Treatment of Diseases and Disorders with IRAK4 Modifying Compounds

Abstract

The present disclosure relates to a method of treating diseases and disorders with IRAK4-modifying compounds, wherein the diseases and disorders are characterized by the presence of a relevant biomarker in a biological sample of a subject.

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority of U.S. Provisional Application No. 63 / 340,692, filed May 11, 2022, the content of which is hereby incorporated by reference in its entirety into this specification.

Background Art

[0002] Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK4) is a serine / threonine kinase enzyme that plays an essential role in signal transduction by Toll / IL-1 receptors (TIR). A variety of IRAK enzymes are important components in the signal transduction pathways mediated by interleukin-1 receptor (IL-1R) and Toll-like receptors (TLR) (Janssens, S, et al. Mol. Cell. 11, 2003, 293-302). The mammalian IRAK family consists of four members: IRAK1, IRAK2, IRAKM3, and IRAK4. These proteins are characterized by a typical N-terminal death domain and a centrally located kinase domain that mediate interaction with MyD88 family adapter proteins. IRAK proteins and MyD88 have been shown to play roles in the transmission of signals other than those derived from the IL-1R receptor, including signals induced by activation of the IL-18 receptor (Kanakaraj, et al. J. Exp. Med. 189(7):1999, 1129-38) and the LPS receptor (Yang, et al., J. Immunol. 163, 1999, 639-643). Among the four members of the mammalian IRAK family, IRAK4 is considered the "master IRAK." Under overexpression conditions, all IRAKs can mediate the activation of the nuclear factor-κB (NF-κB) and stress-induced mitogen-activated protein kinase (MAPK) signal transduction cascades. However, only IRAK-1 and IRAK4 have been shown to have active kinase activity.IRAK-1 kinase activity may not be required for the function in IL-1-induced NF-κB activation (Kanakaraj et al., J. Exp. Med. 187(12), 1998, 2073-2079) and (Xiaoxia Li, et al, Mol. Cell. Biol. 19(7), 1999, 4643-4652), whereas IRAK4 requires kinase activity for signal transduction (Li S, et al. Proc. Natl. Acad. Sci. USA 99(8), 2002, 5567-5572) and (Lye, E et al, J. Biol. Chem. 279(39); 2004, 40653-8). Considering the central role of IRAK4 in Toll-like / IL-1R signaling and immune defense, IRAK4 inhibitors have been associated as valuable therapeutic agents in inflammatory diseases, sepsis and autoimmune disorders (Wietek C, et al, Mol. Interv. 2:2002, 212-215).

[0003] Mice lacking IRAK4 are viable and show complete inhibition of inflammatory cytokine production in response to IL-1, IL-18, or LPS (Suzuki et al. Nature, 416(6882), 2002, 750 - 756). Similarly, human patients lacking IRAK4 are severely immunodeficient and do not respond to these cytokines (Medvedev et al. J. Exp. Med., 198(4), 2003, 521 - 531 and Picard et al. Science 299(5615), 2003, 2076 - 2079). Knock-in mice containing inactive IRAK4 are completely resistant to lipopolysaccharide and CpG-induced shock (Kim TW, et al. J Exp Med 204:2007, 1025 - 36) and (Kawagoe T, et al. J Exp Med 204(5):2007, 1013 - 1024), indicating that IRAK4 kinase activity is essential for cytokine production, MAPK activation, and induction of NF-κB-regulated genes in response to TLR ligands (Koziczak-Holbro M, et al. J Biol Chem; 282(18):2007; 13552 - 13560). Inactivation of IRAK4 kinase (IRAK4 kinase, IRAK4 KI) in mice confers resistance to EAE due to a decrease in infiltration of inflammatory cells into the CNS and a decrease in antigen-specific CD4+ T cell-mediated IL-17 production (Kirk A et al. The Journal of Immunology, 183(1), 2009, 568 - 577).

[0004] Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in adults. In the United States, there were an estimated approximately 78,000 new cases in 2020, and approximately 20,000 people died. The molecular pathology driving NHL is diverse, but a common feature is its effect on the activity of the NF-κB signaling pathway. The specific molecular changes identified that drive this pathway are subsets of NHL. For example, diffuse large B-cell lymphoma (hereinafter also referred to as "DLBCL") is an aggressive lymphoma that can occur in lymph nodes or outside the lymphatic system, the gastrointestinal tract, the testis, the thyroid, the skin, the breast, the bone, or the brain. DLBCL is a cancer of B cells, a type of white blood cell responsible for antibody production. This is the most common type of non-Hodgkin lymphoma among adults, with an annual incidence of 7-8 cases per 100,000 people / year. This cancer mainly occurs in the elderly, with a median age at diagnosis of approximately 70 years, but in rare cases, it can also occur in children and young adults. DLBCL is an aggressive tumor, and the first sign of this disease is typically the rapid growth of a mass being observed. The 5-year survival rate is only 58%. DLBCL is named according to the cells of its origin and has subtypes, including germinal center B-cell-like (GCB) and activated B-cell-like (ABC). They differ in having a worse prognosis and, in some cases, require a special approach to treatment.

[0005] Another example of NHL is Waldenstrom’s macroglobulinemia (WM). WM is a non-Hodgkin lymphoma that affects two types of B cells, lymphoplasmacytoid cells and plasma cells. WM is characterized by high levels of circulating antibody immunoglobulin M (IgM) that is made and secreted by the cells involved in this disease. WM is a rare disease, with only about 1,500 cases per year in the United States. There is no single approved treatment for WM, and there is significant variability in clinical outcomes due to differences in knowledge of the molecular basis of the disease. The objective response rate is high (>80%), but the complete response rate is low (0-15%).

[0006] Other types of non-Hodgkin lymphoma include mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), CNS lymphoma, and testicular lymphoma. Non-Hodgkin lymphoma can be caused by various factors such as infectious agents (Epstein-Barr virus, hepatitis C virus, and human T-cell leukemia virus), radiation and chemotherapy treatments, and autoimmune diseases. As a group, non-Hodgkin lymphoma affects 2.1% of the US population over their lifetime. The percentage of people who survive more than 5 years after diagnosis is 71%.

[0007] In view of the above, there is a clear and unmet need for additional therapies for the treatment of cancer and other diseases associated with IRAK4. SUMMARY OF THE INVENTION

[0008] In certain aspects, the present disclosure is a method of treating a disease or disorder in a subject, comprising Obtaining one or more biological samples (plural possible) from a subject, Analyzing the biological sample(s) for the presence of a first biomarker in the cell nuclei of the biological sample(s), When the presence of the first biomarker is detected in the cell nuclei of the biological sample(s), administering to the subject an IRAK4-modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader, The first biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88, providing a method.

[0009] In some embodiments, the present disclosure is a method of treating a disease or disorder in a subject, Obtaining one or more biological samples (plural possible) from a subject, Measuring the sample expression level of a first biomarker in the biological sample(s), Comparing the sample expression level of the first biomarker with a reference expression level of the first biomarker, When the sample expression level of the first biomarker is elevated in the sample(s) as compared to the reference expression level of the first biomarker, administering to the subject an IRAK4-modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader, The first biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88, providing a method.

[0010] In other embodiments, the present disclosure is a method of treating a disease or disorder in a subject, Obtaining one or more biological samples (plural possible) from a subject, Measuring the sample expression level of a first biomarker in the biological sample(s), Comparing the sample expression level of the first biomarker with a reference expression level of the first biomarker, Analyzing a biological sample(s) for the presence of a first biomarker in the cell nuclei of the biological sample(s), in the following cases: the presence of the first biomarker is detected in the cell nuclei of the biological sample(s), and the sample expression level of the first biomarker is elevated in the sample(s) compared to the reference expression level of the first biomarker, only in the case of administering to a subject an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader, wherein the first biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88, providing a method. BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

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Mode for Carrying Out the Invention

[0012] Acute myeloid leukemia (AML) is the second most common leukemia in adults and remains a very lethal disease. Interleukin-1 receptor-associated kinase 4 (IRAK4) has been demonstrated as a potential therapeutic target in human AML. IRAK4-mediated activation of the NF-kappa B signaling pathway may play an important role in cancer cell survival and chemotherapy resistance by NF-kappa B regulation. Results from an ongoing Phase 1 trial have demonstrated the clinical activity of the IRAK4 inhibitor emavusertib (Compound 1) in patients with relapsed / refractory AML and high-risk MDS. To support the development of a companion diagnostic for emavusertib, an immunohistochemistry (IHC) assay was developed and the expression of potential biomarkers in bone marrow (BM) samples obtained from AML patients was investigated. This disclosure relates to methods for analyzing the expression of IRAK4, NF-kappa B p-p50, and NF-kappa B p-p65, including IHC staining in human AML, and further evaluation of these molecules as potential biomarkers for emavusertib therapy in AML patients.

[0013] In some embodiments of the present disclosure, IHC staining and immunoblotting were used to determine the expression of IRAK4, NF-kappaB p-p50 S337, and NF-kappaB p-p65 S536 proteins in human leukemia cell lines and clinical AML samples. Serial sections of formalin-fixed paraffin-embedded BM clot samples obtained from 19 AML patients were used to perform exploratory biomarker evaluation. Eight BM AML samples were purchased from Analytical Biological Services, and 11 BM samples were obtained from patients evaluable for relapsed / refractory AML at the time of screening. Nuclear expression of IRAK4 was found in blasts of 9 out of 19 AML cases using IHC staining. To the best of the inventors' knowledge, this is the first report showing nuclear accumulation of IRAK4 in cancer cells. To corroborate the inventors' findings in clinical AML samples, IRAK4 protein expression was detected in nuclear lysates prepared from leukemia cell lines THP-1, HL-60, and K562. Using AML BM samples, nuclear expression of IRAK4 was found to be significantly correlated with activation of NF-kappaB determined by nuclear accumulation of NF-kappaB p-p50 and p-p65 in 9 out of 19 cases. Cytoplasmic expression of IRAK4 was detected in 2 out of 19 cases, but expression of IRAK4, NF-kappaB p-p50, and p-p65 was not detected in 8 out of 19 AML cases. Clinical response data are presented in relation to these new findings.

[0014] The inventors' findings have revealed the hitherto unknown nuclear expression of IRAK4 in leukemia cells. The inventors' results demonstrate co-expression of nuclear IRAK4, NF-kappaB p-p50, and p-p65 in blasts, suggesting a potentially new mode of interaction between IRAK4 and NF-kappaB in human AML. The role of nuclear IRAK4 in leukemia cells is still under investigation, but the inventors' preliminary findings have revealed a new perspective for stratification of emabselitide treatment and demonstrated the possibility of discovering new biomarkers through IHC analysis of clinical samples.

[0015] Activation of IRAK4 leads to activation of the NF-κB signaling pathway, including phosphorylation of NF-κB p50, which is required for DNA binding and transcriptional activity of NF-κB (Hou S et al. Phosphorylation of serine 337 of NF-kB p50 is critical for DNA binding. J Biol Chem. 2003). Phosphorylation of S536 in the transactivation domain (TAD) of NF-κB p65 leads to enhanced transactivation through increased binding of CBP / p300 and acetylation of K310 of p65.

[0016] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject, comprising: obtaining one or more biological sample(s) from the subject; analyzing the biological sample(s) for the presence of a first biomarker in the cell nucleus of the biological sample(s); administering to the subject an IRAK4-modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader if the presence of the first biomarker is detected in the cell nucleus of the biological sample(s). The first biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0017] In certain embodiments, the method of the present disclosure further comprises: analyzing the biological sample(s) for the presence of a second biomarker in the cell nucleus of the biological sample(s); administering to the subject an IRAK4-modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader only if the presence of the first biomarker and the second biomarker are detected in the cell nucleus of the biological sample(s). The second biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0018] In some embodiments, the method of the present disclosure analyzing the biological sample(s) for the presence of a third biomarker in the cell nuclei of the biological sample(s); administering an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader to the subject only if the presence of a first biomarker, a second biomarker, and a third biomarker is detected in the cell nuclei of the biological sample(s), and the third biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0019] In certain embodiments, the method of the present disclosure analyzing the biological sample(s) for the presence of a fourth biomarker in the cell nuclei of the biological sample(s); administering an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader to the subject only if the presence of a first biomarker, a second biomarker, a third biomarker, and a fourth biomarker is detected in the cell nuclei of the biological sample(s), and the fourth biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0020] In some aspects, the present disclosure is a method of treating a disease or disorder in a subject, the method comprising: obtaining one or more biological sample(s) from the subject; measuring a sample expression level of a first biomarker in the biological sample(s); comparing the sample expression level of the first biomarker to a reference expression level of the first biomarker; If the sample expression level of the first biomarker is elevated in the sample(s) compared to the reference expression level of the first biomarker, administering to the subject an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader, The first biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88, and provides a method.

[0021] In certain embodiments, the methods of the present disclosure measuring the sample expression level of a second biomarker in a biological sample(s); comparing the sample expression level of the second biomarker to the reference expression level of the second biomarker; administering to the subject an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader only if the sample expression levels of the first and second biomarkers are both elevated in the sample(s) compared to the reference expression levels of the first and second biomarkers; and The second biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0022] In some embodiments, the methods of the present disclosure measuring the sample expression level of a third biomarker in a biological sample(s); comparing the sample expression level of the third biomarker to the reference expression level of the third biomarker; administering to the subject an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader only if the sample expression levels of the first biomarker, the second biomarker, and the third biomarker are each elevated in the sample compared to the reference expression levels of the first biomarker, the second biomarker, and the third biomarker; and The third biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0023] In certain embodiments, the methods of the disclosure comprise measuring the sample expression level of a fourth biomarker in a biological sample(s), comparing the sample expression level of the fourth biomarker to a reference expression level of the fourth biomarker, and administering to the subject an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader only if the sample expression levels of the first biomarker, the second biomarker, the third biomarker, and the fourth biomarker are each elevated in the sample as compared to the reference expression levels of the first biomarker, the second biomarker, the third biomarker, and the fourth biomarker. The fourth biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0024] In other aspects, the disclosure is a method of treating a disease or disorder in a subject, comprising obtaining one or more biological sample(s) from the subject, measuring the sample expression level of a first biomarker in the biological sample(s), comparing the sample expression level of the first biomarker to a reference expression level of the first biomarker, analyzing the biological sample(s) for the presence of the first biomarker in the cell nucleus of the biological sample(s), wherein if the presence of the first biomarker is detected in the cell nucleus of the biological sample(s), and Administering an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader only if the sample expression level of a first biomarker is elevated in the sample(s) compared to the reference expression level of the first biomarker, Providing a method wherein the first biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0025] In certain embodiments, the methods of the disclosure comprise measuring the sample expression level of a second biomarker in a biological sample(s); comparing the sample expression level of the second biomarker to the reference expression level of the second biomarker; analyzing the biological sample(s) for the presence of the second biomarker in the cell nuclei of the biological sample(s); and, in the following cases: both the first biomarker and the second biomarker are detected in the cell nuclei of the biological sample(s); and administering an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader only if the sample expression levels of both the first biomarker and the second biomarker are elevated in the sample(s) compared to the reference expression levels of the first biomarker and the second biomarker. The second biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0026] In some embodiments, the methods of the disclosure comprise measuring the sample expression level of a third biomarker in a biological sample(s); comparing the sample expression level of the third biomarker to the reference expression level of the third biomarker; Analyzing a biological sample(s) for the presence of a third biomarker in the cell nuclei of the biological sample(s), in the following cases: wherein the presence of each of a first biomarker, a second biomarker, and the third biomarker is detected in the cell nuclei of the biological sample(s), and wherein the sample expression level of each of the first biomarker, the second biomarker, and the third biomarker is elevated in the sample(s) as compared to the respective reference expression level of each of the first biomarker, the second biomarker, and the third biomarker, administering only in such cases to a subject an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader, and further comprising, the third biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0027] In certain embodiments, the methods of the disclosure comprise measuring the sample expression level of a fourth biomarker in the biological sample(s), comparing the sample expression level of the fourth biomarker to the reference expression level of the fourth biomarker, analyzing the biological sample(s) for the presence of the fourth biomarker in the cell nuclei of the biological sample(s), in the following cases: wherein the presence of each of the first biomarker, the second biomarker, the third biomarker, and the fourth biomarker is detected in the cell nuclei of the biological sample(s), and Administering an IRAK4 modifying compound selected from an IRAK4 inhibitor or an IRAK4 degrader only when the sample expression level of each of the first biomarker, the second biomarker, the third biomarker, and the fourth biomarker is elevated in the sample(s) as compared to the respective reference expression level of each of the first biomarker, the second biomarker, the third biomarker, and the fourth biomarker, The fourth biomarker is selected from IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, and MYD88.

[0028] In certain embodiments of the present disclosure, the first biomarker is IRAK4. In other embodiments, the first biomarker is NF-κB p-p65. In still other embodiments, the first biomarker is NF-κB p-p50. In certain embodiments, the first biomarker is p-IRAK1. In other embodiments, the first biomarker is FLT3. In still other embodiments, the first biomarker is MYD88.

[0029] In certain embodiments, the second biomarker is IRAK4. In other embodiments, the second biomarker is NF-κB p-p65. In still other embodiments, the second biomarker is NF-κB p-p50. In certain embodiments, the second biomarker is p-IRAK1. In other embodiments, the second biomarker is FLT3. In still other embodiments, the second biomarker is MYD88.

[0030] In certain embodiments, a third biomarker is present in the sample. In certain such embodiments, when present, the third biomarker is IRAK4. In other embodiments, when present, the third biomarker is NF-κB p-p65. In still other embodiments, when present, the third biomarker is NF-κB p-p50. In certain embodiments, the third biomarker is p-IRAK1. In other embodiments, when present, the third biomarker is FLT3. In still other embodiments, when present, the third biomarker is MYD88.

[0031] In certain embodiments, a fourth biomarker is present in the sample. In certain such embodiments, when present, the fourth biomarker is IRAK4. In other embodiments, when present, the fourth biomarker is NF-κB p-p65. In still other embodiments, when present, the fourth biomarker is NF-κB p-p50. In certain embodiments, the fourth biomarker is p-IRAK1. In other embodiments, when present, the fourth biomarker is FLT3. In still other embodiments, when present, the fourth biomarker is MYD88.

[0032] In some embodiments, the sample expression level of the first biomarker indicates the nuclear expression level of the first biomarker, and the corresponding reference expression level of the first biomarker represents the nuclear expression level of the first biomarker. In other embodiments, the sample expression level of the first biomarker indicates the cytoplasmic expression level of the first biomarker, and the corresponding reference expression level of the first biomarker represents the cytoplasmic expression level of the first biomarker. In still other embodiments, the sample expression level of the first biomarker indicates the membrane expression level of the first biomarker, and the corresponding reference expression level of the first biomarker represents the membrane expression level of the first biomarker.

[0033] In some embodiments, the sample expression level of the second biomarker represents the nuclear expression level of the second biomarker, and the reference expression level of the second biomarker indicates the nuclear expression level of the second biomarker. In other embodiments, the sample expression level of the second biomarker represents the cytoplasmic expression level of the second biomarker, and the reference expression level of the second biomarker indicates the cytoplasmic expression level of the second biomarker. In still other embodiments, the sample expression level of the second biomarker represents the membrane expression level of the second biomarker, and the reference expression level of the second biomarker indicates the membrane expression level of the second biomarker.

[0034] In some embodiments, when present, the sample expression level of the third biomarker represents the nuclear expression level of the third biomarker, and when present, the reference expression level of the third biomarker indicates the nuclear expression level of the third biomarker. In other embodiments, when present, the sample expression level of the third biomarker represents the cytoplasmic expression level of the third biomarker, and when present, the reference expression level of the third biomarker indicates the cytoplasmic expression level of the third biomarker. In still other embodiments, when present, the sample expression level of the third biomarker represents the membrane expression level of the third biomarker, and when present, the reference expression level of the third biomarker indicates the membrane expression level of the third biomarker.

[0035] In some embodiments, when present, the sample expression level of the fourth biomarker represents the nuclear expression level of the fourth biomarker, and when present, the reference expression level of the fourth biomarker indicates the nuclear expression level of the fourth biomarker. In other embodiments, when present, the sample expression level of the fourth biomarker represents the cytoplasmic expression level of the fourth biomarker, and when present, the reference expression level of the fourth biomarker indicates the cytoplasmic expression level of the fourth biomarker. In still other embodiments, when present, the sample expression level of the fourth biomarker represents the membrane expression level of the fourth biomarker, and when present, the reference expression level of the fourth biomarker indicates the membrane expression level of the fourth biomarker.

[0036] In some embodiments, if present, the sample expression level of IRAK4 indicates the nuclear expression level of IRAK4, and if present, the reference expression level of IRAK4 indicates the nuclear expression level of IRAK4. In other embodiments, if present, the sample expression level of IRAK4 indicates the cytoplasmic expression level of IRAK4, and if present, the reference expression level of IRAK4 indicates the cytoplasmic expression level of IRAK4.

[0037] In some embodiments, the sample expression level of NF-κB p-p65 indicates the nuclear expression level of NF-κB p-p65 if present. In certain embodiments, the reference expression level of NF-κB p-p65 indicates the nuclear expression level of NF-κB p-p65 if present. In some embodiments, the sample expression level of NF-κB p-p65 indicates the cytoplasmic expression level of NF-κB p-p65 if present. In certain embodiments, the reference expression level of NF-κB p-p65 indicates the cytoplasmic expression level of NF-κB p-p65 if present.

[0038] In some embodiments, the sample expression level of NF-κB p-p50 indicates the nuclear expression level of NF-κB p-p50 if present. In certain embodiments, the reference expression level of NF-κB p-p50 indicates the nuclear expression level of NF-κB p-p50 if present. In some embodiments, the sample expression level of NF-κB p-p50 indicates the cytoplasmic expression level of NF-κB p-p50 if present. In certain embodiments, the reference expression level of NF-κB p-p50 indicates the cytoplasmic expression level of NF-κB p-p50 if present.

[0039] In some embodiments, the sample expression level of p-IRAK1 indicates the nuclear expression level of p-IRAK1 if present, and the reference expression level of p-IRAK1 indicates the nuclear expression level of p-IRAK1 if present. In other embodiments, the sample expression level of p-IRAK1 indicates the cytoplasmic expression level of p-IRAK1 if present, and the reference expression level of p-IRAK1 indicates the cytoplasmic expression level of p-IRAK1 if present.

[0040] In some embodiments, the sample expression level of FLT3, if present, indicates the cytoplasmic expression level of FLT3. In certain embodiments, the reference expression level of FLT3, if present, indicates the cytoplasmic expression level of FLT3. In some embodiments, the sample expression level of FLT3, if present, indicates the membrane expression level of FLT3. In certain embodiments, the reference expression level of FLT3, if present, indicates the membrane expression level of FLT3.

[0041] In some embodiments, the sample expression level of MYD88, if present, indicates the nuclear expression level of MYD88. In certain embodiments, the reference expression level of MYD88, if present, indicates the nuclear expression level of MYD88. In some embodiments, the sample expression level of MYD88, if present, indicates the cytoplasmic expression level of MYD88. In certain embodiments, the reference expression level of MYD88, if present, indicates the cytoplasmic expression level of MYD88.

[0042] In some embodiments, the reference expression level is a representative value of, or a value obtained from, a subject or subjects not suffering from the disease or disorder. In further embodiments, the value of the reference expression level is obtained from tissue or blood. In further embodiments, the value is obtained from blood.

[0043] In certain embodiments, the IRAK4 modifying compound is an IRAK4 inhibitor. In other embodiments, the IRAK4 modifying compound is an IRAK4 degrader.

[0044] The methods and compounds related to the content of the present disclosure can be found, for example, in U.S. Patent Nos. 10,160,753, 9,732,095, 10,758,518, U.S. Patent Application Publication No. 20210290628, U.S. Patent Application No. 17 / 680,995, and PCT Application Nos. PCT / WO2022 / 031330 and PCT / US2021 / 59668, the contents of which are hereby incorporated by reference in their entirety herein, particularly with respect to the IRAK4 inhibitors, treatment regimens, and disease indications disclosed in those references.

[0045] IRAK4 inhibitor More broadly, the methods disclosed herein can be practiced using any IRAK4 inhibitor. For example, the methods can be practiced using IRAK4 inhibitors disclosed in PCT / IB2015 / 050119, PCT / IB2015 / 050217, PCT / IB2015 / 0054620, PCT / IB2016 / 054203, and / or PCT / IB2016 / 054229. The content of each of the aforementioned international applications is hereby incorporated by reference in its entirety herein, particularly with respect to the IRAK4 inhibitors disclosed in the same document.

[0046] In certain embodiments, the IRAK4 inhibitor is of formula I:

Chemical formula

[0047] In certain embodiments, A is O or S, Y is -CH 2 - or O, Z is aryl or heterocyclyl, R 1 is, for each occurrence, independently halo or optionally substituted heterocyclyl, and the substituent is alkyl, aminoalkyl, halo, or -NR a R b and R a and R b are independently hydrogen, alkyl, or heterocyclyl, and R 2 is hydrogen, cycloalkyl, heterocyclyl, or -NR a R b and “m” is 0 and “n” is 1.

[0048] In other embodiments, A is O or S, Y is -CH 2 - or O, Z is aryl or heterocyclyl, R 1 is, for each occurrence, independently halo or optionally substituted heterocyclyl, and the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR a R b and R a and R b are independently hydrogen, alkyl, or heterocyclyl, and R 2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR a R band the substituent is selected from amino, halo, or hydroxyl, "m" and "n" are independently 0, 1, or 2, and "p" is 0 or 1.

[0049] In certain embodiments,

Chemical Structure

Chemical Structure

[0050] In certain embodiments, Z is aryl or a 5- or 6-membered heterocyclyl. In certain embodiments, Z is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxido thiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, and azabicyclo[3.2.1]octanyl, an optionally substituted heterocyclyl selected from these, each of which is alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or -NR a R b optionally substituted by a and R b are independently hydrogen, alkyl, or acyl.

[0051] In certain embodiments, the IRAK4 inhibitor is of formula (IA):

Chemical Structure

[0052] In certain embodiments, the IRAK4 inhibitor is of formula (IB):

Chemical formula

[0053] In certain embodiments, the IRAK4 inhibitor is of formula (IC):

Chemical formula

[0054] In certain embodiments, R 1 is optionally substituted heterocyclyl, and the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR a R b and R a and R b are, independently, hydrogen or acyl. In other embodiments, R 1 is optionally substituted heterocyclyl, and the substituent is alkyl, aminoalkyl, halo, or -NR aR b is, and R a and R b are, independently, hydrogen or acyl. In yet other embodiments, R 1 is optionally substituted heterocyclyl, and the substituents are alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR a R b wherein R a and R b are, independently, hydrogen, alkyl, or heterocyclyl. In certain embodiments, R 1 is pyridyl, pyrazolyl, pyrrolidinyl, or piperidinyl. In certain embodiments, R 1 is optionally substituted pyrazolyl, and the substituents are alkyl, hydroxyl, or -NR a R b In other embodiments, R 1 is halo.

[0055] In certain embodiments, R 2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR a R b wherein the substituents are selected from amino, halo, or hydroxyl. In certain embodiments, R 2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR a R b wherein the substituents are selected from amino, halo, or hydroxyl. In certain embodiments, R 2 is optionally substituted heterocyclyl selected from piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanyl, or azabicyclo[3.2.1]octanyl, and the substituents are hydroxyl, halo, alkyl, or amino. In certain embodiments, R 2 is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl. In other embodiments, R 2is hydrogen. In still other embodiments, is cycloalkyl. In certain embodiments, R 2 is cyclopropyl.

[0056] In certain embodiments, R 3 is alkyl.

[0057] In certain embodiments, m is 0 and p is 1. In other embodiments, m is 0 or 2 and p is 0 or 1.

[0058] In certain embodiments, the IRAK4 inhibitor is 6'-Amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide, 6'-Amino-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide hydrochloride, N-(5-Cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride, N-(2,5-Di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride, N-(2,5-Di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(2-Morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide, 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 6-Chloro-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide, N-(2,5-Di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolylamide, 2-(2-Chloropyridin-4-yl)-N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, (S)-2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 6’-Amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3’-bipyridine]-6-carboxamide, 6’-Amino-N-(2-morpholinothiazolo[4,5-c]pyridin-6-yl)-[2,3’-bipyridine]-6-carboxamide, 6’-Amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3’-bipyridine]-6-carboxamide, 2-(2-Methylpyridin-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 6’-Amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3’-bipyridine]-6-carboxamide, N-(2-Morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolylamide, 3-(4-(Aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide, 2-(4-(Aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide, 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, N-(2-Morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolylamide, N-(2,5-Di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolylamide, N-(2,5-Di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(2,5-Dimorpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(4-Methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(2,5-Di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide, N-(2,5-Di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamide, N-(2,5-Di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-yl)oxazole-4-carboxamide, 2-(2-Hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, N-(2,5-Di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-hydroxypyridin-3-yl)oxazole-4-carboxamide, 2-(2-Methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 2-(2-Methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 2-(3-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, N-(2,5-Di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(6-Methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolylamide, N-(2,5-Di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-yl)oxazole-4-carboxamide, (S)-N-(5-(3-Aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (S)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (R)-N-(5-(3-Aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (R)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (S)-2-(3-Aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, (S)-6-(3-Hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolylamide, (S)-6-(3-Aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolylamide, (S)-2-(3-Hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, (S)-N-(5-Cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide, (S)-2-(3-Aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 2-(2-Methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride, N-(2-(2,6-Dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride, N-(2,5-Di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolylamide hydrochloride, 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolylamide, N-(2,5-Di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamide hydrochloride, N-(2-((2S,6R)-2,6-Dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(2-Methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 2-(2-Hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, N-(2,5-Di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methoxypyridin-4-yl)oxazole-4-carboxamide, 2-(6-Methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 2-(2-Methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, (S)-N-(5-(3-Fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(6-Methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 2-(3-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, (S)-6-(3-Aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolylamide, (S)-6-(3-Hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolylamide, (S)-6-(3-Aminopyrrolidin-1-yl)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolylamide, (S)-N-(2,5-Di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolylamide, (S)-2-(3-Aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, (S)-N-(5-(3-Aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (S)-2-(3-Aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, N-(5-Cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (S)-2-(3-Hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, (S)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (S)-N-(5-Cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolylamide, (S)-N-(5-Cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide, (S)-N-(5-Cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolylamide, (S)-N-(5-Cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide, N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide, (S)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide, (R)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide, (S)-N-(5-(Azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolylamide, N-(5-(3-Hydroxyazetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (S)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide, (S)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide, (S)-N-(5-(3-Hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(4-Hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (R)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(4-Hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide, N-(5-(Azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(2-Methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 5-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide, N-(5-(Azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(2-Aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride, N-(5-(Azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (R)-N-(5-(3-Hydroxy piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (R)-N-(5-(3-Hydroxy piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide, (S)-6-(1-(2-Hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolylamide N-(5-(4-Fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide N-(5-(4-Fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride N-(5-(1-Methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(3-Fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(4-Hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide, N-(5-(3-Fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide, (S)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide, N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (R)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide, N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide, (S)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide, (S)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide, N-(5-(Azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(2-Methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 5-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide, N-(5-(Azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, N-(5-(4-Hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide, (R)-N-(5-(3-Hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide, N-(5-(Furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(3-Fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(4-Hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(4-Fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, (S)-N-(5-(3-Aminopiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, N-(5-(6-Fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(3-Hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(2-(3-Hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(2-Acetamidopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, N-(2-(3-Hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, 2-(2-Acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide, 2-(2-Aminopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride, 5-(2-Aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)furan-3-carboxamide hydrochloride, 2-(2-Aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride, 2-(2-Aminopyridin-4-yl)-N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride, N-(5-(2-Fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(4-Fluoropiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide, N-(5-(4-Aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride, and N-(5-(2-Hydroxypyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0059] In certain embodiments, the IRAK4 inhibitor is

Chemical formula

[0060] In a certain specific preferred embodiment, the IRAK4 inhibitor is

Chemical formula

Chemical formula

[0061] Compound 1 can be administered in any amount or manner that induces the desired response in a subject. For example, 100 to 400 mg of Compound 1 can be administered to the subject twice a day, or 200 to 1000 mg of Compound 1 can be administered to the subject once a day. In certain embodiments, 100 to 400 mg of Compound 1 is administered to the subject twice a day. In certain embodiments, 200 to 400 mg of Compound 1 is administered to the subject twice a day. In certain preferred embodiments, 250 to 350 mg of Compound 1 is administered to the subject twice a day. In certain embodiments, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of Compound 1 is administered to the subject twice a day. In certain embodiments, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of Compound 1 is administered to the subject twice a day. In certain embodiments, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of Compound 1 is administered to the subject twice a day. In certain embodiments, about 50 mg of Compound 1 is administered to the subject twice a day. In other embodiments, about 200 mg of Compound 1 is administered to the subject twice a day. In other embodiments, about 225 mg of Compound 1 is administered to the subject twice a day. In other embodiments, about 250 mg of Compound 1 is administered to the subject twice a day. In other embodiments, about 275 mg of Compound 1 is administered to the subject twice a day. In particularly preferred embodiments, about 300 mg of Compound 1 is administered to the subject twice a day. In other embodiments, about 325 mg of Compound 1 is administered to the subject twice a day. In other embodiments, about 350 mg of Compound 1 is administered to the subject twice a day. In other embodiments, about 375 mg of Compound 1 is administered to the subject twice a day. In other embodiments, about 400 mg of Compound 1 is administered to the subject twice a day.

[0062] In certain embodiments, Compound 1 at about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg is administered once daily to a subject. In certain embodiments, Compound 1 at about 50 mg is administered once daily to a subject. In certain embodiments, Compound 1 at about 75 mg is administered once daily to a subject. In certain embodiments, Compound 1 at about 100 mg is administered once daily to a subject. In certain embodiments, Compound 1 at about 125 mg is administered once daily to a subject. In certain embodiments, Compound 1 at about 150 mg is administered once daily to a subject.

[0063] In certain preferred embodiments, Compound 1 is administered orally to a subject. In certain embodiments, Compound 1 at about 50 mg is administered orally twice daily to a subject. In other embodiments, Compound 1 at about 200 mg is administered orally twice daily to a subject. In other embodiments, Compound 1 at about 250 mg is administered orally twice daily to a subject. In particularly preferred embodiments, Compound 1 at about 300 mg is administered orally twice daily to a subject. In other embodiments, Compound 1 at about 325 mg is administered orally twice daily to a subject. In other embodiments, Compound 1 at about 350 mg is administered orally twice daily to a subject. In other embodiments, Compound 1 at about 375 mg is administered orally twice daily to a subject. In other embodiments, Compound 1 at about 400 mg is administered orally twice daily to a subject. In other embodiments, Compound 1 at about 50 mg is administered once daily to a subject. In still other embodiments, Compound 1 at about 75 mg is administered once daily to a subject. In still other embodiments, Compound 1 at about 100 mg is administered once daily to a subject. In still other embodiments, Compound 1 at about 125 mg is administered once daily to a subject. In still other embodiments, Compound 1 at about 150 mg is administered once daily to a subject.

[0064] In other embodiments, the IRAK4 inhibitor is PF-06650833 or BAY1830839.

[0065] IRAK4 degrading agent In certain embodiments, the method comprises administering an IRAK4 degrading agent. In certain embodiments, the IRAK4 degrading agent is KT-474.

[0066] Combination therapy In certain embodiments of the methods disclosed herein, the method further comprises co-administering a BCL-2 inhibitor to the subject. In certain preferred embodiments, the BCL-2 inhibitor is venetoclax. In certain embodiments, the method further comprises administering 400 mg of venetoclax daily. In certain embodiments, venetoclax is administered orally. In certain preferred embodiments, the method further comprises orally administering 400 mg of venetoclax daily.

[0067] In other embodiments, the method further comprises co-administering a BTK inhibitor to the subject. In certain embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM71224. In certain embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM71224. In certain embodiments, the BTK inhibitor is acalabrutinib. In certain embodiments, the method comprises administering 200 mg of acalabrutinib daily. In certain embodiments, acalabrutinib is administered orally. In certain embodiments, the method comprises orally administering 200 mg of acalabrutinib daily. In certain preferred embodiments, the BTK inhibitor is ibrutinib. In certain embodiments, the method comprises administering 420 mg of ibrutinib daily. In other embodiments, the method comprises administering 420 mg of ibrutinib daily. In certain embodiments, ibrutinib is administered orally. In certain preferred embodiments, 420 mg of ibrutinib is orally administered daily. In other preferred embodiments, the method comprises administering 560 mg of ibrutinib daily. In certain embodiments, the BTK inhibitor is zanubrutinib. In certain embodiments, the method comprises administering 160 mg of zanubrutinib twice a day. In other embodiments, the method comprises administering 320 mg of zanubrutinib once a day. In certain embodiments, zanubrutinib is administered orally. In certain embodiments, the method comprises orally administering 160 mg of zanubrutinib twice a day. In other embodiments, the method comprises orally administering 320 mg of zanubrutinib once a day. In certain embodiments, the method comprises ABT-737, BAY-1143572, 5-fluorouracil, abiraterone acetate, acetylcholine, ado-trastuzumab emtansine, afatinib, aldesleukin, alectinib, alemtuzumab, alitretinoin, aminolevulinic acid, anastrozole, anastrozole, aprepitant, arsenic trioxide, asparaginase Erwinia chrysanthemi, atezolizumab,Axitinib, Azacitidine, Belinostat, Bendamustine, Benzyl Isothiocyanate, Bevacizumab, Bexarotene, Bicalutamide, Bleomycin, Blinatumomab, Bortezomib, Bosutinib, Brentuximab Vedotin, Busulfan, Cabazitaxel, Cabozantinib, Capecitabine, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Cetuximab, Chlorambucil, Cisplatin, Clofarabine, Cobimetinib, Copanlisib, Crizotinib, Cyclophosphamide, Cytarabine, Dabrafenib, Dacarbazine, Dactinomycin, Daratumumab, Dasatinib, Daunorubicin, Decitabine, Defibrotide Sodium, Degarelix, Denileukin Diftitox, Denosumab, Dexamethasone, Dexrazoxane, Dihydrotestosterone (DHT), Dinutuximab, Docetaxel, Doxorubicin, Elotuzumab, Eltrombopag, Enzalutamide, Epirubicin, Erythromycin Mesylate, Erlotinib, Etoposide, Everolimus, Exemestane, Filgrastim, Fludarabine Phosphate, Flutamide, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Gemtuzumab Ozogamicin, Glucarpidase, Goserelin Acetate, Hydroxyurea, Ibritumomab Tiuxetan, Ibrutinib, Idarubicin, Idelalisib, Ifosfamide, Imatinib, Imiquimod, Interferon Alfa-2b, Ipilimumab, Irinotecan, Ixabepilone, Ixazomib, Lanreotide, Lapatinib, Lenalidomide, Lenvatinib, Letrozole, Leucovorin, Leuprolide, Lomustine, Mechlorethamine, Megestrol Acetate, Melphalan, Mercaptopurine, Mesna, Methotrexate, Mitomycin C, Mitoxantrone, Navitoclax, Necitumumab, Nelarabine, Netupitant, Nilotinib, Nilutamide, Nivolumab, Obinutuzumab, Ofatumumab, Olaparib, Omacetaxine Mepesuccinate, Osimertinib, Oxaliplatin, Ozogamicin, Paclitaxel, Palbociclib, Parifermin, Pamidronate, Panitumumab, Panobinostat, Pazopanib, Pegaspargase, Peginterferon Alfa-2b, Pembrolizumab, Pemetrexed,Further comprising co-administering one or more of pertuzumab, prexasertib, pomalidomide, ponatinib, pralatrexate, prednisone, procarbazine, propranolol, radium chloride 223, raloxifene, ramucirumab, rasburicase, regorafenib, rituximab, rolapitant, romidepsin, romiplostim, ruxolitinib, siltuximab, sipuleucel-t, sonidegib, sorafenib, sunitinib, talimogene laherparepvec, tamoxifen, temozolomide, temsirolimus, thalidomide, thioguanine, thiotepa, tipiracil, topotecan, toremifene, toremifene, tositumomab, trabectedin, trametinib, trastuzumab, tretinoin, trifluridine, uridine triacetate, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vinorelbine, visimodegib, vorinostat, ziv-aflibercept, zoledronic acid, and pharmaceutically acceptable salts thereof. In some embodiments, the second therapeutic agent is one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.,

[0068] Diseases and disorders The methods disclosed herein relate to the treatment of many diseases and disorders. For example, the methods can be used for the treatment of diseases and disorders associated with IRAK4. In certain embodiments, the disease or disorder is cancer, preferably a hematological malignancy, such as leukemia or lymphoma, such as non-Hodgkin lymphoma. In certain embodiments, the hematological malignancy is myelogenous leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphoblastic leukemia (e.g., acute lymphoblastic leukemia), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., DLBCL or ABC-DLBLC), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt lymphoma, non-Burkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, transformed high grade B-cell lymphoma (HGBL), lymphoplasmacytic lymphoma (LPL), central nervous system lymphoma (CNSL), or MALT lymphoma. In certain embodiments, the hematological malignancy is myelogenous leukemia. In other embodiments, the hematological malignancy is myeloid leukemia (e.g., acute myeloid leukemia). In certain embodiments, the hematological malignancy is acute myeloid leukemia (e.g., AML). In certain embodiments, the AML is primary AML. In other embodiments, the AML is secondary AML. In still other embodiments, the hematological malignancy is myelodysplastic syndrome. In certain embodiments, the myelodysplastic syndrome is high-grade.In other embodiments, myelodysplastic syndromes are of low malignancy. In certain embodiments, myelodysplastic syndromes are of high risk. In still other embodiments, the hematologic malignancy is lymphoblastic leukemia (e.g., acute lymphoblastic leukemia). In still other embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL). In certain embodiments, CLL is high-risk CLL. In still other embodiments, the hematologic malignancy is small lymphocytic lymphoma (SLL). In still other embodiments, the hematologic malignancy is follicular lymphoma. In still other embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In still other embodiments, the hematologic malignancy is activated B-cell-like (ABC) DLBCL. In still other embodiments, the hematologic malignancy is germinal center B-cell-like (GCB) DLBCL. In certain embodiments, DLBCL is extranodal. In certain embodiments, DLBCL is extranodal leg lymphoma, extranodal testicular lymphoma, or extranodal not otherwise specified (NOS) type lymphoma. In still other embodiments, the hematologic malignancy is mantle cell lymphoma. In further embodiments, the hematologic malignancy is Waldenström macroglobulinemia. In still other embodiments, the hematologic malignancy is multiple myeloma. In still other embodiments, the hematologic malignancy is marginal zone lymphoma. In still other embodiments, the hematologic malignancy is Burkitt lymphoma. In still other embodiments, the hematologic malignancy is non-Burkitt high-grade B-cell lymphoma. In still other embodiments, the hematologic malignancy is extranodal marginal zone B-cell lymphoma. In still other embodiments, the hematologic malignancy is transformed high-grade B-cell lymphoma (HGBL). In still other embodiments, the hematologic malignancy is lymphoplasmacytic lymphoma (LPL). In still other embodiments, the hematologic malignancy is CNS lymphoma. In still other embodiments, CNS lymphoma is primary CNS lymphoma (PCNSL). In still other embodiments, the hematologic malignancy is MALT lymphoma. In certain embodiments, the above hematologic malignancies can be recurrent or refractory.In certain embodiments, the above blood malignancies are resistant to treatment with a BTK inhibitor. In certain embodiments, the above blood malignancies are resistant to treatment with a BTK inhibitor as a monotherapy. In certain embodiments, the blood malignancy is resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM71224. In certain preferred embodiments, the blood malignancy is resistant to treatment with ibrutinib.

[0069] In certain embodiments, the cancer is selected from brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, gastric cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, skin cancer, prostate cancer, head and neck cancer. In certain preferred embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is colon cancer. In certain embodiments, the cancer is a solid tumor. In various such embodiments, the cancer can be recurrent or refractory. In certain embodiments, the above cancer is resistant to treatment with a BTK inhibitor. In certain embodiments, the above cancer is resistant to treatment with a BTK inhibitor as a monotherapy. In certain embodiments, the cancer is resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM71224. In certain preferred embodiments, the cancer is resistant to treatment with ibrutinib.

[0070] In other embodiments, the disease or disorder is an inflammatory disease or disorder. In certain embodiments, the inflammatory disease or disorder is an autoimmune disease or disorder. In certain embodiments, the inflammatory disease or disorder is ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, autoimmune blood disease, hemolytic anemia, aplastic anemia, erythroblastosis, idiopathic thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic malabsorption syndrome, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, pulmonary fibrosis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonia, primary biliary cirrhosis, uveitis (anterior or posterior), Sjogren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy, chronic granulomatous disease, endometriosis, leptospiral kidney disease, glaucoma, retinal disease, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolism disorder, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic urticaria dysplasia, Behcet's disease, dyschromatosis, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, allergy, anaphylaxis, fibrosis, gastritis, gastroenteritis, sinusitis, ocular allergy, silica-induced disease, chronic obstructive pulmonarydisease, COPD), cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuritis, cataract, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, cystitis, dacryadenitis, dermatitis, juvenile rheumatoid arthritis, encephalitis, endocarditis, endometritis, enteritis, panenteritis, maxillitis, epididymitis, fasciitis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, urticaria, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acute or chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, cryopyrin-associated periodic syndrome (CAPS), and osteoarthritis. In certain preferred embodiments, the inflammatory disease or disorder is hypercytokinemia. In certain embodiments, hypercytokinemia is induced by an infective agent. In certain embodiments, the infective agent is a virus. In certain preferred embodiments, the virus is a coronavirus (e.g., COVID-19). In other embodiments, the infective agent is a bacterium. In certain embodiments, the inflammatory disease or disorder is graft vs host disease (GVHD). In certain embodiments, GVHD is chronic graft vs hosta disease, cGVHD). In certain embodiments, GVHD is sclerodermatous GVHD, steroid-resistant GVHD, cyclosporine-resistant GVHD, GVHD, oral GVHD, reticular oral GVHD, erosive GVHD, or ulcerative oral GVHD. In certain embodiments, GVHD is sclerodermatous GVHD. In certain embodiments, GVHD is oral GVHD. In certain embodiments, GVHD is reticular oral GVHD. In certain embodiments, GVHD is erosive GVHD. In certain embodiments, GVHD is ulcerative oral GVHD. In certain embodiments, GVHD is overlapping chronic GVHD. In certain embodiments, GVHD is classic chronic GVHD. In certain embodiments, GVHD is steroid-resistant GVHD. In certain embodiments, GVHD is cyclosporine-resistant GVHD. In certain embodiments, GVHD is refractory. In certain embodiments, GVHD is recurrent.

[0071] In certain embodiments, the above-mentioned disease or disorder is resistant to treatment with a BTK inhibitor alone. In certain embodiments, the above-mentioned disease or disorder is resistant to treatment with a BTK inhibitor as a monotherapy. In certain embodiments, the disease or disorder is resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM71224. In certain preferred embodiments, the disease or disorder is resistant to treatment with ibrutinib.

[0072] In certain embodiments, the disease or disorder is associated with chronic anemia. In certain embodiments, the disease or disorder is chronic anemia. In certain embodiments, the disease or disorder is associated with transfusion dependence.

[0073] In certain embodiments, the subject is a human adult.

[0074] In certain embodiments, the IRAK4 inhibitor is Compound 1, Compound 1 is orally administered once daily at a dose of about 50 mg, and the disease or disorder is DLBCL. In certain embodiments, the DLBCL is relapsed or refractory.

[0075] In certain embodiments, the IRAK4 inhibitor is Compound 1, Compound 1 is orally administered once daily at a dose of about 50 mg, and the disease or disorder is FL. In certain embodiments, the FL is relapsed or refractory.

[0076] In certain embodiments, the IRAK4 inhibitor is Compound 1, Compound 1 is orally administered once daily at a dose of about 300 mg, and the disease or disorder is WM. In certain embodiments, the WM is relapsed or refractory.

[0077] In certain embodiments, the IRAK4 inhibitor is Compound 1, Compound 1 is orally administered twice daily at a dose of about 50 mg, and the disease or disorder is DLBCL. In certain embodiments, the DLBCL is relapsed or refractory.

[0078] In certain embodiments, the IRAK4 inhibitor is Compound 1, Compound 1 is orally administered twice daily at a dose of about 300 mg, and the disease or disorder is LPL. In certain embodiments, the LPL is relapsed or refractory.

[0079] In certain embodiments, the IRAK4 inhibitor is Compound 1, Compound 1 is orally administered twice daily at a dose of about 300 mg, and the disease or disorder is GCB DLBCL. In certain embodiments, the GCB DLBCL is relapsed or refractory.

[0080] In certain embodiments, the IRAK4 inhibitor is Compound 1, Compound 1 is orally administered twice daily at a dose of about 50 mg, and the disease or disorder is ABC DLBCL. In certain embodiments, the ABC DLBCL is relapsed or refractory.

[0081] In certain embodiments, the IRAK4 inhibitor is Compound 1, which is orally administered twice daily at a dosage of about 50 mg, and the disease or disorder is MZL. In certain embodiments, the MZL is relapsed or refractory.

[0082] In certain embodiments, the IRAK4 inhibitor is Compound 1, which is orally administered twice daily at a dosage of about 300 mg, and the disease or disorder is MZL. In certain embodiments, the MZL is relapsed or refractory.

[0083] In certain embodiments, the IRAK4 inhibitor is Compound 1, which is orally administered twice daily at a dosage of about 300 mg, and the disease or disorder is MALT. In certain embodiments, the MALT is relapsed or refractory.

[0084] In certain embodiments, Compound 1 is administered continuously (e.g., Compound 1 is administered without a drug holiday). In other embodiments, Compound 1 is administered intermittently (e.g., Compound 1 is administered continuously with interruptions by drug holidays of one or more days). In certain embodiments, each drug holiday lasts 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In certain preferred embodiments, the drug holiday lasts 7 days. In a more preferred embodiment, Compound 1 is administered daily for 3 weeks, followed by a 1-week drug holiday, and optionally, followed by 3 weeks of daily administration and a 1-week drug holiday, and this cycle can be further repeated. In certain embodiments, the aforementioned dosing regimen continues with alternating dosing periods and drug holidays until a change in the disease state is observed (e.g., until complete response, partial response, or unacceptable toxicity is observed). A method of treating certain diseases and disorders with Compound 1 is disclosed in PCT / US2021 / 030192, the content of which is hereby incorporated by reference in its entirety.

[0085] Previous treatment The methods disclosed herein can be used as a first-line alternative therapy or can be applied to patients who have not achieved either a partial or complete response using one or more previous anti-cancer or anti-inflammatory therapies. In certain embodiments, the subject has previously received at least one anti-cancer therapy. In certain embodiments, the patient has previously received one anti-cancer therapy. In other embodiments, the patient has previously received two anti-cancer therapies. In yet other embodiments, the patient has previously received three anti-cancer therapies. In yet other embodiments, the patient has previously received four anti-cancer therapies. In yet other embodiments, the patient has previously received five anti-cancer therapies. In certain embodiments, at least one anti-cancer therapy is selected from anti-CD20 antibodies, nitrogen mustards, steroids, purine analogs, DNA topoisomerase inhibitors, DNA intercalators, tubulin inhibitors, BCL-2 inhibitors, proteasome inhibitors, toll-like receptor inhibitors, kinase inhibitors, SRC kinase inhibitors, PI3K kinase inhibitors, BTK inhibitors, glutaminase inhibitors, PD-1 inhibitors, PD-L1 inhibitors, and methylating agents, or combinations thereof. In certain embodiments, the anti-cancer therapy is selected from ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, oprozomib, ixazomib, acalabrutinib, zanubrutinib, IMO-08400, idelalisib, ambruticin, CB-839, fludarabine, and thalidomide, or combinations thereof. In certain embodiments, the anti-cancer therapy is ibrutinib. In certain embodiments, the anti-cancer therapy is ibrutinib and rituximab. In certain embodiments, the anti-cancer therapy is bendamustine. In certain embodiments, the anti-cancer therapy is bendamustine and rituximab. In certain embodiments, the anti-cancer therapy is bortezomib. In certain embodiments, the anti-cancer therapy is bortezomib and dexamethasone. In certain embodiments, the anti-cancer therapy is bortezomib and rituximab.In certain embodiments, the anti-cancer therapy is bortezomib, rituximab, and dexamethasone. In certain embodiments, it is chlorambucil. In certain embodiments, the anti-cancer therapy is cladribine. In certain embodiments, the anti-cancer therapy is cladribine and rituximab. In certain embodiments, the anti-cancer therapy is cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R). In certain embodiments, the anti-cancer therapy is cyclophosphamide, prednisone, and rituximab (i.e., CPR). In certain embodiments, the anti-cancer therapy is fludarabine. In certain embodiments, the anti-cancer therapy is fludarabine and rituximab. In certain embodiments, the anti-cancer therapy is fludarabine, cyclophosphamide, and rituximab. In certain preferred embodiments, the anti-cancer therapy is rituximab. In certain preferred embodiments, the anti-cancer therapy comprises rituximab. In certain embodiments, the anti-cancer therapy is rituximab, cyclophosphamide, and dexamethasone (i.e., RCD). In certain embodiments, the anti-cancer therapy is thalidomide. In certain embodiments, the anti-cancer therapy is thalidomide and rituximab. In certain embodiments, the anti-cancer therapy is venetoclax. In certain embodiments, the anti-cancer therapy is cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD). In certain embodiments, the anti-cancer therapy is a hypomethylating agent. In certain embodiments, the subject has previously been administered at least 6 cycles of a hypomethylating agent. In certain embodiments, the anti-cancer therapy is any combination of the above, for example, the subject may first receive rituximab and then, at a later date, receive a combination of rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).

[0086] In certain embodiments, the subject has previously received at least one anti-inflammatory therapy. In certain embodiments, the patient has previously received one anti-inflammatory therapy. In other embodiments, the patient has previously received two anti-inflammatory therapies. In still other embodiments, the patient has previously received three anti-inflammatory therapies. In still other embodiments, the patient has previously received four anti-inflammatory therapies. In certain embodiments, the anti-inflammatory agent is a steroid (e.g., corticosteroid). In certain embodiments, the anti-inflammatory therapy is hydrocortisone, cortisone, etamethasone neb, prednisone, prednisolone, triamcinolone, dexamethasone, or fludrocortisone, or a combination thereof.

[0087] The subject may also have received or be prepared for other non-chemotherapy treatments, such as surgery, radiation, or bone marrow transplantation. In certain embodiments, the subject has previously received etoposide chemo-mobilization therapy. In certain embodiments, the subject has previously received a bone marrow transplantation. In certain embodiments, the subject has previously received a stem cell transplantation. In certain embodiments, the subject has previously received an autologous cell transplantation. In certain embodiments, the subject has previously received an allogeneic stem cell transplantation. In certain embodiments, the subject has previously received a hematopoietic cell transplantation. In certain embodiments, the subject has previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM conditioning). In certain embodiments, the subject has previously received a reintroduction therapy.

[0088] The subject may also have previously demonstrated a favorable outcome to previous therapy, requiring only additional treatment at a later date. In certain embodiments, the subject has previously achieved a partial response. In certain embodiments, the subject has previously achieved a good partial response. In certain embodiments, the subject has previously achieved a complete response. In certain embodiments, the cancer is recurrent. In certain embodiments, the cancer is refractory.

[0089] The subject may also have one or more existing or developed genetic mutations that render the subject's cancer more or less resistant to therapy. In certain embodiments, the subject has a mutation in RICTOR. In certain embodiments, the subject has an N1065S mutation in RICTOR. In certain embodiments, the subject has a mutation in MYD88. In a still more preferred embodiment, the subject has an L265P mutation in MYD88. In certain embodiments, the subject has a mutation in TET2. In certain embodiments, the subject does not have a mutation in CXCR4. In other embodiments, the subject has a mutation in CXCR4. In certain embodiments, the subject exhibits early progression. In certain embodiments, the subject has not previously received a BTK inhibitor.

[0090] In certain embodiments, after administration of the compound, the subject achieves a partial response. In certain embodiments, after administration of the compound, the subject achieves a favorable partial response. In other embodiments, after administration of the compound, the subject achieves a complete response. In certain embodiments, the subject achieves a partial response within 7 days after receiving the compound. In certain embodiments, the subject achieves a favorable partial response within 7 days after receiving the compound. In certain embodiments, the subject achieves a complete response within 7 days after receiving the compound. In certain embodiments, the tumor volume of the subject decreases by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In certain embodiments, the tumor volume of the subject decreases by 5%. In certain embodiments, the tumor volume of the subject decreases by 10%. In certain embodiments, the tumor volume of the subject decreases by 15%. In certain embodiments, the tumor volume of the subject decreases by 20%. In certain embodiments, the tumor volume of the subject decreases by 25%. In certain embodiments, the tumor volume of the subject decreases by 30%. In certain embodiments, the tumor volume of the subject decreases by 35%. In certain embodiments, the tumor volume of the subject decreases by 40%. In certain embodiments, the tumor volume of the subject decreases by 45%. In certain embodiments, the tumor volume of the subject decreases by 50%. In certain embodiments, the tumor volume of the subject decreases by 55%. In certain embodiments, the tumor volume of the subject decreases by 60%. In certain embodiments, the tumor volume of the subject decreases by 65%. In certain embodiments, the tumor volume of the subject decreases by 70%. In certain embodiments, the tumor volume of the subject decreases by 80%. In certain embodiments, the tumor volume of the subject decreases by 85%. In certain embodiments, the tumor volume of the subject decreases by 90%. In certain embodiments, the tumor volume of the subject decreases by 95%.

[0091] Method for performing immunohistochemical staining In certain embodiments of the methods of the present disclosure, the expression level of NF-κB p-p50 in a sample can be determined by immunohistochemical staining. Methods of performing immunohistochemical staining are generally known to those of skill in the art. Briefly, a tissue sample is contacted with an antibody specific for NF-κB p-p50 or NF-κB p-p65. After an incubation period, the tissue sample is contacted with a secondary antibody. The secondary antibody recognizes and binds to the primary antibody. The secondary antibody can contain a conjugated activity (e.g., enzymatic activity) that is used to detect the presence of the secondary antibody, and thus the primary antibody, and thus the presence of NF-κB p-p50 or NF-κB p-p65. Examples of conjugated activities can be any that are known to those of skill in the art to be useful for creating a detectable immunohistochemical signal. Suitable conjugated enzymes for the secondary antibody can include, for example, horseradish peroxidase (HRP), alkaline phosphatase, glucose oxidase, and β-galactosidase, and fluorescent probes, radioisotopes, chemiluminescent compounds, bioluminescent compounds, or combinations thereof are also contemplated.

[0092] In certain embodiments, the antibody specific for NF-κB p-p50 or NF-κB p-p65 is a commercially available NF-κB p-p50 antibody. In certain embodiments, the antibody specific for NF-κB p-p50 or NF-κB p-p65 is a polyclonal antibody. In certain embodiments, the antibody specific for NF-κB p-p50 or NF-κB p-p65 is a monoclonal antibody. In certain embodiments, the antibody specific for NF-κB p-p50 or NF-κB p-p65 is a rabbit antibody. In certain embodiments, the NF-κB p-p50 specific antibody is phospho-p50 NF-kappa B (Ser337) (sc-271908) Ab (supplied by Santa Cruz Biotechnology). In certain embodiments, the NF-κB p-p65 specific antibody is phospho-p65 NF-kappa B (Ser536) (ab86299) Ab (supplied by Abcam). In certain embodiments, the NF-κB p-p65 specific antibody is phospho-p65 NF-kappa B (Ser276) (ab194726) Ab (supplied by Abcam).

[0093] In certain embodiments, the secondary antibody is commercially available. In certain embodiments, the secondary antibody is a goat anti-rabbit immunoglobulin conjugated with a peroxidase-labeled polymer (such as that included in the EnVision+ System-HRP kit (DAKO, Carpinteria, CA)).

[0094] In the method of the present disclosure, after the level of expression of NF-κB p-p50 or NF-κB p-p65 in a tissue sample is determined, the level is compared with the expression level of NF-κB p-p50 in a reference sample. In certain embodiments, the reference sample has the same or equivalent tissue type as the tissue sample, but the expression level of NF-κB p-p50 or NF-κB p-p65 is normal, or it is known that NF-κB p-p50 or NF-κB p-p65 is not expressed. In certain embodiments, the reference sample is normal tissue or non-affected tissue collected from an individual or population of individuals known to have the same tissue type as the tissue sample and whose expression level of NF-κB p-p50 or NF-κB p-p65 is normal or indicates that NF-κB p-p50 or NF-κB p-p65 is not expressed. In certain embodiments, the reference sample has the same or equivalent tissue type as the tissue sample and is normal tissue or non-affected tissue collected from the same individual as the tissue sample. In certain embodiments, the reference sample includes a normal cell subpopulation or non-affected cell subpopulation in the tissue sample. In certain embodiments, the reference sample is a plurality of cells or tissues that do not exhibit a phenotype with an increased expression level of NF-κB p-p50 or NF-κB p-p65.

[0095] An increase in the expression level would be detected when the expression level of NF-κB p-p50 or NF-κB p-p65 in the tissue sample is higher compared to the expression level of NF-κB p-p50 or NF-κB p-p65 in the reference sample. Positive expression of NF-κB p-p50 or NF-κB p-p65 can be defined as more than 50% of the cancer cells being cytoplasmically and / or nuclearly positively stained.

[0096] In the immunohistochemical staining method of the present disclosure, a biological sample is obtained. The biological sample can be any tissue specimen or any collection of cells derived from tissue. The biological sample can be derived from any animal or human. In certain embodiments, the biological sample is of human origin. In other embodiments, the biological sample is of animal origin.

[0097] In the immunohistochemical staining method of the present disclosure, a biological sample is contacted with a primary antibody specific for NF-κB p-p50 or NF-κB p-p65 to obtain a primary antibody contacted biological sample. The primary antibody is specific for NF-κB p-p50, which means that this antibody selectively binds to NF-κB p-p50 or NF-κB p-p65. In certain embodiments, the primary antibody is a polyclonal antibody. In certain embodiments, the primary antibody is a monoclonal antibody. In certain embodiments, the primary antibody is a rabbit polyclonal antibody. In certain embodiments, the primary antibody is a rabbit monoclonal antibody.

[0098] In the immunohistochemical staining method of the present disclosure, the primary antibody contacted biological sample is contacted with a secondary antibody specific for the primary antibody, and the secondary antibody also has complexed activity. The secondary antibody must selectively bind to the primary antibody. The secondary antibody can be derived from the same species as the primary antibody or from a different species than the primary antibody. The secondary antibody can be a polyclonal antibody or a monoclonal antibody.

[0099] The secondary antibody also has complexed activity, and this activity can be enzyme activity. In certain embodiments, the enzyme activity is the intrinsic activity of the secondary antibody. In other embodiments, the enzyme activity of the secondary antibody is provided by an enzyme complexed with the antibody.

[0100] In certain embodiments, the enzyme activity of the secondary antibody is peroxidase activity. In other embodiments, the enzyme activity of the secondary antibody is alkaline phosphatase activity. Examples of complexed enzyme activities can be any that are known to those skilled in the art to be useful for creating a detectable immunohistochemical signal, and such include, for example, horseradish peroxidase (HRP), alkaline phosphatase, glucose oxidase, and β-galactosidase. Other immunohistochemical signals are also contemplated, and such include, for example, fluorescent probes, radioisotopes, chemiluminescent compounds, bioluminescent compounds, or combinations thereof.

[0101] In the immunohistochemical staining method of the present disclosure, the product obtained by contacting a primary antibody-bound biological sample with a secondary antibody is a biological sample in which the primary antibody is bound and the secondary antibody is bound to this primary antibody. In the method of the present disclosure, this product is contacted with a chromogenic substrate for the enzyme activity of the secondary antibody.

[0102] The chromogenic substrate for the enzyme activity of the secondary antibody is a compound that changes color when reacting with the enzyme activity of the secondary antibody. In certain embodiments, the chromogenic substrate is diaminobenzidine (DAB). In other embodiments, the chromogenic substrate is 3-amino-9-ethylcarbazole (AEC). In other embodiments, the chromogenic substrate is 5-bromo-4-chloro-3-indolyl phosphate / tetranitroblue tetrazolium (BCIP / TNBT). In still other embodiments, the chromogenic substrate is naphthol AS-MX phosphate + Fast Blue BB.

[0103] After treating the sample with the chromogenic substrate, the product is counterstained for a certain period. Any counterstaining that sufficiently brings out the contrast of the color of the chromogenic substrate can be used. Several different counterstains are known to those skilled in the art, and these include, for example, methyl green and hematoxylin.

[0104] In certain embodiments, the product is then counterstained for up to 1 minute. In certain embodiments, the product is counterstained for up to 10 seconds.

[0105] In certain embodiments, the counterstain is hematoxylin. Methods of using hematoxylin are known to those skilled in the art. See, for example, Godwin Avwioro, Histochemical uses of Haematoxylin - A Review, JPCS Vol.1, April - June 2011, 24 - 34. The concentration of hematoxylin is generally about 1 g / L to about 2 g / L.

[0106] Pharmaceutical composition The compositions and methods of the present invention can be utilized to treat an individual in need of treatment. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal such as a human, the composition or compound is preferably administered as a pharmaceutical composition, for example, comprising a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents, vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such a pharmaceutical composition is for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to effect delayed release of the drug or to selectively target one or more cells, tissues, or organs. Pharmaceutical compositions can be in unit dosage forms such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized agents for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system, for example, within a skin patch. The composition can also be present in a solution suitable for topical administration such as a lotion, cream, or ointment.

[0107] A pharmaceutically acceptable carrier can include, for example, a physiologically acceptable agent that acts to stabilize a compound such as a compound of the present invention, increase its solubility, or increase its absorption. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier that includes a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymeric matrix, for example, into which a compound of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and are relatively easy to manufacture and administer.

[0108] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problems and complications, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0109] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers are as follows: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0110] The pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration, including, for example, oral (e.g., as an aqueous or non-aqueous solution or suspension, such as a syrup, tablet, capsule (including sprinkle capsules and gelatin capsules), bolus, powder, granule, paste for application to the tongue), absorption through the oral mucosa (e.g., sublingual), subcutaneous, transdermal (e.g., as a patch applied to the skin), and topical (e.g., as a cream, ointment, or spray applied to the skin). The compounds can also be prepared for inhalation. In certain embodiments, the compounds can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and suitable compositions therefor can be found, for example, in U.S. Pat. Nos. 6,110,973; 5,763,493; 5,731,000; 5,541,231; 5,427,798; 5,358,970; and 4,172,896, and the patents cited therein.

[0111] The formulations can be conveniently presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent of the active ingredient.

[0112] Methods for preparing these formulations or compositions include the step of bringing together an active compound, such as a compound of the invention, with a carrier and, optionally, one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing together the compound of the invention with a liquid carrier or a finely divided solid carrier, or both, and then, optionally, shaping the product.

[0113] The pharmaceutical formulations of the present invention suitable for oral administration can be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavoring base, usually sucrose and acacia or tragacanth), lyophilized agents, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or water-in-oil or oil-in-water emulsions, or pastilles or syrups, or troches (using an inert base, for example, gelatin and glycerin, or sucrose and acacia), and / or in the form of oral rinses, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The composition or compound can also be administered as a bolus, pastille or paste.

[0114] To prepare solid dosage forms for oral administration (including capsule forms (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid, (2) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, (3) humectants such as glycerol, (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) dissolution retardants such as paraffin, (6) absorption promoters such as quaternary ammonium compounds, (7) wetting agents such as cetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, (10) complexing agents such as modified and unmodified cyclodextrins, and (11) coloring agents. In the case of capsule forms (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also contain a buffering agent. Solid compositions of the same type can also be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol.

[0115] Tablets can be made by compression or molding, optionally using one or more auxiliary components. Compressed tablets can be prepared using binders (such as gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersing agents. Wet tablets can be made by shaping a mixture of powdered compounds moistened with an inert liquid diluent using a suitable machine.

[0116] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, can be prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulation art, optionally scored or scored. They can also be prepared to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres in various ratios to provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0117] Liquid dosage forms useful for oral administration include pharma- ceutically acceptable emulsions, lyophilized agents for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor oil, sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0118] In addition to the inert diluent, the oral composition can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents and preservatives.

[0119] The suspending agent can contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxyaluminum, bentonite, agar and tragacanth, and mixtures thereof.

[0120] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed, under aseptic conditions, with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required.

[0121] Ointments, pastes, creams and gels can contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0122] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0123] The transdermal patch has the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Penetration enhancers can also be used to increase the flow of the compound across the skin. The rate of such flow rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0124] As used herein, the terms “parenteral administration” and “administered parenterally” mean modes of administration other than enteral and topical administration by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intrathecal, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration include one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that may be reconstituted into sterile injectable solutions or dispersions immediately prior to use, containing antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents, and one or more active compounds in combination with a sterile powder.

[0125] Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the particle size required in the case of dispersions, and by the use of surfactants.

[0126] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenolsorbic acid and the like. It may also be desirable to include in the composition isotonic agents such as sugars, sodium chloride and the like. Furthermore, sustained absorption of injectable dosage forms can be brought about by including agents that delay absorption such as aluminum monostearate and gelatin.

[0127] In some cases, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection in order to maintain the effect of the drug. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. Next, the absorption rate of the drug depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of parenterally administered drug forms is achieved by dissolving or suspending the drug in an oily vehicle.

[0128] Injectable depot forms are prepared by forming a microencapsulation matrix of the target compound with a biodegradable polymer such as polylactide - polyglycolide. Depending on the ratio of the drug to the polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0129] For use in the method of the present invention, the active compound can be provided as a pharmaceutical composition containing from 0.1 to 99.5% (more preferably from 0.5 to 90%) of the active ingredient, either by itself or in combination with, for example, a pharmaceutically acceptable carrier.

[0130] The method of introduction can also be provided by a replenishable or biodegradable device. For the controlled delivery of drugs, including proteinaceous biopharmaceuticals, various sustained-release polymeric devices have been developed and tested in vivo in recent years. Implants for the sustained release of compounds at specific target sites can be formed using a variety of biocompatible polymers (including hydrogels), including both biodegradable and non-biodegradable polymers.

[0131] The actual dosage level of the active ingredient in the pharmaceutical composition can be varied so that an amount of the active ingredient effective to achieve a therapeutic response for a particular patient, the composition, and mode of administration is obtained without causing toxicity to the patient.

[0132] The selected dosage level depends on a variety of factors including, for example, the activity of the specific compound or combination of compounds being used, or their esters, salts or amides, the route of administration, the time of administration, the rate of excretion of the specific compound being used, the duration of the treatment, other drugs, compounds and / or substances being used in combination with the specific compound being used, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and other factors well known in the medical arts.

[0133] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe a therapeutically effective amount of the pharmaceutical composition. For example, a physician or veterinarian can initiate the dosage of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. "Therapeutically effective amount" means a concentration of the compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary depending on the weight, sex, age, and medical history of the subject. Other factors that can affect the effective amount include the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered in combination with the compounds of the present invention, but are not limited thereto. By multiple administrations of the agent, a number of total dosages can be delivered. Methods for determining efficacy and dosage are known to those of ordinary skill in the art (see Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13th ed., 1814 - 1882, incorporated herein by reference).

[0134] In general, an appropriate daily amount of the active compound used in the compositions and methods of the present invention is the amount of the compound that is the lowest dosage effective to produce a therapeutic effect. Such effective amount generally depends on the factors described above.

[0135] Optionally, the effective daily amount of the active compound can be administered as 1, 2, 3, 4, 5, 6 or more sub - doses, which are optionally in unit dosage forms, separately at appropriate intervals throughout the day. In certain embodiments of the invention, the active compound can be administered 2 or 3 times a day. In a preferred embodiment, the active compound is administered once a day.

[0136] The patient to be treated is any animal in need of treatment, including primates, particularly humans; and other mammals, such as horses, cows, pigs, sheep, cats, and dogs; poultry; and common pets.

[0137] In certain embodiments, the compounds of the invention can be used alone or co-administered with another type of therapeutic agent.

[0138] The present disclosure includes the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benethamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, the salts contemplated by the present invention include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hypophosphoric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0139] Pharmaceutically acceptable acid addition salts can also exist as various solvates with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvates can be from the crystallization solvent, inherent to the preparation or crystallization solvent, or exogenous to such solvents.

[0140] Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition.

[0141] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0142] Definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by a person of ordinary skill in the art. In general, the nomenclature and techniques related to chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are well-known and commonly used in the art.

[0143] The methods and techniques of the present disclosure are generally carried out according to conventional methods described in various general and more specific references cited and considered throughout this specification, unless otherwise indicated, and are well known in the art. See, for example, "Principles of Neural Science", McGraw-Hill Medical, New York, N.Y. (2000), Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", W.H. Freeman & Co., New York (2000), Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", W.H. Freeman & Co., N.Y. (1999), and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0144] Chemical terms used herein are used according to the customary usage in the art, unless otherwise defined, which is exemplified by "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0145] All of the above, and any other publications, patents, and published patent applications mentioned in this application, are specifically incorporated herein by reference. In case of conflict, the present specification, including specific definitions, will control.

[0146] As used herein, the term "agent" refers to a compound (organic or inorganic compound, mixture of compounds, etc.), a biological macromolecule (nucleic acid, antibody, a portion thereof, and humanized, chimeric and human antibodies and monoclonal antibodies, protein or a portion thereof, e.g., peptide, lipid, carbohydrate), or an extract made from biological materials such as cells or tissues of bacteria, plants, fungi, or animals (especially mammals). Agents include, for example, agents with known structure and agents with unknown structure. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as "therapeutic agents" in the methods and compositions of the present disclosure.

[0147] The terms "patient", "subject", or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock (including cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice, rats).

[0148] "Treating" a condition or a patient refers to taking measures to obtain a beneficial or desirable result, including clinical outcomes. Beneficial or desirable clinical outcomes can include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, whether detectable or undetectable, reduction in the degree of a disease, stable (i.e., non-worsening) state of a disease, prevention of disease spread, delay or slowing of disease progression, improvement or temporary alleviation of a medical condition, and remission (partial or complete remission). "Treatment" may also mean prolonging survival as compared to expected survival in the absence of treatment.

[0149] The term "prevent" is recognized in the art and, when used in connection with a condition such as local recurrence (e.g., pain), a disease such as cancer, a syndrome such as heart failure, or any other medical condition, is well understood in the art to include administration of a composition that reduces the frequency of symptoms of the condition or delays the onset of the condition in a subject as compared to a subject not receiving the composition. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment as compared to an untreated control population and / or delaying the appearance of detectable cancerous growths in a treated population relative to an untreated control population by a statistically and / or clinically significant amount.

[0150] "Administering" or "administration" of a substance, compound or agent to a subject can be effected using one of a variety of methods known in the art. For example, a compound or agent can be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ophthalmically, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracranially, and transdermally (by absorption, e.g., through a skin patch). A compound or agent can also be suitably introduced by a depot or biodegradable polymer device or other device, such as a patch and a pump, or a formulation that provides for sustained, slow release or controlled release of the compound or agent. Administration can also be effected, for example, once, a plurality of times, and / or over an extended period of time for one or more periods.

[0151] The appropriate method of administering a substance, compound or agent to a subject also depends, for example, on the age and / or physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In certain embodiments, a compound or agent is administered to the subject orally, e.g., by ingestion. In certain embodiments, an orally administered compound or agent is a sustained release or slow release formulation or is administered using a device for such sustained or slow release.

[0152] As used herein, the phrase "co - administration" refers to the administration in any form of two or more different therapeutic agents such that a second agent is administered while a previously administered therapeutic agent is still active in the body (e.g., the two agents are effective simultaneously in a patient and a synergistic effect of the two agents may be included). For example, different therapeutic compounds can be administered simultaneously or sequentially, in the same formulation or in separate formulations. Thus, an individual undergoing such treatment can benefit from the combined effects of different therapeutic agents.

[0153] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is the amount of the drug or agent that has the intended therapeutic effect when administered to a subject. A complete therapeutic effect does not necessarily occur upon a single administration and may occur only after a series of administrations. Thus, a therapeutically effective amount can be administered in one or more administrations. The exact effective amount required for a subject depends, for example, on the size, health and age of the subject, and the nature and extent of the condition being treated such as cancer or MDS. One of ordinary skill in the art can readily determine the effective amount for a given situation by routine experimentation.

[0154] As used herein, the term "optionally" or "optionally selected" means that the event or situation described hereinafter may or may not occur, and the description includes both the case where the event or situation occurs and the case where it does not occur. For example, "optionally substituted alkyl" refers to the case where the alkyl may be substituted as well as the case where the alkyl is not substituted.

[0155] It will be understood that those skilled in the art can select substituents and substitution patterns for the compounds of the present invention such that chemically stable compounds can be readily synthesized from readily available starting materials by techniques known in the art as well as by the methods described hereinafter. When a substituent itself is substituted with a plurality of groups, it will be understood that such a plurality of groups can be present on the same carbon or on different carbons as long as a stable structure results.

[0156] As used herein, the term "optionally substituted" refers to one to six hydrogen radicals in a given structure being replaced by radicals of specific substituents, and such substituents include, but are not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH 2 -O-alkyl, -OP(O)(O-alkyl) 2 or -CH 2 -OP(O)(O-alkyl) 2 is included. Preferably, "optionally substituted" refers to one to four hydrogen radicals in a given structure being replaced by the above-mentioned substituents. More preferably, one to three hydrogen radicals are replaced by the above-mentioned substituents. It will be understood that the substituents may be further substituted.

[0157] As used herein, the term "alkyl" refers to a saturated aliphatic group, and such saturated aliphatic groups include, but are not limited to, C 1 -C 10 linear alkyl groups or C 1 -C 10 branched-chain alkyl groups are included. Preferably, the "alkyl" group refers to a C 1 -C 6 linear alkyl group or a C 1 -C 6 branched-chain alkyl group. Most preferably, the "alkyl" group refers to a C 1 -C 4 linear alkyl group or a C 1 -C 4 branched-chain alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl, and the like. The "alkyl" group may be optionally substituted.

[0158] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0159] The term "acylamino" is recognized in the art and refers to an amino group substituted with an acyl group and can be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0160] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0161] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0162] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0163] The term "alkyl" refers to a saturated aliphatic group, and such saturated aliphatic groups include straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In a preferred embodiment, the straight-chain alkyl or branched-chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C for straight-chain 1-30 , C for branched-chain 3-30 ), and more preferably 20 or fewer carbon atoms.

[0164] Furthermore, as used throughout this specification, examples, and claims, the term "alkyl" is intended to include both unsubstituted alkyl groups and substituted alkyl groups, the latter of which refers to an alkyl moiety having substituents that replace one or more hydrogens on one or more carbons of the hydrocarbon backbone, and such alkyl moieties include haloalkyl groups (such as trifluoromethyl and 2,2,2-trifluoroethyl).

[0165] “C x-y ” or “C x -C y ” when used with a chemical moiety (such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy) is intended to include groups containing from x to y carbons in the chain. C 0 alkyl represents hydrogen when the group is at a terminal position and a bond when the group is internal. C 1-6 Alkyl groups, for example, contain from 1 to 6 carbon atoms in the chain.

[0166] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0167] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0168] As used herein, the term "amide" refers to

Chemical formula

[0169] The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted and substituted amines and their salts (e.g.,

Chem.

[0170] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0171] The term "aralkyl" as used herein refers to an alkyl group substituted with an aryl group.

[0172] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of these rings being aromatic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0173] The term "carbamate" is recognized in the art,

Chem.

[0174] As used herein, the term "carbocyclic alkyl" refers to an alkyl group substituted with a carbocyclic group.

[0175] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. A carbocycle includes bicyclic molecules in which one, two, three, or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocycle can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. In one exemplary embodiment, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Combinations of saturated bicyclic rings, unsaturated bicyclic rings, and aromatic bicyclic rings are all included in the definition of carbocyclic as long as the valences permit. Examples of "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Examples of fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" can be substituted at any one or more positions where a hydrogen atom can be present.

[0176] As used herein, the term "carbocyclic alkyl" refers to an alkyl group substituted with a carbocyclic group.

[0177] The term "carbonate" is recognized in the art and refers to the -OCO 2 - group.

[0178] As used herein, the term "carboxy" refers to a group represented by the formula -CO 2 H.

[0179] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of these rings being cycloalkyl, and substituents (e.g., R 100 ) are attached to the cycloalkyl ring. For example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.

[0180] As used herein, the term "ester" refers to a group of the formula -C(O)OR 9 , where R 9 represents a hydrocarbyl group.

[0181] As used herein, the term "ether" refers to a hydrocarbyl group linked through oxygen to another hydrocarbyl group. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers can include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0182] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo, and iodo.

[0183] As used herein, the terms "hetaralkyl" and "heteroalkyl" refer to an alkyl group substituted with a heteroaryl group.

[0184] The terms "heteroaryl" and "heteroaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, and the ring structures of such rings contain at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "heteroaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of these rings is heteroaromatic. For example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0185] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0186] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic group.

[0187] The terms "heterocyclyl", "heterocyclic", and "heterocyclic ring" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, and the ring structures of such rings contain at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic ring" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of these rings is heterocyclic. For example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like.

[0188] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom having no =O substituent or =S substituent, typically having at least one carbon-hydrogen bond and a primary carbon skeleton, but optionally containing heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for the purposes of this application, but substituents such as acetyl (having an =O substituent on the linking carbon) and ethoxy (linked through oxygen rather than carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0189] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0190] The term "lower", when used with a chemical moiety (such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy), means a group having 10 or fewer, preferably 6 or fewer, atoms in the substituent. "Lower alkyl" refers to, for example, an alkyl group having 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, an acyl substituent, acyloxy substituent, alkyl substituent, alkenyl substituent, alkynyl substituent, or alkoxy substituent as defined herein is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether used alone or in combination with other substituents (such as in the description of hydroxyalkyl and aralkyl, where, for example, atoms in the aryl group do not count towards the number of carbon atoms in the alkyl substituent).

[0191] The terms "polysicryl", "polysycle", and "polycyclic" refer to two or more rings (such as cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, for example, such rings are "fused rings". Each of the rings of the polycycle can be either substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0192] The term "sulfate" is recognized in the art and refers to the group -OSO 3 H or a pharmaceutically acceptable salt thereof.

[0193] The term "sulfonamide" is recognized in the art and

Chemical formula

[0194] The term "sulfoxide" is recognized in the art and refers to the -S(O)- group.

[0195] The term "sulfonate" is recognized in the art and refers to the SO 3 group of H or a pharmaceutically acceptable salt thereof.

[0196] The term "sulfone" is recognized in the art and refers to the -S(O) 2 - group.

[0197] The term "substituted" refers to a moiety having a substituent that replaces hydrogen on one or more carbons of a backbone. "Substituted" or "substituted with" is understood to include the implicit condition that such substitution is in accordance with the allowable bonding valences of the atoms being substituted and the substituents, and that the substitution results in a stable compound (i.e., one in which conversions such as rearrangement, cyclization, elimination, etc. do not occur spontaneously). As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compound substituents. Permissible substituents can be one or more and can be the same or different for a suitable organic compound. For the purposes of the present invention, a heteroatom (such as nitrogen) can have a hydrogen substituent and / or any of the permissible organic compound substituents described herein that satisfy the valence of the heteroatom. Substituents can include any of the substituents described herein, and such substituents can be, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. One of ordinary skill in the art will understand that a moiety substituted on a hydrocarbon chain can itself be substituted where appropriate.

[0198] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0199] As used herein, the term "thioester" refers to a group of -C(O)SR 9 or -SC(O)R 9 wherein, R 9 represents a hydrocarbyl.

[0200] As used herein, the term "thioether" is equivalent to an ether, with oxygen replaced by sulfur.

[0201] The term "urea" is recognized in the art, [Chemical formula] can be represented by the general formula wherein R 9 and R 10 each independently represents hydrogen or hydrocarbyl.

[0202] As used herein, the term "modulate" includes inhibiting or suppressing a function or activity (such as cell proliferation), as well as enhancing a function or activity.

[0203] The phrase "pharmaceutically acceptable" is recognized in the art. In certain embodiments, this term refers to compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without undue toxicity, irritation, allergic reaction, or other problems and complications, and that exhibit a reasonable benefit / risk ratio.

[0204] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to acid addition salts or basic addition salts that are suitable or compatible for the treatment of patients.

[0205] As used herein, the term "pharmaceutically acceptable acid addition salt" means any non-toxic organic or inorganic salt of any basic compound represented by Formula 1. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium hydrogen phosphate and potassium bisulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Either mono- or di-salts can be formed, and such salts can exist in any of the forms of hydrates, solvates, or substantially anhydrous forms. Generally, the acid addition salts of the compounds of Formula 1 are soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The selection of suitable salts is known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, can be used, for example, in the isolation of the compounds of Formula 1 for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0206] As used herein, the term "pharmaceutically acceptable basic addition salt" means any non-toxic organic or inorganic base addition salt of any acidic compound represented by either Formula 1 or their intermediates. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline or ammonia. The selection of suitable salts is known to those skilled in the art.

[0207] Many of the compounds useful in the methods and compositions of the present disclosure have at least one asymmetric center in their structure. This asymmetric center can exist in the R configuration or the S configuration, and the R and S notations are used in accordance with the rules described in Pure Appl. Chem. (1976), 45, 11 - 30. The present disclosure contemplates all stereoisomeric forms (such as enantiomeric and diastereomeric forms of the compounds, salts, prodrugs, or mixtures thereof), including all possible mixtures of stereoisomers. See, for example, WO01 / 062726.

[0208] Furthermore, certain compounds containing an alkenyl group can exist as the Z (zusammen) isomer or the E (entgegen) isomer. In each case, the present disclosure includes both the mixture and the separate individual isomers.

[0209] Some compounds can also exist in tautomeric forms. Such forms are not explicitly shown in the formulas described herein but are intended to be included within the scope of the present disclosure.

[0210] "Prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized (e.g., hydrolyzed or oxidized) in a host after administration to form a compound of the present disclosure (e.g., a compound of Formula I). Typical examples of prodrugs include compounds having a biologically labile or cleavable (protecting) group on a functional group of an active compound. Prodrugs include compounds that can undergo oxidation, reduction, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, retro-hydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation, or dephosphorylation to produce an active compound. Examples of prodrugs using esters or phosphoramidates as biologically labile or cleavable (protecting) groups are disclosed in U.S. Pat. Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope prodrugs of the compounds described herein. For ordinary procedures for selecting and preparing suitable prodrugs, see, for example, "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985.

[0211] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material useful in the preparation of a medicament or therapeutic agent.

[0212] As used herein, the terms "logarithm of solubility", "LogS", or "logS" are used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution characteristics. Poor solubility often results in inadequate absorption. The LogS value is the unit strip logarithm (base 10) of the solubility measured in mol / liter.

[0213] As used herein, the term "expression level" refers to the level and / or abundance of expression of an expression product in a sample. For example, the expression level of a protein can be measured by staining a tissue sample (e.g., a plurality of cells) and measuring the abundance (i.e., prevalence) and / or level of the protein spanning one or more cells (preferably, a plurality of cells) of the tissue or spanning the tissue sample as a whole.

Example

[0214] Here, the present invention will be generally described, but it will be more easily understood by referring to the following examples, which are included for illustrative purposes only of certain aspects and embodiments of the present invention and are not intended to limit the present invention.

[0215] Examples of methods and compounds related to the content of the present disclosure can be found, for example, in U.S. Patent Nos. 10 / 160,753, 09 / 732,095, 10 / 758,518, U.S. Patent Application Publication No. 20210290628, co-pending U.S. Patent Application No. 17 / 680,995, and PCT Application Nos. WO22 / 031330 and US21 / 59668, the contents of which are hereby incorporated by reference in their entirety into this specification.

[0216] Example 1: Examples of Antibodies of the Present Disclosure Table 1 describes examples of antibodies of the present disclosure, related procurement information, recommended dilution levels for use in the protocols of Examples 2 and 3, and findings regarding the expression patterns observed in certain embodiments of the present disclosure.

Table 1

[0217] Example 2: Examples of Methods for Determining the Expression of NF-κB p-p50 or NF-κB p-p65 Formalin-fixed paraffin-embedded sections of human tonsils and lymphomas were used. Tissue sections (5 μm) were deparaffinized and antigen retrieval was performed at 90 - 100 °C for 10 - 40 minutes in citrate buffer. The sections were incubated in 1% hydrogen peroxide for 10 minutes to block the activity of endogenous tissue peroxidase. Subsequently, the tissue sections were incubated with an NF-κB p-p50 specific primary antibody at 4 °C for approximately 16 hours. For the NF-κB p-p50 specific primary antibody, NF-κB p-p50 (S337), sc-271908 (supplied by Santa Cruz Biotechnology) was used.

[0218] Slides were stained using the standard EnVision+ System-HRP kit (DAKO, Carpinteria, CA) according to the manufacturer's protocol. Diaminobenzidine was used as the chromogenic peroxidase substrate to produce an immunohistochemical reaction, and the slides were counterstained with hematoxylin. In negative control samples, non-immune IgG1 (Dako) was used instead of the primary antibody.

[0219] Target molecule-specific staining with suppressed background staining was observed in human tonsil samples and lymphoma samples in a 1:100 dilution of NF-κB p-p50 Ab (Figure 12C). Specifically, nuclear and / or cytoplasmic expression of NF-kappa B p-p50 was seen in all six SD cases treated with 50 mg QD (2 cases, tumor regression), 50 mg BID (1 case), 200 BID (1 case, tumor regression), and 400 BID (2 cases). In seven of eight PD cases, including patients treated with 50 mg QD (1 case), 100 mg QD (1 case), 100 mg BID (3 cases), 200 mg BID (1 case), and 400 BID (1 case), expression of NF-kappa B p-p50 was not detected. A statistically significant correlation (p<0.05) was observed between the expression of NF-kappa B p-p50 in tumor biopsy samples from NHL patients treated with Compound 1 and SD. Analysis of NF-kappa B p-p50 expression in tumor biopsy sample pairs (3 cases) taken before and after treatment with Compound 1 revealed that NF-kappa B p-p50 expression in tumors obtained from NHL patients treated with Compound 1 was significantly downregulated. In in vitro experiments, expression of NF-kappa B p-p50 was demonstrated in 3D lymphoma organoids treated with a clinically relevant concentration of Compound 1. The results of the present inventors support further exploration of NF-kappa B p-p50 as a promising predictive pharmacodynamic biomarker for IRAK4 inhibitors.

[0220] In summary, the expression of NF-kappa B p-p50 may serve as a biomarker for predicting an SD response to treatment with an IRAK4-modifying compound in NHL patients. By using an NF-kappa B p-p50 selection strategy in future clinical trials, it may be possible to identify NHL patients most likely to benefit from treatment with an IRAK4-modifying compound in combination with chemotherapy or targeted therapy.

[0221] Example 3: Example of a single IHC staining protocol for the evaluation of antibody expression in FFPE (formalin-fixed paraffin-embedded) AML bone marrow clot samples The tissue sections were deparaffinized by repeating the process three times in xylene for 5 minutes each. The deparaffinized tissue sections were washed by repeating the process twice in 100% ethanol for 5 minutes each, and further washed in 95% ethanol for 5 minutes. The obtained sections were washed with tap water for 5 minutes. The washed tissue sections were incubated with Dual Endogenous Peroxidase Block (Dako Envision, K4065) for 10 minutes, followed by a second wash with tap water for 5 minutes.

[0222] The slides were placed in a container, covered with citrate buffer (Catalog number C9999 - 1000ML, Millipore Sigma), and heated in a microwave while maintaining an amount of citrate buffer sufficient to completely cover the slides. Subsequently, the slides were cooled in buffer at ambient temperature. The slides were washed by repeating the process three times in 1X wash buffer (Envision Flex wash buffer, Agilent, K800721 - 2) for 5 minutes each.

[0223] The slides were incubated overnight at 4°C in a humidified chamber with a primary antibody (selected from the antibodies listed in Table 1). The incubated slides containing the primary antibody were washed three times for 5 minutes each with a washing buffer. A labeled polymer-HRP solution (DAKO EnVision+ system-HRP) was applied to the slides, and the slides were incubated at room temperature for 30 minutes. The resulting slides were washed three times for 5 minutes each with phosphate-buffered saline. A substrate-color developing solution was prepared by mixing 1 mL of substrate buffer and 20 μL of liquid DAB+ chromogen (DAB+ = DAKO EnVision Dual Link System-HRP, catalog number K4065). The resulting substrate-color developing solution was applied to the prepared tissue sections for 5 minutes of staining. Thereafter, the slides were washed with tap water for 5 minutes to stop the staining. The washed slides were counterstained with freshly filtered Mayer's hematoxylin for 5 seconds, and the resulting slides were washed with tap water for 10 minutes. The slides were washed three times for 5 minutes each with 100% ethanol, placed in xylene for 5 seconds, and then mounted and covered with a glass coverslip.

[0224] Example 4: Performance of Compound 1 in WM The patient is a 49-year-old man who complains of severe fatigue but is otherwise healthy. Routine laboratory tests revealed a high erythrocyte sedimentation rate and significant anemia, and thus he was referred to hematology / oncology. Further detailed tests revealed IgM lambda m protein in serum protein electrophoresis, as well as multicellular bone marrow with trilineage hematopoiesis and atypical lymphoplasmacytic infiltration, which was consistent with WM. CT scan did not reveal lymph node enlargement or hepatosplenomegaly.

[0225] Due to symptomatic cytopenia and profound fatigue, treatment was recommended. The patient received rituximab induction 375 mg / m 2The patient received IV once a week for 8 weeks and then received rituximab maintenance every 3 months for 8 doses from 2005 to 2007, achieving a very good partial remission. The patient was well for about 4 years, but during that about 4-year period, the disease progressed, and the patient developed relapsing symptomatic anemia and new grade 1 peripheral sensory neuropathy including hands and feet. The patient was retreated with rituximab from June to September 2011. During this period, IgM increased numerically from 1476 to 2042 mg / dL, and a stable disease without symptom improvement was achieved. Repeat bone marrow biopsy in November 2011 showed 90% cellular marrow, WM accounting for 20% of the cellularity, IgM lambda plasma cells accounting for 5 - 10% of the cellularity, normal cytogenetics, no increase in reticulin staining, and slightly stainable iron. CT scan at that time showed no lymph node enlargement or organomegaly. By December 2012, the patient's serum IgM had increased to 3380 mg / dL and IgM lambda m protein was 2.37 g / dL. The patient was referred to a tertiary medical center for further management, and autologous stem cell transplantation following induction chemotherapy was recommended. In early 2013, the patient received 2 cycles of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBorD), with IgM decreasing to 1285 mg / dL and m protein decreasing to 0.88 g / dL, achieving a partial remission (PR). Then, the patient received rituximab, ifosfamide, etoposide mobilization, and stem cell collection in June 2013, after which IgM and m protein remained unchanged. Further cytoreduction before transplantation was performed using 2 cycles of bendamustine and rituximab (BR), leading to further partial response in the patient (IgM 454 mg / dL, m protein 0.30 g.dL).Subsequently, in October 2013, the patient received autologous stem cell transplantation without complications along with BEAM conditioning (carmustine, etoposide, cytarabine, melphalan). The post-transplant IgM nadir was 135 mg / dL, and the m protein became detectable by immunofixation only in January 2014, achieving a very good partial response (VGPR).

[0226] The patient remained asymptomatic for over 4 years, during which the m protein and IgM slowly increased. By mid-2017, the patient began to experience increased fatigue. Bone marrow evaluation in November 2017 revealed normal cell bone marrow with 30% involvement by WM and normal cell genetics. Next-generation sequencing revealed RICTOR N1065S mutations, as well as MYD88 L265P and TET2 mutations in the subclonal population. There was no evidence of CXCR4 genomic changes. By late 2018, the fatigue began to interfere with the patient's ability to perform normal activities, so treatment was recommended again. Several options were discussed, including clinical trials and standard treatment with Bruton's tyrosine kinase inhibitor (BTKi) therapy. Considering the patient's medical history, current symptoms, known mutational landscape, and personal preferences, the patient was enrolled in a phase 1 dose-escalation trial of compound 1, a novel oral IRAK4 inhibitor for patients with relapsed or refractory B-cell malignancies (NCT03328078).

[0227] The baseline tests in December 2018 included a bone marrow biopsy showing 5 - 10% involvement by WM, an m protein of 1.66 g / dL, an IgM of 2,801 mg / dL, and a computed tomography scan without pathological lymph node enlargement or hepatosplenomegaly. Quantitative immunoglobulins and serum protein electrophoresis were obtained in each cycle to determine the response to treatment (Figure 1).

[0228] The patient started treatment at an initial dose level of 50 mg. The patient was sufficiently tolerant to the treatment without adverse events. During the first six 21-day cycles, m-protein trended slowly but steadily downward to 1.55 g / dL, and IgM first increased from 2801 to 2866 mg / dL during the first two cycles and then decreased to 2639 by day 1 of cycle 6 (Figure 1). Using a standard 3+3 design, the subsequent dose level of 100 mg po BID was cleared protocol by protocol. Considering the evidence of response without notable toxicity, the patient became a candidate to escalate to 100 mg po BID starting on day 1 of cycle 7 in April 2019. The patient had a decreasing trend in IgM and m-protein during cycles 7 and 8, continued stable disease (SD) without evidence of toxicity, and thus became a candidate to escalate to the next defined dose level of 200 mg po BID starting on day 1 of cycle 9 in May 2019. Prior to the 200 mg BID dose escalation, the baseline IgM was 2245 mg / dL and the m-protein was 1.37 g / dL. The baseline symptom of fatigue improved slightly but persisted. The patient continued to enjoy an apparent dose-dependent decrease in tumor markers at the 200 mg po BID dose level, and by the summer of 2019, the fatigue had completely resolved. The patient reported a significant improvement in quality of life with the resolution of fatigue and returned to a rigorous daily exercise program that had not been possible for the past two years due to WM-related symptoms. In August 2019, the patient was found to have an asymptomatic grade 2 elevation of creatine phosphokinase (CPK) that did not become apparent on extensive laboratory and physical examinations. The patient decreased the intensity of the exercise program, and the asymptomatic CPK elevation resolved completely without the need to delay or reduce the dose of compound 1. During cycles 15-20, at the 200 mg po BID dose, the patient's IgM reached a plateau at approximately 1500 mg / dL and the m-protein reached a plateau at approximately 0.9 g / dL. Based on the development of safety data at higher dose levels, the patient escalated to 300 g po BID starting from cycle 20 in January 2020.The patient again experienced a seemingly dose-dependent response promoted without significant toxicity and achieved a PR at day 1 of C22 (m protein 0.68 g / dL, IgM 1241 mg / dL). The patient is maintaining compound 1 300 mg po BID.

[0229] Treatment in WM involves targeting pathways associated with known mutations in MYD88 and CXCR-4. Previous studies have shown the role of IRAK4 in the signaling cascade involved in the stimulatory effect of inflammatory cytokines by forming a complex with MYD88. Thus, IRAK4 is an essential component in regulating the immune response, and those with dysfunction in any part of the complex can lead to immunodeficiency or immunomodulatory deficiency. Adding an IRAK4 inhibitor forms a strong association between IRAK4 and MYD88 and a weak association with IRAK-1, thus ultimately resulting in a decrease in IL-1-induced signaling and cytokine production due to a decrease in the ubiquitination of IRAK1.

[0230] By inhibiting IRAK4, compound 1 prevents NF-kB activation, thereby resulting in a decrease in inflammatory cytokine production and potential anti-tumor, immunomodulatory, and anti-inflammatory effects. Preclinical studies also suggest that compound 1 affects TLR / IL1R signaling, which can prevent the inflammatory process in autoimmune conditions.

[0231] This patient has received well-tolerated continuous oral treatment with compound 1 for nearly 18 months. The patient's tumor mass decreased in a dose-dependent manner and reached a partial response (PR) according to the 6th International Workshop on WM response criteria (Figure 1). The patient's quality of life improved from baseline with resolution of fatigue, enabling even active physical activities that the patient enjoyed before the onset of the disease. However, this resulted in intermittent asymptomatic grade 2 CK elevation, which resolved with exercise moderation without the need to maintain or reduce compound 1 exposure.

[0232] Example 5: Performance of Compound 1 in DLBCL, FL, HGBL, WM, LPL, MZL, and MCL Test Design and Methods The Phase I trial of Compound 1 is a dose-escalation trial using a 3+3 design. The seven dosing cohorts included daily continuous oral monotherapy at 50 and 100 mg QD, and 50, 100, 200, 300, or 400 mg BID on a 21-day cycle. The objectives included safety and tolerability (primary), pk / pd and early efficacy (secondary), and biomarker correlation (exploratory). Thirty-one patients with relapsed or refractory progressive NHL were enrolled. Details of the patient population are shown in Table 2 below. [Table 2]

[0233] Results Compound 1 showed good tolerability. Eight patients were exposed to a maximum dose level of 400 mg BID: two out of five evaluable patients for DLT had grade 3 rhabdomyolysis (DLT), without complications and reversibility after treatment interruption and hydration / analgesic treatment (subsequently, both continued treatment at lower doses of 200 or 300 mg BID, respectively). Six patients were well tolerated at 300 mg BID without DLT. Most non-hematological TEAEs were grade 1 or 2 and manageable, including diarrhea, vomiting, fatigue, dyspnea, and myalgia. Mild / moderate neutropenia, anemia, thrombocytopenia; at dose levels in the range of 200 - 400 mg BID, there were only four grade 3 episode combinations in 18 patients without complications (Table 3). No toxic deaths. Pharmacokinetics showed favorable characteristics with increasing exposure proportional to the dose. Similar pharmacodynamic changes were shown in cytokine reduction. The treatment duration ranged from less than 1 month to 18 months +, and disease control was sustained. Eight out of 28 evaluable patients experienced a reduction in total tumor volume of 20% or more from baseline (more at higher doses) (Table 5). WM patients with sustained PR received dose escalation within the patient and had a dose / response relationship and very good treatment tolerability (Figure 20). It shows molecular characteristics including pharmacodynamic markers downstream of IRAK4 and progenitor cells. [Table 3] [Table 4] [Table 5]

[0234] In summary, Compound 1 showed good safety and tolerability, desirable pharmacokinetic properties, and preliminary clinical activity.

[0235] Example 6: Performance of Compound 1 in AML and MDS Study Design and Methods This is a single-arm dose-escalation Phase 1 trial of orally administered Compound 1 monotherapy in adult patients with AML or high-risk MDS (NCT04278768). This trial is conducted in two parts: an initial dose-escalation and a dose-expansion phase. The starting dose level is 200 mg BID, which was determined to be safe and was able to achieve relevant levels of drug exposure and show signs of biological activity and clinical efficacy in the NHL trial. Three patients with AML or MDS are enrolled at the designated dose. If none of the first three patients experience a DLT during the first cycle, the patients may be enrolled at the next higher dose level of 300 mg BID until a safe and effective RP2D is established.

[0236] This trial is expected to enroll approximately 18 patients to establish the initial RP2D. The safety population includes all patients in the trial who received any dose of Compound 1, and the efficacy population includes patients who had a valid baseline and post-baseline disease assessment and received at least one dose of the investigational drug. Each treatment cycle of Compound 1 is 28 days in length and is repeated in the absence of toxicity or disease progression.

[0237] The main trial inclusion and exclusion criteria are as follows: Relapsed or refractory AML (primary or secondary, including treatment-related) after at least one standard treatment (including chemotherapy, reintroduction therapy, or stem cell transplantation) based on the assessment of the treating physician after at least 6 cycles of hypomethylating agent [HMA] or evidence of early progression or assessment of high-risk / very high-risk relapsed / refractory MDS (IPSS-R criteria). Patients diagnosed with acute promyelocytic leukemia (APL, M3), blast crisis of CML, allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of Compound 1, or clinically significant graft-versus-host disease (GVHD) that requires continuous escalation of immunosuppressive drugs prior to the start of Compound 1 are excluded.

[0238] The primary objective is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of Compound 1 in patients with AML and high-risk MDS based on safety and tolerability, DLT, and PK / PD findings.

[0239] Results All initial patients completed Cycle 1 with myeloblast reduction, including some complete myeloid responses. Cohort 1 (200 mg BID, cycle duration 4 weeks) Three patients with hr-MDS, all on treatment (currently 2 - 4 cycles). No DLT in Cycle 1. One dose reduction for Grade 3 dizziness at C2. Cohort 2 (300 mg BID) Four patients (3 with AML, 1 with hr-MDS), all on treatment (currently 1 - 2 cycles). No DLT in the first 3 patients. Cohort 3 open (400 mg BID) Open for enrollment.

[0240] Example 7: Performance of Compound 1 in relapsed or refractory hematological malignancies Study design and methods This is a study of Compound 1 administered orally in combination with ibrutinib in adult patients with relapsed or refractory hematologic malignancies (NCT03328078). It has two parts: an initial dose escalation phase (Part A2) and an expansion part with four cohorts. In a 3x3 dose escalation design, the starting oral dose of Compound 1 is 200 mg BID and is administered daily. Concurrently, patients receive ibrutinib at a labeled dose (560 mg or 420 mg) for each NHL subtype daily. If tolerance is good, the dose of Compound 1 is escalated to 300 mg BID. Objectives include safety / tolerance, pharmacokinetics, preliminary efficacy assessment, and exploratory biomarker correlation. Once the recommended Phase 2 dose (RP2D) for the combination dose is determined, the expansion phase (Part B) evaluates the efficacy (CR / ORR rate / duration), safety / tolerance, population PK, and biomarker correlation of the combination of Compound 1 and ibrutinib. Part B includes four cohorts including 1-MZL, 2-DLBCL, 3-CNSL, and 4-NHL with ibrutinib-adapted resistance (basket design).

[0241] Cohorts 1-3 must be naive to BTK inhibitors. The latter population has received ibrutinib monotherapy and responded (no primary resistance). When a patient develops adaptive secondary resistance and shows tumor progression, the combination of ibrutinib and Compound 1 is administered. (Ibrutinib treatment with a short interval of less than 3 weeks is acceptable.) This cohort includes patients with ibrutinib approval or NCCN-recommended indications: MCL, MZL, CLL / SLL, WM / LPL, PCNSL (listed in NCCN).

[0242] Primary objectives: Identification of a preliminary efficacy signal of improved objective response in Cohorts 1-3 compared to past data, and demonstration of reversal of resistance in Cohort 4 by showing an objective response after prior progression.

[0243] The estimated sample size of up to approximately 18 patients in Part A2 is based on the standard 3+3 trial design for dose escalation. The exact number of patients is determined by the number of cohorts required to establish the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) for Compound 1 when administered in combination with ibrutinib. For dose expansion in Part B, up to 46 patients are enrolled in each of the 4 NHL cohorts. The safety population includes all patients in the trials who received any dose of Compound 1 in combination with ibrutinib, and the efficacy population includes patients who had a valid baseline and post-baseline disease assessment and received at least 1 dose of the combination study drug. Safety observations and measurements include drug exposure, AEs, safety clinical laboratory tests, vital signs, physical examinations, ECGs, and ECOG performance status. Each treatment cycle of Compound 1 is 21 days in length and is repeated in the absence of toxicity or tumor progression, and ibrutinib is administered according to the label.

[0244] The primary trial inclusion and exclusion criteria for Part A2 of the combination therapy dose escalation are as follows: Histopathologically confirmed diagnosis of B-cell NHL according to the WHO 2016 classification. Eligible NHL subtypes include follicular lymphoma, MZL, mantle cell lymphoma, DLBCL (including leg, testicular, or unspecified nodal extranodal lymphoma), CLL / SLL, primary or secondary CNS lymphoma, and Waldenström macroglobulinemia / LPL. Patients with mantle cell lymphoma, MZL, WM / LPL, or CLL / SLL must meet the clinical criteria for the required treatment of their disease. Patients with acute or chronic toxicity from prior anticancer therapy, excluding alopecia, that has not resolved to grade 1 or less as determined by NCI CTCAE v4.03 within 7 days prior to trial start are excluded.

[0245] The trial treatment endpoint is to determine the safety, tolerability, DLT, MTD, and RP2D of oral compound 1 in combination with ibrutinib, and the secondary endpoint is to evaluate the objective response rate (ORR), duration response rate (DOR), DCR, PFS, and OS after treatment with compound 1 in combination with ibrutinib.

[0246] Example 8: Performance of Compound 1 in Autoimmune Diseases Compound 1 is administered to subjects suffering from an autoimmune condition (e.g., graft-versus-host disease) in a dose escalation study starting at 50 mg. The efficacy of compound 1 is determined by methods known to those of skill in the art.

[0247] Example 9: Treatment Examples of OCL-LY10 Cells and TF-1 Cells with Compound 1 OCL-LY10 cells and TF-1 cells were treated with different concentrations of 3 μM and 10 μM of compound 1. Cell lysates were obtained at 48 hours after treatment. Protein sample concentrations were quantified, and total protein extracts adjusted to 20 μg in amount were loaded into each well of an SDS-polyacrylamide gel. Cell extracts were separated by 10% SDS-PAGE, transferred to a nitrocellulose membrane, and probed as indicated. The following antibodies were used for immunoblot analysis: NF-kB p-p50 S337 (Santa Cruz Biotechnology) and β-actin (Cell Signaling Technology). In the OCL-Ly10 cell line and TF-1 cell line treated with compound 1, the expression of NF-kB p-p50 S337 was downregulated.

[0248] Incorporation by Reference All publications and patents mentioned in this specification are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In case of conflict, this application, including the definitions herein, will control.

[0249] Equivalents Particular embodiments of the subject disclosure have been discussed, but the above specification is exemplary and not limiting. Upon consideration of this specification and the following claims, many variations of this disclosure will become apparent to those skilled in the art. The full scope of this disclosure should be determined by reference to the claims, along with the full scope of equivalents, and the specification together with such variations.

Claims

1. A pharmaceutical composition for use in the treatment of a disease or disorder, comprising an IRAK4 inhibitor or an IRAK4 degrading agent, The pharmaceutical composition is for administration to a subject identified as expressing at least one of IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, or MYD88 in its cells.

2. The pharmaceutical composition according to claim 1, wherein IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, or MYD88 is expressed in the target cell nucleus.

3. The pharmaceutical composition according to claim 1, wherein IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, or MYD88 is expressed in the cytoplasm of the target.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for administration to the subject only when the amount of IRAK4, NF-κB p-p65, NF-κB p-p50, p-IRAK1, FLT3, or MYD88 is greater than the reference expression level.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for co-administration with a BCL-2 inhibitor.

6. The pharmaceutical composition according to claim 5, wherein the BCL-2 inhibitor is venetoclax.

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for co-administration with a BTK inhibitor.

8. The pharmaceutical composition according to claim 7, wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebratinib, or HM7 1224.

9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for co-administration with a PD-1 inhibitor or a PD-L1 inhibitor.

10. The pharmaceutical composition according to claim 1, wherein the disease or disorder is cancer.

11. The cancer is non-Hodgkin lymphoma, leukemia, lymphoma, myeloid leukemia, myeloid leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), ABC-DLBLC, mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM) The pharmaceutical composition according to claim 10, which is a hematological malignancy selected from multiple myeloma, marginal zone lymphoma (MZL), Burkitt lymphoma, non-Burkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, transformed high-grade B-cell lymphoma (HGBL), lymphoplasmacytic lymphoma (LPL), central nervous system lymphoma (CNSL), primary central nervous system lymphoma (PCNSL), and MALT lymphoma.

12. The pharmaceutical composition according to claim 10, wherein the cancer is selected from brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, gastric cancer, breast cancer, bladder cancer, colon cancer, pancreatic cancer, lung cancer, cervical cancer, epidermal cancer, prostate cancer, or head and neck cancer.

13. The pharmaceutical composition according to claim 10, wherein the cancer is a solid tumor.

14. The pharmaceutical composition according to claim 10, wherein the cells are cancer cells.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition comprises an IRAK4 inhibitor.

16. The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition comprises an IRAK4 degrading agent.

17. The aforementioned IRAK4 inhibitor has formula I: 【Chemistry 1】 Or, the pharmaceutically acceptable salt Represented by, During the ceremony, X １ and X ３ However, independently, it is CH or N, and X ２ However, CR ２ Or N, however X １ , X ２ , or X ３ Only one of them is N, A is either O or S, Y is -CH ２ - or O, Z is an aryl or heterocycline, R １ is, for each occurrence independently, halo or optionally substituted heterocyclyl, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR ａ R ｂ and is R ２ However, hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR ａ R ｂ The substituent is alkyl, amino, halo, or hydroxyl, R ３ However, depending on the presence, it is either alkyl or hydroxyl. R ａ and R ｂ However, independently, they are hydrogen, alkyl, acyl, or heterocyclyl. "m" and "n" are independently 0, 1, or 2. The pharmaceutical composition according to claim 15, wherein "p" is 0 or 1.

18. R1 is a heterocycline that is independently substituted with a halo or optionally substituted with each presence, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ And R ａ and R ｂ However, independently, they are hydrogen, alkyl, or heterocyclyl. R ２ However, hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR ａ R ｂ The pharmaceutical composition according to claim 17, wherein the substituent is selected from amino, halo, or hydroxyl.

19. The pharmaceutical composition according to claim 17, wherein Z is an aryl or a five-membered or six-membered heterocycline.

20. The aforementioned IRAK4 inhibitor is given by formula (IA): 【Chemistry 2】 The pharmaceutical composition according to claim 17, or represented by a pharmaceutically acceptable salt thereof.

21. R1 is a heterocycline that is independently substituted with a halo or optionally substituted with each presence, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ And R ａ and R ｂ However, independently, they are hydrogen, alkyl, or heterocyclyl. R ２ However, hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR ａ R ｂ The pharmaceutical composition according to claim 20, wherein the substituent is selected from amino, halo, or hydroxyl.

22. The aforementioned IRAK4 inhibitor is given by formula (IB): 【Transformation 3】 The pharmaceutical composition according to claim 17, or represented by a pharmaceutically acceptable salt thereof.

23. R1 is a heterocycline that is independently substituted with a halo or optionally substituted with each presence, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ And R ａ and R ｂ However, independently, they are hydrogen, alkyl, or heterocyclyl. R ２ However, hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR ａ R ｂ The pharmaceutical composition according to claim 22, wherein the substituent is selected from amino, halo, or hydroxyl.

24. The IRAK4 inhibitor is of formula (IC): 【Chemistry 4】 The pharmaceutical composition according to claim 17, or represented by a pharmaceutically acceptable salt thereof.

25. The aforementioned IRAK4 inhibitor Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 The pharmaceutical composition according to claim 17, selected from a pharmaceutically acceptable salt thereof.

26. The aforementioned IRAK4 inhibitor 【Transformation 5】 The pharmaceutical composition according to claim 17.

27. The aforementioned IRAK4 inhibitor 【Transformation 6】 The pharmaceutical composition according to claim 17, wherein the salt is pharmaceutically acceptable.

28. The IRAK4 inhibitor is 【Transformation 7】 The pharmaceutical composition according to claim 17.

29. The IRAK4 inhibitor is 【Transformation 8】 The pharmaceutical composition according to claim 17, wherein the salt is pharmaceutically acceptable.

30. The IRAK4 inhibitor is 【Chemistry 9】 The pharmaceutical composition according to claim 17.

31. The IRAK4 inhibitor is 【Chemistry 10】 The pharmaceutical composition according to claim 17, wherein the salt is pharmaceutically acceptable.

32. The IRAK4 inhibitor is 【Chemistry 11】 The pharmaceutical composition according to claim 17.

33. The IRAK4 inhibitor is 【Chemistry 12】 The pharmaceutical composition according to claim 17, wherein the salt is pharmaceutically acceptable.

34. The IRAK4 inhibitor is 【Chemistry 13】 The pharmaceutical composition according to claim 17.

35. The IRAK4 inhibitor is 【Chemistry 14】 The pharmaceutical composition according to claim 17, wherein the salt is pharmaceutically acceptable.

36. The IRAK4 inhibitor is 【Chemistry 15】 The pharmaceutical composition according to claim 17.

37. The IRAK4 inhibitor is 【Chemistry 16】 The pharmaceutical composition according to claim 17, wherein the salt is pharmaceutically acceptable.

38. The IRAK4 inhibitor is 【Chemistry 17】 The pharmaceutical composition according to claim 17.

39. The IRAK4 inhibitor is [Chemistry 18] The pharmaceutical composition according to claim 17, wherein the salt is pharmaceutically acceptable.

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