis in a subject, comprising administering to the subject the compound of any one of embodiments 1-12.

[0259] Embodiment 24 is a method of sensitizing a tumor in a subject to treatment, comprising administering to the subject the compound of any one of embodiments 1-12.

[0260] Embodiment 25 is a method of treating a pain disorder in a subject, comprising administering to the subject the compound of any one of embodiments 1-12.

[0261] Embodiment 26 is the method of embodiment 25, wherein the pain disorder is one or more selected from the group consisting of inflammatory pain, post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

[0262] Embodiment 27 is the method of embodiment 25, wherein the pain disorder comprises neuropathic or nociceptive pain.

[0263] Embodiment 28 is the method of embodiment 27, wherein the subject with a pain disorder comprising neuropathic pain has one or more selected from the group consisting of spinal cord injury, multiple sclerosis, stroke, diabetes, herpes zoster infection, HIV infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune- related disorders, and physical trauma to the nerve trunk.

[0264] Embodiment 29 is a method of inducing IL-10-induced activation of NF-KB in a subject, comprising administering to the subject the compound of any one of embodiments 1-12. Embodiment 30 is a method of inducing stem cell mobilization and engraftment in a subject, comprising administering to the subject the compound of any one of embodiments 1-12.

[0265] EXPERIMENTAL EXAMPLES

[0266] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0267] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples, therefore, specifically point out certain embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

[0268] Example 1 : A novel small molecule degrader of IRAK4

[0269] Therapeutic agents targeting IRAK4 have been suggested as potentially useful for the treatment of high-risk malignancies. In a comparison of the survival outcomes, patients with high IRAK4 expression exhibited poor survival in all forms of cancer examined (Figure 1 through Figure 4).

[0270] Development of novel IRAK4 degraders:

[0271] Two IRAK4 degraders (PS 102 and PSP-119) were prepared, and their ability to induce degradation of IRAK4 in vitro. PSP102 demonstrated significant degradation of IRAK4 at 0.5 pM and 1.0 pM treatment (Figure 5), while PSP-119 demonstrated near complete degradation of IRAK4 with 10 nM treatment (Figure 6).

[0272] Degradation of IRAK4 in Cancer Cells

[0273] The ability or PSP-119 to induce degradation of IRAK4 was investigated in two acute myeloid leukemia cell lines, MV-4-11 and MOLM-13, which carry fms-like tyrosine kinase 3 (FLT-3) mutations. Cells were treated with PSP-119 for 24 hours and levels of two IRAK4 isoforms were examined by Western blotting. The levels of large isoform of IRAK4 (IRAK4-L) were significantly reduced in both MV-4-11 and MOLM-13 cells exposed to PSP-119, with near-complete elimination of IRAK4-L in MV-4-11 cells at a 40 nM dose (Figure 7 and Figure 8).

[0274] IRAK4 Activity

[0275] The ability of PSP-119 to inhibit IRAK4 activity, in addition to the ability to induce IRAK4 degradation, was investigated in vitro. It was observed that the PSP-119 had an ICso of 2.33 nM against IRAK4 (Figure 9).

[0276] Decrease in Cancer Cell Viability

[0277] PSP-119 was administered to three different acute myeloid leukemia cells to examine its impact on cell viability. While PSP-119 reduced cell viability of MV-4-11 and M0LM13 cells, carrying FLT-3 mutations, THP-1 cells, which have wildtype FLT-3, experienced no reduction in viability (Figure 10).

[0278] Inhibition of Tumor Growth

[0279] As PSP-119 was successfully demonstrated to reduce FLT-3 mutant cancer cells, its impact on tumor growth was examined through a tumor xenograft model. NSG mice implanted with a MOLM-13 xenograft were treated with PSP-119 (10 mg / kg) or vehicle once daily through intraperitoneal injection (IP). Tumor volume of mice treated with PSP-119 remained significantly less than that of control cells after eight days (Figure 11). From this, it can be seen that PSP-119 significantly inhibits tumor development and growth.

[0280] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:A1is selected from the group consisting of arylene and heteroarlyene;RA1is represents mono to the maximum allowable substitution, or no substitution; each occurrence of RA1is independently selected from the group consisting of H, D, F, CH3, CDS, CF3, OCH3, OCD3, and OCF3;L represents a divalent linking group; andUbiig is an E3 ubiquitin ligase ligand.

2. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (II), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:Formula (II), wherein:A1is selected from the group consisting of arylene and heteroarlyene;RA1represents mono to the maximum allowable substitution, or no substitution; each occurrence of RA1is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3;L1and L2each independently represent a divalent linking group; andUbiig is an E3 ubiquitin ligase ligand.

3. The compound of claim 1, wherein A1is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl, wherein A1is optionally further substituted.

4. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (III) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:Formula (III) wherein: each of X1, X2, X3, and X4is selected from N and CR1; and each instance of R1is independently selected from the group consisting of H, D,F, CH3, CD3. CF3, OCH3, OCD3, and OCF3.

5. The compound of claim 2, wherein L1and L2are each independently selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

6. The compound of claim 2, wherein L1and L2are each independently selected from the group consisting of alkylene, heteroalkylene, cycloalkylene, heteroalkylene, ester, and amide.

7. The compound of claim 2, wherein L1and L2are each independently selected from thewherein:R is selected from the group consisting of H, D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10.

8. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (IV) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:Formula (IV).

9. The compound of claim 8, wherein L1is selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.

10. The compound of claim 9, wherein L1is selected from the group consisting of:R is selected from the group consisting of H, D, CH3, CD3, and CF3; and each instance of n is independently an integer selected from 1-10.

11. The compound of claim 1, wherein Ubiig is selected from the group consisting of, and stereoisomers thereof; wherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl;wherein RA2represents mono to the maximum allowable substitution, or no substitution; and each occurrence of RA2is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

12. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:stereoisomers, prodrugs, derivatives, and pharmaceutically acceptable salts and solvates thereof.

13. A method of decreasing IRAK4 protein levels in a subject, comprising administering to the subject the compound of claim 1.

14. A method of treating a disease or disorder associated with increased IRAK4 activity in a subject, comprising administering to the subject the compound of claim 1.

15. The method of claim 14, wherein the disease or disorder associated with IRAK4 activity is selected from the group consisting of cancer, Parkinson’s disease, Alzheimer’s disease, fibrosis, inflammatory diseases and disorders, and autoimmune diseases and disorders.

16. The method of claim 15, wherein the inflammatory disease or disorder is selected from the group consisting of 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 boweldisease, 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 hepatitisjuvenile 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, atherosclerosis, psoriatic arthritis, vasculitis, Polymyalgia, Rheumatica, Wegener’s granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, and ataxia telangiectasia.

17. The method of claim 15, wherein the fibrosis is one or more selected from the group consisting of renal fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, Crohn’s disease, liver fibrosis, heart fibrosis, scleroderma, or progressive massive fibrosis.

18. The method of claim 15, wherein the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, uterine cancer, 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, gelatinformcarcinoma, 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, mucinous carcinoma, 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 liposarcomas, leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing’s tumors, 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, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, chondrosarcoma, mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acutelymphoblastic 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 syndrome / acute myeloid leukemia, non-Hodgkin’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, pancreatic biliary adenocarcinoma, and pancreatic ductal adenocarcinomas.

19. The method of claim 18, wherein the cells of the cancer have a mutation in an fms- like tyrosine kinase 3 (FLT-3) gene.

20. The method of claim 19, wherein the mutation in an FLT-3 gene is an internal tandem duplication (ITD) mutation.

21. The method of claim 18, wherein the compound is administered in combination with one or more therapies selected from the group consisting of radiation therapy, surgery, chemotherapy, and checkpoint inhibitors.

22. The method of claim 21, wherein the therapy comprises one or more selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinum agents, topoisomerase I inhibitors, topoisomerase II inhibitors, vinca alkaloids, taxanes, epipodophyllotoxins, nucleoside analogs, angiogenesis inhibitors, and23. A method of inhibiting angiogenesis in a subject, comprising administering to the subject the compound of claim 1.

24. A method of sensitizing a tumor in a subject to treatment, comprising administering to the subject the compound of claim 1.

25. A method of treating a pain disorder in a subject, comprising administering to the subject the compound of claim 1.

26. The method of claim 25, wherein the pain disorder is one or more selected from the group consisting of inflammatory pain, post-operative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia, diabeticneuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

27. The method of claim 25, wherein the pain disorder comprises neuropathic or nociceptive pain.

28. The method of claim 27, wherein the subject with a pain disorder comprising neuropathic pain has one or more selected from the group consisting of spinal cord injury, multiple sclerosis, stroke, diabetes, herpes zoster infection, HIV infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune-related disorders, and physical trauma to the nerve trunk.

29. A method of inducing IL-ip-induced activation of NF-KB in a subject, comprising administering to the subject the compound of claim 1.

30. A method of inducing stem cell mobilization and engraftment in a subject, comprising administering to the subject the compound of claim 1.

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