Methods of treating cancers associated with reduced expression of interleukin 1 [beta]

Abstract

The present disclosure relates to methods of treating cancer comprising administering to a subject an IRAK4 modifying compound wherein the subject has irregular expression of a gene associated with NF-KB.

Description

Treatment methods for cancers associated with decreased interleukin 1β expression

[0001] Related application This application claims the benefit of U.S. Provisional Patent Application No. 63 / 546,016, filed October 27, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK4) is a serine / threonine kinase that plays a crucial role in signal transduction via the Toll / IL-1 receptor (TIR). Multiple IRAK enzymes are key components of signal transduction pathways mediated by the interleukin-1 receptor (IL-1R) and Toll-like receptors (TLRs) (Janssens, S. et al., Mol. Cell. 11, 2003, 293–302). The mammalian IRAK family comprises four members: IRAK1, IRAK2, IRAK3, and IRAK4. These proteins are characterized by a typical N-terminal death domain and a central kinase domain that mediates interactions with MyD88 family adaptor proteins. IRAK proteins, including MyD88, have been shown to play a role in transducing signals other than those derived from the IL-1R receptor, including those triggered by activation of the IL-18 receptor (Kankaraj et al., J. Exp. Med. 189(7): 1999, 1129-38) and those triggered by activation of the LPS receptor (Yang et al., J. Immunol. 163, 1999, 639-643). Of the four members of the mammalian IRAK family, IRAK4 is considered the “mother IRAK.” Under overexpression conditions, all IRAKs mediate activation of the nuclear factor-κB (NF-κB) and stress-induced mitogen-activated protein kinase (MAPK) signaling cascade amplification. However, only IRAK-1 and IRAK4 have shown active kinase activity. While IRAK-1 kinase activity may be unnecessary for its function in IL-1-induced NF-KB activation (Kankaraj et al., J. Exp. Med. 187(12), 1998, 2073–2079) and (Xiaoxia Li et al., Mol. Cell. Biol. 19(7), 1999, 4643–4652), IRAK4 signal transduction requires its kinase activity (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). Given the central role of IRAK4 in Toll-like / IL-1R signaling and immune protection, IRAK4 inhibitors have been considered valuable therapeutic agents for inflammatory diseases, sepsis and autoimmune diseases (Wietek C et al., Mol. Interv. 2: 2002, 212–215).

[0003] Mice lacking IRAK4 survived and showed complete elimination of the production of inflammatory cytokines in response to IL-1, IL-18, or LPS (Suzuki et al., Nature, 416(6882), 2002, 750-756). Similarly, human patients lacking IRAK4 were severely immunocompromised and unresponsive 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 were 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) and showed that IRAK4 kinase activity is essential for cytokine production, MAPK activation and induction of NF-κB regulatory genes in response to TLR ligands (Koziczak-Holbro M et al., J Biol Chem; 282(18): 2007; 13552-13560). Inactivation of IRAK4 kinase (IRAK4 KI) in mice leads to resistance to EAE due to a reduction in inflammatory cells infiltrating 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 blood malignancy in adults, with an estimated 80,000 new cases and 20,000 deaths in the United States in 2023. The molecular pathology driving NHL is diverse, but a common theme is the overactivity of the NF-κB signaling pathway. Specific molecular changes driving this pathway have been identified in NHL subgroups. For example, diffuse large B-cell lymphoma (hereinafter also referred to as “DLBCL”) is an aggressive lymphoma that can occur in or outside the lymphatic system, in the gastrointestinal tract, testes, thyroid gland, skin, breast, bone, or brain. DLBCL is a cancer of B cells, a type of white blood cell responsible for producing antibodies. It is the most common type of non-Hodgkin lymphoma in adults, occurring in 7–8 cases per 100,000 people annually. This cancer primarily occurs in older individuals, with a median age of diagnosis of approximately 70 years, but it can also occur in children and young adults in rare cases. DLBCL is an aggressive tumor, and the first symptom is usually the observation of a rapidly growing mass. The five-year survival rate is only 58%. DLBCL has subtypes named according to their cellular origin and includes germinal center B-cell-like (GCB) and activated B-cell-like (ABC). They are distinguished by their poor prognosis and, in some cases, require specific treatments.

[0005] Acute myeloid leukemia (AML) is one of the most common forms of leukemia in adults, with approximately 20,000 new cases diagnosed each year. AML remains a highly fatal disease, with a five-year survival rate of only 28.3%. Interleukin-1 receptor-associated kinase 4 (IRAK4) has been shown to be a potential therapeutic target for human AML. Although AML is a heterogeneous disease, common characteristics of leukemia blasts include high proliferative potential, increased stem cell self-renewal, and inhibited differentiation in a relatively immature state within the mitotic pool. It is also generally believed that specific genetic mutations present in AML cells can guide treatment and determine the patient's potential survival time.

[0006] Myelodysplastic syndromes (MDS) are conditions that can occur when hematopoietic cells in the bone marrow become abnormal. The main clinical problems in these diseases are the morbidity caused by low blood cell counts and the likelihood of MDS progressing to AML. In the general population, the incidence of MDS is approximately 4.9 per 100,000 people per year. High-risk MDS (hrMDS) is defined as having a high risk, an IPSS score ≥2.5, and immature blasts likely comprising more than 5% of the cells in the bone marrow. Low blood cell counts may lead to anemia, neutropenia, or thrombocytopenia. HrMDS has a greater risk of progressing to AML and a shorter survival, with a median survival of only 0.8 years when patients are untreated. Most MDS diagnoses are low-risk MDS (LR-MDS). Although LR-MDS has a lower risk of death in the short term, it is associated with a high risk of anemia and treatment complications, leading to a high mortality rate (Brunner, AM et al., Blood Cancer J. 12:166 (2022)).

[0007] Another example of NHL is Waldenström macroglobulinemia (WM). WM is a non-Hodgkin lymphoma that affects two types of B cells: lymphoplasmacytic cells and plasma cells. WM is characterized by high levels of circulating antibodies, immunoglobulin M (IgM), which are produced and secreted by cells involved in the disease. WM is a rare disease, with only about 1,500 cases diagnosed annually in the United States. There is no single, universally accepted treatment for WM, and clinical outcomes vary significantly due to gaps in our understanding of the molecular basis of the disease. Objective response rates are high (>80%), but complete response rates are low (0%–15%).

[0008] 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 a variety of 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 population, non-Hodgkin lymphoma affects 2.1% of the U.S. population in their lifetime. The percentage of people who survive more than five years after diagnosis is 71%.

[0009] Targeting intratumoral immune cells with immune checkpoint inhibitors has enabled new therapeutic approaches for many cancers. While several other targets are under development, major clinically approved treatments focus on the programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways. These treatments have proven effective for both Hodgkin's lymphoma and non-Hodgkin's lymphoma, although not all patients respond to these therapies.

[0010] Given the above, there is a clear and unmet need for supplemental therapies for the treatment of cancer and other IRAK4-related diseases. Summary of the Invention

[0011] In some respects, this disclosure provides a method for treating cancer in a subject, the method comprising administering an IRAK4 modified compound wherein the subject has irregular expression of a gene associated with NF-KB. Attached Figure Description

[0012] Figure 1 shows the differences in IL1B expression in patients with hRMDS before and after treatment with emavusertib. Compared with hRMDS patients who responded to emavusertib (responders), IL1B expression was higher in patients who did not respond to emavusertib (non-responders) both before treatment (“baseline”) and during treatment (“On_Tx”) (P≤0.01).

[0013] Figure 2 illustrates the differences in IER3 expression in patients with hRMDS before and after emavusertib treatment. IER3 expression was significantly higher in patients who did not respond to emavusertib (“non-responders”) both before treatment (“baseline”) and during treatment (“On_Tx”) compared to hRMDS patients who responded to emavusertib (“responders”) (P≤0.01).

[0014] Figure 3 illustrates the differences in IL1B expression in AML patients before and after treatment with emavusertib. IL1B expression was significantly higher in AML patients who did not respond to emavusertib (“responders”) both before treatment (“baseline”) and during treatment (“On_Tx”) compared to AML patients who responded to emavusertib (“responders”) (P≤0.01).

[0015] Figure 4 illustrates the differences in IER3 expression in AML patients before and after treatment with emavusertib. IER3 expression was significantly higher in patients who did not respond to emavusertib (“non-responders”) both before treatment (“baseline”) and during treatment (“On_Tx”) compared to AML patients who responded to emavusertib (“responders”) (P=0.57).

[0016] Figure 5 shows the difference in CCL4 expression between patients with AML and those with high-risk MDS. In AML patients, CCL4 expression was lower both before treatment (“baseline”) and during treatment (“On_Tx”) compared to hrMDL patients (P≤0.01).

[0017] Figure 6 illustrates the differential expression of genes in the IRAK4 / NF-KB pathway, highlighting the alterations in gene expression caused by diagnosis, treatment status, and response.

[0018] Figure 7 shows Hallmark pathway analysis in AML and MDS patients treated with emavusertib.

[0019] Figure 8 shows the gene enrichment map of the Hallmark G2M checkpoint pathway.

[0020] Figure 9 shows the gene enrichment map of the Hallmark E2F target pathway.

[0021] Figure 10 shows a gene enrichment map of the Hallmark heme metabolism pathway.

[0022] Figure 11 shows a gene enrichment map of TNF-α / NF-KB signaling. Detailed Implementation

[0023] Results from an ongoing Phase 1 study demonstrated the clinical activity of the IRAK4 inhibitor emavusertib in patients with AML and high-risk MDS. To support the development of effective emavusertib treatment regimens, a study was conducted to monitor changes in gene expression in pre-treatment and post-treatment samples obtained from AML and high-risk MDS. Clinical response data showed that patients who responded to emavusertib treatment had reduced expression levels of IL1B and IER3 (targets of NF-κB) compared to non-responders. This disclosure relates to methods of treating cancer with emavusertib and other IRAK4 inhibitors or degraders, wherein subjects have altered expression of genes associated with NF-κB.

[0024] In some aspects, this disclosure provides a method for treating cancer in a subject, the method comprising administering an IRAK4-modifying compound to the subject, wherein the subject’s expression of interleukin-1β or immediate early response gene 3 is reduced.

[0025] In some preferred embodiments, the expression of interleukin-1β in the subject is reduced.

[0026] In some implementations, subjects showed reduced expression of interleukin-1β compared to subjects without cancer.

[0027] In some implementations, subjects showed reduced expression of interleukin-1β compared to subjects with cancer.

[0028] In some implementations, the expression of the immediate early response gene 3 in the subjects is reduced.

[0029] In some implementations, the expression of the immediate early response gene 3 was reduced in subjects compared to subjects without cancer.

[0030] In some implementations, the expression of the immediate early response gene 3 was reduced in subjects compared to subjects with cancer.

[0031] In another embodiment, the method includes: obtaining a biological sample from a subject; determining the expression level of interleukin-1β or immediate early response gene 3 in the biological sample; comparing the expression level of the one or more genes with a reference expression level; and administering an IRAK4 modified compound.

[0032] In some implementations, the method includes determining the expression level of interleukin-1β in a biological sample.

[0033] In some implementations, the method includes determining the expression level of the immediate early response gene 3 in a biological sample.

[0034] In some implementations, biological samples include tissues (e.g., bone marrow).

[0035] In some implementations, biological samples include blood (e.g., peripheral blood samples).

[0036] In some implementations, the method includes administering an interleukin-1 blocker to the subject.

[0037] In some implementations, the interleukin-1 blocker is an interleukin-1 receptor antagonist.

[0038] In some implementations, the interleukin-1 blocker is an interleukin-1 receptor antagonist protein or a homolog thereof.

[0039] In some preferred embodiments, the interleukin-1 blocker is anakinra.

[0040] In some implementations, the interleukin-1 blocker is a soluble decoy receptor.

[0041] In some embodiments, the interleukin-1 blocker is a dimer fusion protein comprising a ligand-binding domain of the extracellular portion of the human interleukin-1 receptor component (IL-1R1) and the IL-1 receptor accessory protein (IL-1RAcP) linked to the Fc region of human IgG1.

[0042] In some preferred embodiments, the interleukin-1 blocker is rilonacept.

[0043] In some implementations, the interleukin-1 blocker is an IL-1β neutralizing antibody.

[0044] In some preferred embodiments, the interleukin-1 blocker is canakinumab.

[0045] In some implementations, the interleukin-1 blocker is gevokizumab.

[0046] In some implementations, the interleukin-1 blocker is LY2189102.

[0047] In some implementations, the interleukin-1 blocker is an IL-1α neutralizing antibody.

[0048] In some implementations, the interleukin-1 blocker is MABp1.

[0049] In some implementations, the interleukin-1 blocker is an interleukin-1 receptor 1 blocking antibody.

[0050] In some implementations, the interleukin-1 blocker is MEDI-8968.

[0051] In some implementations, the interleukin-1 blocker is a caspase-1 inhibitor.

[0052] In some embodiments, the method further includes administering an agent that inhibits the activity of NF-KB.

[0053] In some embodiments, the IRAK4-modifying compound is an IRAK4 inhibitor. In other embodiments, the IRAK4-modifying compound is an IRAK4 degrader.

[0054] IRAK4 inhibitorsIn a broad sense, the methods disclosed herein can be performed using any IRAK4 inhibitor. For example, these methods can be performed using the IRAK4 inhibitors disclosed in PCT / IB2015 / 050119, PCT / IB2015 / 050217, PCT / IB2015 / 0054620, PCT / IB2016 / 054203 and / or PCT / IB2016 / 054229. The contents of each of the foregoing international applications (in particular the IRAK4 inhibitors disclosed therein) are incorporated herein by reference in their entirety.

[0055] In some implementations, IRAK4 inhibitors are represented by Formula I: (I) or a pharmaceutically acceptable salt thereof; wherein X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2, or X3 is N; A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently halogenated or optionally substituted heterocyclic in each occurrence; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, hydroxyalkyl, or -NR. a R b R2 is hydrogen, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or -NR. a R b The substituents are alkyl, amino, halogen, or hydroxyl; R3 is alkyl or hydroxyl in each occurrence; R a and R b Independently hydrogen, alkyl, acyl or heterocyclic; “m” and “n” are independently 0, 1 or 2; “p” is 0 or 1.

[0056] In some embodiments, A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears, wherein the substituent is alkyl, aminoalkyl, halogenated, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b "m" is 0; and "n" is 1.

[0057] In other embodiments, A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NR. a R b ;where R a and R bR2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogen or hydroxyl groups; "m" and "n" are independently 0, 1 or 2; and "p" is 0 or 1.

[0058] In some implementations, for: .

[0059] In some embodiments, Z is an aryl, a 5-membered heterocyclic group, or a 6-membered heterocyclic group. In some embodiments, Z is an optionally substituted heterocyclic group selected from: phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azacyclic butyl, oxacyclic butyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, thiazolyl. [3.2.1]octyl alkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanecycloyl, thiomorpholinyl dioxide, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydropyranyl and azabicyclo[3.2.1]octyl; each of these heterocyclic groups is optionally converted by an alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl or -NR a R b Replace; and R a and R b It can be hydrogen, alkyl, or acyl on its own.

[0060] In some implementations, IRAK4 inhibitors are represented by formula (IA): (IA) or a pharmaceutically acceptable salt thereof. In some embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears, wherein the substituent is alkyl, aminoalkyl, halogenated, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b "m" is 0; and "n" is 1. In other embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, or -NR. a R b ;where Ra and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogen or hydroxyl groups; and "m" and "n" are independently 0, 1 or 2.

[0061] In some implementations, IRAK4 inhibitors are represented by formula (IB): (IB) or a pharmaceutically acceptable salt thereof. In some embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears, wherein the substituent is alkyl, aminoalkyl, halogenated, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b And “n” is 1. In other embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogen or hydroxyl groups; and "m" and "n" are independently 0, 1 or 2.

[0062] In some implementations, IRAK4 inhibitors are represented by formula (IC): (IC) or its pharmaceutically acceptable salt.

[0063] In some embodiments, R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl, or -NR. a R b And R a and R b It can be hydrogen or acyl independently. In other embodiments, R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, aminoalkyl, halogen, or -NR. a R b And R a and R bIt is independently hydrogen or acyl. In yet another embodiment, R1 is an optionally substituted heterocyclic group; and the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NR. a R b ;where R a and R b R1 is independently hydrogen, alkyl, or heterocyclic. In some embodiments, R1 is pyridinyl, pyrazolyl, pyrrolidinyl, or piperidinyl. In some embodiments, R1 is an optionally substituted pyrazolyl group, wherein the substituent is alkyl, hydroxyl, or -NR. a R b In other implementations, R1 is a halogen.

[0064] In some embodiments, R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogen, or hydroxyl groups. In some embodiments, R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogen, or hydroxyl groups. In some embodiments, R2 is an optionally substituted heterocyclic group selected from: piperidinyl, pyrrolyl, morpholinyl, piperazine, aziridine, pyrazolyl, furanyl, or azirbicyclo[3.2.1]octyl; wherein the substituent is hydroxyl, halogen, alkyl, or amino. In some embodiments, R2 is piperidinyl, pyrrolyl, morpholinyl, or piperazine. In other embodiments, R2 is hydrogen. In yet another embodiment, it is cycloalkyl. In some embodiments, R2 is cyclopropyl.

[0065] In some embodiments, R3 is an alkyl group.

[0066] In some implementations, m is 0 and p is 1. In other implementations, m is 0 or 2, and p is 0 or 1.

[0067] In some implementations, the IRAK4 inhibitor is selected from: Or their pharmaceutically acceptable salts or stereoisomers.

[0068] In some preferred embodiments, the IRAK4 inhibitor is In other implementations, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0069] In some preferred embodiments, the IRAK4 inhibitor is In other implementations, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0070] In some preferred embodiments, the IRAK4 inhibitor is In other implementations, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0071] In some preferred embodiments, the IRAK4 inhibitor is [specifically, a specific component]. In other embodiments, the IRAK4 inhibitor is [specifically, a specific component]. Pharmaceutically acceptable salts.

[0072] In some preferred embodiments, the IRAK4 inhibitor is [specifically, a specific component]. In other embodiments, the IRAK4 inhibitor is [specifically, a specific component]. Pharmaceutically acceptable salts.

[0073] In some preferred embodiments, the IRAK4 inhibitor is In other implementations, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0074] In some preferred embodiments, the IRAK4 inhibitor is In other implementations, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0075] In some preferred embodiments, the IRAK4 inhibitor is In other implementations, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0076] In some preferred embodiments, the IRAK4 inhibitor is In other implementations, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0077] Generally, the compounds described herein can be administered in any amount or manner that elicits the desired response in a subject. For example, a 100 mg to 400 mg IRAK4 inhibitor selected from the compounds described herein may be administered to a subject twice daily, or a 200 mg to 1000 mg IRAK4 inhibitor may be administered to a subject once daily. In some embodiments, a 100 mg to 400 mg IRAK4 inhibitor is administered to a subject twice daily. In some embodiments, a 200 mg to 400 mg IRAK4 inhibitor is administered to a subject twice daily. In some preferred embodiments, a 250 mg to 350 mg IRAK4 inhibitor is administered to a subject twice daily. In some implementations, the subject is given approximately 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg of an IRAK4 inhibitor twice daily. In some embodiments, a subject is given about 50 mg, about 100 mg, about 200 mg, or about 300 mg of an IRAK4 inhibitor twice daily. In some embodiments, a subject is given about 50 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 200 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 225 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 250 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 275 mg of an IRAK4 inhibitor twice daily. In a particularly preferred embodiment, a subject is given about 300 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 325 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 350 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 375 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 400 mg of an IRAK4 inhibitor twice daily.

[0078] In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of 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. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 50 mg. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 75 mg. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 100 mg. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 125 mg. In some embodiments, a subject is given an IRAK4 inhibitor once daily at a dose of about 150 mg.

[0079] In some preferred embodiments, an IRAK4 inhibitor or degrader is administered orally to the subject. In some embodiments, approximately 50 mg of an IRAK4 inhibitor or degrader is administered orally twice daily to the subject. In other embodiments, approximately 200 mg of an IRAK4 inhibitor or degrader is administered orally twice daily to the subject. In other embodiments, approximately 250 mg of an IRAK4 inhibitor or degrader is administered orally twice daily to the subject. In a particularly preferred embodiment, approximately 300 mg of an IRAK4 inhibitor or degrader is administered orally twice daily to the subject. In other embodiments, approximately 325 mg of an IRAK4 inhibitor or degrader is administered orally twice daily to the subject. In other embodiments, approximately 350 mg of an IRAK4 inhibitor or degrader is administered orally twice daily to the subject. In other embodiments, approximately 375 mg of an IRAK4 inhibitor or degrader is administered orally twice daily to the subject. In other embodiments, approximately 400 mg of an IRAK4 inhibitor or degrader is administered orally twice daily to the subject. In other embodiments, approximately 50 mg of an IRAK4 inhibitor or degrader is administered orally once daily to the subject. In yet another embodiment, a subject is given an oral dose of about 75 mg of an IRAK4 inhibitor or degrader once daily. In yet another embodiment, a subject is given an oral dose of about 100 mg of an IRAK4 inhibitor or degrader once daily. In yet another embodiment, a subject is given an oral dose of about 125 mg of an IRAK4 inhibitor or degrader once daily. In yet another embodiment, a subject is given an oral dose of about 150 mg of an IRAK4 inhibitor or degrader once daily.

[0080] In other implementations, the IRAK4 inhibitor is PF-06650833 or BAY 1830839.

[0081] IRAK4 Degrading Agent In some embodiments, the method includes applying an IRAK4 degrading agent. In some embodiments, the IRAK4 degrading agent is KT-474.

[0082] combination therapy In some embodiments of the methods disclosed herein, the method further includes administering an IL-1β inhibitor or antagonist to a subject. In some embodiments, the IL-1β inhibitor is an antibody targeting IL-1β. In some preferred embodiments, the IL-1β inhibitor is kanamycin. In some embodiments, the IL-1β inhibitor is a protein having at least 90% sequence identity with the interleukin-1 receptor antagonist protein (IL-1RN). In some preferred embodiments, the IL-1β inhibitor is anakinin. In some embodiments, the IL-1β inhibitor is a dimer fusion protein comprising a ligand-binding domain of the extracellular portion of the human interleukin-1 receptor component (IL-1R1) and the IL-1 receptor accessory protein (IL-1RAcP) linked to the Fc region of human IgG1. In some preferred embodiments, the IL-1β inhibitor is linacip.

[0083] In some embodiments of the method disclosed herein, the method further includes co-administering a BCL-2 inhibitor to the subject. In some preferred embodiments, the BCL-2 inhibitor is venetoclax. In some embodiments, the method further includes administering 400 mg of venetoclax daily. In some embodiments, venetoclax is administered orally. In some preferred embodiments, the method further includes administering 400 mg of venetoclax orally daily.

[0084] In other embodiments, the method further includes co-administering a BTK inhibitor to the subject. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM7 1224. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM7 1224. In some embodiments, the BTK inhibitor is acalabrutinib. In some embodiments, the method includes administering 200 mg of acalabrutinib daily. In some embodiments, acalabrutinib is administered orally. In some embodiments, the method includes administering 200 mg of acalabrutinib orally daily. In some preferred embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the method includes administering 420 mg of ibrutinib daily. In other embodiments, the method includes administering 420 mg of ibrutinib daily. In some embodiments, ibrutinib is administered orally. In some preferred embodiments, 420 mg of ibrutinib is administered orally daily. In other preferred embodiments, the method includes administering 560 mg of ibrutinib daily. In some embodiments, the BTK inhibitor is zanubrutinib. In some embodiments, the method includes administering 160 mg of zanubrutinib twice daily. In other embodiments, the method includes administering 320 mg of zanubrutinib once daily. In some embodiments, zanubrutinib is administered orally. In some embodiments, the method includes administering 160 mg of zanubrutinib orally twice daily. In other embodiments, the method includes administering 320 mg of zanubrutinib orally once daily. In some embodiments, the method further includes the combined administration of one or more of the following: ABT-737, BAY-1143572, 5-fluorouracil, abiraterone acetate, acetylcholine, trastuzumab emtansine, afatinib, interleukin, alectinib, alemtuzumab, retinoic acid, aminolevulinic acid, anastrozole, aprepitant, arsenic trioxide, Erwinia chrysogenum asparaginase, atezolizumab, axitinib, azacitidine, belistat, bendamustine, benzyl isothiocyanate, bevacizumab, bexarotin, bicalutamide, bleomycin, and berberine. Tumonab, Bortezomib, Bosutinib, Bentuximab, Busulfan, Cabazitaxel, Cabozantinib, Capecitabine, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Cetuximab, Chlorambucil, Cisplatin, Clofabrab, Cobitinib, Cupannixicin, Crizotinib, Cyclophosphamide, Cytarabine, Dabrafenib, Dacarbazine, Actinomycin D, Daramonumab, Dasatinib, Dasorubicin, Decitabine, Defibrinolytic sodium, Degarelix, Denisil interleukin, Denosumab, Dexamethasone, Dexrazoxen, Dihydrotestosterone (DHT), Dentuximab, Docetaxel, DoxorubicinElotuzumab, Eltrombopag, Enzalutamide, Epirubicin, Erebulin Mesylate, Erlotinib, Etoposide, Everolimus, Exemestane, Exemestane, Filgrastim, Fludarabine Phosphate, Flutamide, Fulvestrant, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Gemtuzumab ozomicin, Glucuronyl Glucosidase, Goserelin Acetate, Hydroxyurea, Tiimomab, Ibrutinib, Idarubicin, Adelaide, Ifosfamide, Imatinib, Imiquimod, Interferon Alpha-2b, Ipilimumab Monoclonal antibodies, irinotecan, ixaprilone, ixazomib, lanreotide, lapatinib, lenalidomide, lenvatinib, letrozole, leucovorin, leuprorelin, lomustine, nitrogen mustard, megestrol acetate, melphalan, mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, navitoclax, nexituzumab, nerabine, netutopeptide, nilotinib, nilumet, nivolumab, oxadiazine, oxadiazine, olaparib, homoharringtonine mesylate, osimertinib, oxaliplatin, oxaliplatin Zormicin, Paclitaxel, Palbociclib, Palivmin, Pamidronate, Panitumumab, Pabistat, Pazopanib, Pegaspargase, Pegylated Interferon Alpha-2b, Pembrolizumab, Pemetrexed, Pertuzumab, Plesoxafor, Pomalidomide, Ponatinib, Pratretinoin, Prednisone, Procarbazine, Propranolol, Radium-223 Dichloride, Raloxifene, Ramucirumab, Raburicase, Regorafenib, Rituximab, Lorapipitan, Romidixin, Romistachytin, Ruxotinib, Sesutuximab, Sipuleuce L-T, Sonidegavir, Sorafenib, Sunitinib, Talimumab, Tamoxifen, Temozolomide, Tesirolimus, Thalidomide, Thioguanine, Thiotepa, Tipyrimidine, Topotecan, Toremifene, Toremifene, Tosimomab, Trabectedin, Trametinib, Trastuzumab, Retinoic acid, Trifluuridine, Triacetyluridine, Vandetanib, Vemurafenib, Venetoclax, Vincristine, Vincristine, Vinorelbine, Vemmodegavir, Vorinostat, Aflibercept, Zoledronic acid, and their pharmaceutically acceptable salts. In some embodiments, the second therapeutic agent is one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

[0085] Diseases and symptomsThe methods disclosed herein relate to the treatment of cancer. In some implementations, the cancer is a blood malignancy, such as leukemia or lymphoma, for example, non-Hodgkin's lymphoma. In some implementations, hematologic malignancies are myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphocytic 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), Waldenström macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt lymphoma, non-Burkkitt 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 some implementations, the hematologic malignancy is myeloid leukemia. In other embodiments, the hematologic malignancy is myeloid leukemia (e.g., acute myeloid leukemia). In some embodiments, the hematologic malignancy is acute myeloid leukemia (e.g., AML). In some embodiments, AML is primary AML. In other embodiments, AML is secondary AML. In other embodiments, the hematologic malignancy is myelodysplastic syndrome. In some embodiments, myelodysplastic syndrome is high-grade. In other embodiments, myelodysplastic syndrome is low-grade. In some embodiments, myelodysplastic syndrome is high-risk. In other embodiments, myelodysplastic syndrome is low-risk. In yet another embodiment, the hematologic malignancy is lymphocytic leukemia (e.g., acute lymphoblastic leukemia). In other embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, CLL is high-risk CLL. In other embodiments, the hematologic malignancy is small lymphocytic lymphoma (SLL). In other embodiments, the hematologic malignancy is follicular lymphoma. In other embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In other embodiments, the hematologic malignancy is activated B-cell-like (ABC) DLBCL. In other embodiments, the hematologic malignancy is germinal center B-cell-like (GCB) DLBCL. In some embodiments, the DLBCL is extranodal. In some embodiments, the DLBCL is extranodal leg lymphoma, extranodal testicular lymphoma, or extranodal nonspecific (NOS) lymphoma. In other embodiments, the hematologic malignancy is mantle cell lymphoma. In yet another embodiment, the hematologic malignancy is Waldenström macroglobulinemia. In other embodiments, the hematologic malignancy is multiple myeloma.In other embodiments, the hematologic malignancy is marginal zone lymphoma. In other embodiments, the hematologic malignancy is Burkitt lymphoma. In other embodiments, the hematologic malignancy is non-Burkitt high-grade B-cell lymphoma. In other embodiments, the hematologic malignancy is extranodal marginal zone B-cell lymphoma. In other embodiments, the hematologic malignancy is transformed high-grade B-cell lymphoma (HGBL). In other embodiments, the hematologic malignancy is lymphoplasmacytic lymphoma (LPL). In other embodiments, the hematologic malignancy is CNS lymphoma. In other embodiments, the CNS lymphoma is primary CNS lymphoma (PCNSL). In other embodiments, the hematologic malignancy is MALT lymphoma. In some embodiments, the aforementioned hematologic malignancies are relapsed or refractory.

[0086] In some embodiments, the subject has previously received BTK inhibitors for cancer treatment. In some embodiments, the aforementioned hematologic malignancies are resistant to BTK inhibitor treatment. In some embodiments, the aforementioned hematologic malignancies are resistant to BTK inhibitor treatment as monotherapy. In some embodiments, the hematologic malignancies are resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, évorabutinib, ONO-4059, spetinib, or HM7 1224. In some preferred embodiments, the hematologic malignancies are resistant to ibrutinib treatment. In some embodiments, the cancer is selected from brain cancer, kidney cancer, liver cancer, gastric cancer, penile cancer, vaginal cancer, ovarian cancer, gastric cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, epidermal cancer, melanoma, prostate cancer, and head and neck cancer. In some preferred embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is colon cancer. In some embodiments, the cancer is a solid tumor. In various such embodiments, the cancer may be relapsed or refractory. In some embodiments, the aforementioned cancers are resistant to treatment with BTK inhibitors. In some embodiments, the aforementioned cancers are resistant to treatment with BTK inhibitors as monotherapy. In some embodiments, the cancers are resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spetinib, or HM7 1224. In some preferred embodiments, the cancers are resistant to treatment with ibrutinib.

[0087] In some implementations, the subjects are adults.

[0088] In some embodiments, the IRAK4 inhibitor or degrader is administered orally once daily at a dose of approximately 50 mg; and the cancer is DLBCL. In some embodiments, the DLBCL is relapsed or refractory.

[0089] In some embodiments, the IRAK4 inhibitor or degrader is administered orally once daily at a dose of approximately 50 mg; and the cancer is FL. In some embodiments, the FL is relapsed or refractory.

[0090] In some embodiments, the IRAK4 inhibitor or degrader is administered orally once daily at a dose of approximately 300 mg; and the cancer is WM. In some embodiments, the WM is relapsed or refractory.

[0091] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 50 mg; and the cancer is DLBCL. In some embodiments, the DLBCL is relapsed or refractory.

[0092] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 300 mg; and the cancer is LPL. In some embodiments, the LPL is relapsed or refractory.

[0093] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 300 mg; and the cancer is GCB DLBCL. In some embodiments, the GCB DLBCL is relapsed or refractory.

[0094] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 400 mg; and the cancer is ABC DLBCL. In some embodiments, ABC DLBCL is relapsed or refractory.

[0095] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 400 mg; and the cancer is MZL. In some embodiments, the MZL is relapsed or refractory.

[0096] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 300 mg; and the cancer is MZL. In some embodiments, the MZL is relapsed or refractory.

[0097] In some embodiments, the IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 300 mg; and the cancer is MALT. In some embodiments, the MALT is relapsed or refractory.

[0098] In some embodiments, the IRAK4 inhibitor or degrader is administered continuously (e.g., emavusertib is administered without a withdrawal period). In other embodiments, the IRAK4 inhibitor or degrader is administered intermittently (e.g., emavusertib is administered continuously with interruptions of one or more withdrawal periods). In some embodiments, each withdrawal period lasts for a duration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some preferred embodiments, the withdrawal period lasts for 7 days. In another preferred embodiment, the IRAK4 inhibitor or degrader is administered daily for three weeks, followed by a one-week withdrawal period, optionally followed by three weeks of daily administration and a one-week withdrawal period, which may be repeated further. In some embodiments, the above dosing regimen is continued, alternating between dosing and withdrawal periods, until a change in disease status is observed (e.g., until a complete response, partial response, or unacceptable toxicity is observed). Methods of treating certain diseases and conditions with emavusertib are disclosed in PCT / US2021 / 030192 and PCT / US23 / 21812, the contents of which are incorporated herein by reference in their entirety.

[0099] Existing treatmentsThe methods disclosed herein can be used as first-line therapies or applied to patients who have failed to achieve a partial or complete response to one or more prior anticancer or anti-inflammatory therapies. In some embodiments, the subject has previously received at least one anticancer therapy. In some embodiments, the patient has previously received one anticancer therapy. In other embodiments, the patient has previously received two anticancer therapies. In other embodiments, the patient has previously received three anticancer therapies. In other embodiments, the patient has previously received four anticancer therapies. In other embodiments, the patient has previously received five anticancer therapies. In some embodiments, at least one anticancer therapy comprises: an antiCD20 antibody, nitrogen mustard, a steroid, a purine analog, a DNA topoisomerase inhibitor, a DNA intercalating agent, a tubulin inhibitor, a BCL-2 inhibitor, a proteasome inhibitor, a Toll-like receptor inhibitor, a kinase inhibitor, an SRC kinase inhibitor, a PI3K kinase inhibitor, a BTK inhibitor, a glutaminase inhibitor, or a methylating agent; or a combination thereof. In some embodiments, the anticancer therapy includes: ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, oprozomib, ixazomib, acalabrutinib, zanubrutinib, IMO-08400, ederaris, umbrelasib, CB-839, fludarabine, or thalidomide; or combinations thereof. In some embodiments, the anticancer therapy includes ibrutinib. In some embodiments, the anticancer therapy includes ibrutinib and rituximab. In some embodiments, the anticancer therapy includes bendamustine. In some embodiments, the anticancer therapy includes bendamustine and rituximab. In some embodiments, the anticancer therapy includes bortezomib. In some embodiments, the anticancer therapy includes bortezomib and dexamethasone. In some embodiments, the anticancer therapy includes bortezomib and rituximab. In some embodiments, the anticancer therapy includes bortezomib, rituximab, and dexamethasone. In some embodiments, chlorambucil. In some embodiments, the anticancer therapy includes cladribine. In some embodiments, the anticancer therapy includes cladribine and rituximab. In some embodiments, the anticancer therapy includes cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R). In some embodiments, the anticancer therapy includes cyclophosphamide, prednisone, and rituximab (i.e., CPR). In some embodiments, the anticancer therapy includes fludarabine. In some embodiments, the anticancer therapy includes fludarabine and rituximab. In some embodiments, the anticancer therapy includes fludarabine, cyclophosphamide, and rituximab. In some preferred embodiments, the anticancer therapy comprises rituximab. In some preferred embodiments, the anticancer therapy comprises rituximab.In some embodiments, the anticancer therapy includes rituximab, cyclophosphamide, and dexamethasone (i.e., RCD). In some embodiments, the anticancer therapy includes thalidomide. In some embodiments, the anticancer therapy includes thalidomide and rituximab. In some embodiments, the anticancer therapy includes venetoclax. In some embodiments, the anticancer therapy includes cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD). In some embodiments, the anticancer therapy includes a hypomethylating agent. In some embodiments, the subject has previously received at least 6 cycles of a hypomethylating agent. In some embodiments, the anticancer therapy includes any of the foregoing combinations, for example, the subject may first receive rituximab and then subsequently receive a combination of rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).

[0100] Subjects may also have received or be prepared for other non-chemotherapy treatments, such as surgery, radiation therapy, or bone marrow transplantation. In some embodiments, subjects have previously received etoposide chemotherapy. In some embodiments, subjects have previously received a bone marrow transplant. In some embodiments, subjects have previously received a stem cell transplant. In some embodiments, subjects have previously received an autologous stem cell transplant. In some embodiments, subjects have previously received an allogeneic stem cell transplant. In some embodiments, subjects have previously received a hematopoietic cell transplant. In some embodiments, subjects have previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM conditioning). In some embodiments, subjects have previously received re-induction therapy.

[0101] The subject may have previously shown favorable results with prior therapy and only require additional treatment later. In some embodiments, the subject has previously achieved a partial response. In some embodiments, the subject has previously achieved a good partial response. In some embodiments, the subject has previously achieved a complete response. In some embodiments, the cancer is recurrent. In some embodiments, the cancer is refractory.

[0102] In some implementations, the subjects have not previously received BTK inhibitors for cancer treatment.

[0103] In some implementations, the subject has previously received one or more immune checkpoint inhibitors for cancer treatment.

[0104] Subjects may also have one or more pre-existing or developed genetic mutations that make their cancer more or less resistant to the therapy. In some embodiments, the subject has a mutation in RICTOR. In some embodiments, the subject has an N1065S mutation in RICTOR. In some preferred embodiments, the subject has a mutation in MYD88. In some, and even more preferred, embodiments, the subject has an L265P mutation in MYD88. In some embodiments, the subject has a mutation in TET2. In some embodiments, the subject does not have a mutation in CXCR4. In other embodiments, the subject has a mutation in CXCR4. In some preferred embodiments, the subject has a mutation in SF3B1 (e.g., insertion, deletion, loss, or spliceosome mutation). In some preferred embodiments, the subject has a mutation in U2AF1 (e.g., insertion, deletion, loss, or spliceosome mutation). In some preferred embodiments, the subject has a mutation in FLT3 kinase (e.g., insertion, deletion, loss, or internal tandem duplication). In some preferred embodiments, the mutation in the FLT3 kinase is selected from one or more of the following: internal tandem repeat (ITD), mutation in D835, mutation in F691, mutation in K663, and / or mutation in N841. In some embodiments, the mutation in the FLT3 kinase includes the D835H mutation. In some embodiments, the mutation in the FLT3 kinase includes the D835V mutation. In some embodiments, the mutation in the FLT3 kinase includes the D835Y mutation. In some embodiments, the mutation in the FLT3 kinase includes the K663Q mutation. In some embodiments, the mutation in the FLT3 kinase includes the N841I mutation. In some embodiments, the mutation in the FLT3 kinase includes both ITD and D835V mutations. In some embodiments, the mutation in the FLT3 kinase includes both ITD and F691L mutations. In some embodiments, the mutation in the FLT3 kinase includes both ITD and D835Y mutations. In some embodiments, the subject has a mutation in STAG2 (e.g., insertion, deletion, or loss). In some embodiments, the subject has a mutation in DNMT3A (e.g., insertion, deletion, or loss). In some embodiments, the subject has a mutation in BCOR (e.g., insertion, deletion, or loss). In some embodiments, the subject has a mutation in WT1 (e.g., insertion, deletion, or loss). In some embodiments, the subject has a mutation in NRAS. In some embodiments, the subject shows early progression.

[0105] In some embodiments, the subject achieves a partial response after administration of the compound. In some embodiments, the subject achieves a good partial response after administration of the compound. In other embodiments, the subject achieves a complete response after administration of the compound. In some embodiments, the subject achieves a partial response within 7 days of receiving the compound. In some embodiments, the subject achieves a good partial response within 7 days of receiving the compound. In some embodiments, the subject achieves a complete response within 7 days of receiving the compound. In some embodiments, the subject's tumor volume decreases by approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95%. In some embodiments, the subject's tumor volume decreases by 5%. In some embodiments, the subject's tumor volume decreases by 10%. In some embodiments, the subject's tumor volume decreases by 15%. In some embodiments, the subject's tumor volume decreases by 20%. In some embodiments, the subject's tumor volume decreases by 25%. In some embodiments, the subject's tumor volume decreases by 30%. In some embodiments, the subject's tumor volume is reduced by 35%. In some embodiments, the subject's tumor volume is reduced by 40%. In some embodiments, the subject's tumor volume is reduced by 45%. In some embodiments, the subject's tumor volume is reduced by 50%. In some embodiments, the subject's tumor volume is reduced by 55%. In some embodiments, the subject's tumor volume is reduced by 60%. In some embodiments, the subject's tumor volume is reduced by 65%. In some embodiments, the subject's tumor volume is reduced by 70%. In some embodiments, the subject's tumor volume is reduced by 80%. In some embodiments, the subject's tumor volume is reduced by 85%. In some embodiments, the subject's tumor volume is reduced by 90%. In some embodiments, the subject's tumor volume is reduced by 95%.

[0106] Pharmaceutical CompositionThe compositions and methods of the present invention can be used to treat individuals in need. In some embodiments, the individuals are mammals such as humans, or non-human mammals. When administered to animals (such as humans), the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, the compounds 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 or carriers such as ethylene glycol, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are used for human administration, particularly for invasive routes of administration (i.e., routes that avoid transport or diffusion across the epithelial barrier, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. For example, excipients may be selected to achieve delayed release of the agent or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of dosage units, such as tablets, capsules (including spray capsules and gelatin capsules), granules, lyophilized formulations for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in transdermal delivery systems, such as skin patches. The composition may also be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0107] Pharmaceutically acceptable carriers may contain physiologically acceptable agents that, for example, stabilize, increase solubility, or enhance the absorption of compounds such as those of the present invention. 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. For example, the choice of pharmaceutically acceptable carriers (including physiologically acceptable agents) depends on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix in which compounds such as those of the present invention may be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and their preparation and administration are relatively simple.

[0108] The phrase “pharmaceutically acceptable” as used in this article refers to compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0109] As used herein, the phrase “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” and harmless to the patient in the sense of compatibility with other components of the formulation. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (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) powdered tragacanth gum; (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, and corn oil. (10) Soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Atherless water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic compatible substances used in pharmaceutical preparations.

[0110] The pharmaceutical composition (formulation) can be administered to a subject via any of a variety of routes of administration, including oral (e.g., as an lavage in an aqueous or non-aqueous solution or suspension, tablets, capsules (including spray capsules and gelatin capsules), pills, powders, granules, or pastes applied 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 compound can also be formulated for inhalation. In some embodiments, the compound can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions applicable thereto can be found, for example, in U.S. Patent 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 referenced therein.

[0111] The formulation can be conveniently present in a single dosage form and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Typically, in one hundred percent, this amount accounts for about 1 percent to about 99 percent of the active ingredient, preferably about 5 percent to about 70 percent, and most preferably about 10 percent to about 30 percent.

[0112] Methods for preparing these formulations or compositions include the step of associating an active compound (such as the compound of the present invention) with a carrier and optionally one or more auxiliary components. Typically, formulations are prepared by uniformly and tightly associating the compound of the present invention with a liquid carrier or a finely chopped solid carrier, or both, and then, if desired, shaping the product.

[0113] Formulations of the present invention suitable for oral administration may be in the form of capsules (including spray capsules and gelatin capsules), granules, pills, tablets, lozenges (using a flavoring base, typically sucrose and gum arabic or tragacanth), lyophilized forms, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as lozenges (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic) and / or as mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compositions or compounds may also be administered as pills, granules, or pastes.

[0114] To prepare solid dosage forms (capsules (including spray capsules and gelatin capsules), tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, 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, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants. (3) Disintegrants, such as glycerin; (4) Disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) Solution blockers, such as paraffin; (6) Absorption enhancers, such as quaternary ammonium compounds; (7) Wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; (10) Complexing agents, such as modified and unmodified cyclodextrins; and (11) Colorants. In the case of capsules (including spray capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules that use excipients such as lactose or lactose and high molecular weight polyethylene glycol.

[0115] Tablets can be made by compression or molding, optionally using one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0116] Tablets and other solid dosage forms of pharmaceutical compositions, such as sugar-coated pills, capsules (including spray capsules and gelatin capsules), pellets, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the field of pharmaceutical formulation. They may also be formulated using, for example, varying proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a slow or controlled release of the active ingredient therein, thereby providing the desired release profile. They may be sterilized, for example, by filtration through a bacterial trap filter, or by adding a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain an opacifying agent and may be compositions that release the active ingredient, optionally in a delayed manner, only or preferably in a specific portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymers and waxes. If suitable, the active ingredient may also be in a microencapsulated form with one or more of the excipients described above.

[0117] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitol, as well as mixtures thereof.

[0118] In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, flavoring agents and preservatives.

[0119] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

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

[0121] In addition to active compounds, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gum, cellulose derivatives, polyethylene glycols, organosilicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0122] In addition to the active compound, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may also contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0123] Transdermal patches offer the added advantage of controlled delivery of the compounds of the present invention to the body. This dosage form can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of this flux can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0124] As used herein, the phrases “parenteral administration” and “administered parenterally” refer to a route of administration other than enteral and local administration, typically by injection, and including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-capsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, intra-articular, subcapsular, subarachnoid, spinal, and intrasternal injections and infusions. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0125] Examples of suitable aqueous and non-aqueous 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. For example, appropriate flowability can be maintained by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0126] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action can be ensured by adding various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolic sorbic acid. Isotonic agents, such as sugars and sodium chloride, may also need to be included in the composition. Furthermore, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0127] In some cases, to prolong the effect of a drug, it is necessary to slow its absorption from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The absorption rate of a drug depends on its dissolution rate, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of parenteral drug administration can be achieved by dissolving or suspending the drug in an oil carrier.

[0128] Injectable long-acting formulations are prepared by forming a microencapsulated matrix of the test compound in a biodegradable polymer such as polylactide-polyglycolic acid. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include polyorthoesters and polyanhydrides. Long-acting injectable formulations can also be prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0129] For use in the methods of the present invention, the active compound may be administered either on its own or as a pharmaceutical composition comprising, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0130] Introduction methods can also be provided via rechargeable or biodegradable devices. In recent years, various sustained-release polymer devices have been developed and tested in vivo for controlled drug delivery, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), both biodegradable and non-degradable, can be used to form implants that sustainably release compounds at specific target sites.

[0131] The actual dose level of the active ingredient in a pharmaceutical composition can be varied to obtain an amount of active ingredient that is non-toxic to the patient while effectively achieving the desired therapeutic response for a particular patient, composition, and route of administration.

[0132] The chosen dose level will depend on a variety of factors, including the activity of the specific compound or combination of compounds used or its esters, salts or amides, the route of administration, the time of administration, the excretion rate of the specific compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound used, the age, sex, weight, condition, general health and medical history of the patient being treated, and similar factors well known in the medical field.

[0133] Physicians or veterinarians with general skills in the art can readily determine and prescribe a therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may initially use a dose of the pharmaceutical composition or compound below the required level to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. A “therapeutically effective amount” means a concentration of compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the subject’s weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient’s condition, the condition being treated, the stability of the compound, and, if necessary, other types of therapeutic agents administered with the compound of the present invention. A larger total dose can be delivered through multiple administrations. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al., (1996) Harrison's Principles of Internal Medicine, 13th edition, 1814-1882, incorporated herein by reference).

[0134] Generally, the appropriate daily dose of the active compound used in the compositions and methods of the present invention will be the amount of the compound at the lowest effective dose to produce a therapeutic effect. This effective dose generally depends on the factors mentioned above.

[0135] If desired, the effective daily dose of the active compound may be administered in one, two, three, four, five, six or more sub-dose intervals throughout the day, optionally in unit dosage form. In some embodiments of the invention, the active compound may be administered two or three times daily. In a preferred embodiment, the active compound will be administered once daily.

[0136] Patients receiving this treatment are any animals in need, including primates, specifically humans; as well as other mammals such as horses, cattle, pigs, sheep, cats, and dogs; poultry; and pets in general.

[0137] In some embodiments, the compounds of the present invention may be used alone or in combination with another type of therapeutic agent.

[0138] This disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In some embodiments, the intended salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In some embodiments, the intended salts of the present invention include, but are not limited to, L-arginine, benzylamine, benzathine, betaine, calcium hydroxide, choline, tannin, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, hepatoside, 1H-imidazolium, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In some embodiments, the intended salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In some embodiments, the intended salts of the present invention include, but are not limited to, 1-hydroxy-2-naphtholic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetaminobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, caprylic acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (caprylic acid), carbonic acid, cinnamic acid, citric acid, cyclohexylaminoethanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, etc. Acids, galactobionic acid, gentic acid, d-glucoheptanoic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutamate, glutaric acid, glycerophosphate, glycolic acid, hippuric 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, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, and undecanoic acid salts.

[0139] Pharmaceutically acceptable acid addition salts can also exist as various solvates, such as those with water, methanol, ethanol, dimethylformamide, etc. Mixtures of these solvates can also be prepared. The sources of such solvates can be from the crystallization solvent, inherent in the preparation solvent or crystallization solvent, or unrelated to such solvents.

[0140] Wetting agents, emulsifiers and lubricants, such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and aromatizers, 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 bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0142] definition Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the nomenclature and techniques described herein relating 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 are those well-known and commonly used in the art.

[0143] Unless otherwise stated, the methods and techniques disclosed herein are generally practiced according to conventional methods known in the art and as described in the various general and more specific references cited and discussed in this specification. See, for example, “Principles of Neural Science”, McGraw-Hill Medical, New York, NY (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th Edition”, WH Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th Edition”, WH Freeman & Co., NY (1999); and Gilbert et al., “Developmental Biology, 6th Edition”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0144] Unless otherwise defined herein, chemical terms used herein are used in accordance with conventional usage in the art, citing “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, CA (1985) as an example.

[0145] All the foregoing content, as well as any other publications, patents, and published patent applications mentioned in this application, are specifically incorporated herein by reference. In case of conflict, this specification (including its specific definitions) shall prevail.

[0146] The term "agent" is used herein to refer to chemical compounds (such as organic or inorganic compounds, mixtures of compounds), biological macromolecules (such as nucleic acids, antibodies (including portions thereof as well as humanized, chimeric, and human antibodies and monoclonal antibodies), proteins or portions thereof, such as peptides, lipids, and carbohydrates), or extracts made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. For example, an agent includes agents with known structures and agents with unknown structures. The ability of such agents to inhibit AR or promote AR degradation makes them suitable as "therapeutic agents" in the methods and compositions of this disclosure.

[0147] The terms “patient,” “subject,” or “individual” are used interchangeably to refer to human or non-human animals. These terms include mammals such as humans, primates, livestock (including cattle, pigs, etc.), companion animals (e.g., canines, felines, etc.), and rodents (e.g., mice and rats).

[0148] "Treating a condition or patient means taking measures to achieve a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, the reduction or improvement of one or more symptoms or conditions, a reduction in the severity of the disease, a stable (i.e., non-worsening) disease state, prevention of disease spread, delay or slowing of disease progression, improvement or remission of the disease state, and remission (whether partial or complete), whether detectable or undetectable. 'Treatment' may also mean an extended lifespan compared to the expected lifespan without treatment."

[0149] The term "prevention" is recognized in the art and is well known in the art when used to describe conditions related to illnesses such as local recurrence (e.g., pain), diseases such as cancer, syndromes such as heart failure, or any other medical condition. It includes the administration of a composition that, relative to a subject not receiving the composition, reduces the frequency of the subject's medical condition symptoms or delays their onset. Therefore, cancer prevention includes, for example, reducing the number of detectable cancer growths in a patient population receiving prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancer growths in a treated population relative to an untreated control population, for example, delaying a statistically and / or clinically significant amount.

[0150] A substance, compound, or agent may be “administered” to a subject using one of a variety of methods known to those skilled in the art. For example, the compound or agent may be administered intravenously, via artery, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and percutaneously (by absorption, e.g., via a skin catheter). The compound or agent may also be suitably introduced via a rechargeable or biodegradable polymer device or other device, such as patches and pumps, or formulations that provide a prolonged, slow, or controlled release of the compound or agent. For example, administration may be performed once, multiple times, and / or over one or more prolonged time periods.

[0151] For example, the appropriate method of administering a substance, compound, or agent to a subject will also depend on factors such as the subject's age and / or physical condition, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered orally, for example, by ingestion. In some embodiments, the orally administered compound or agent is in a slow-release or sustained-release formulation, or is administered using a device for such slow-release or sustained-release formulations.

[0152] As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered agent remains effective in the body (e.g., both agents are effective for the patient simultaneously, which may include synergistic effects between the two agents). For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or as separate formulations. Thus, an individual receiving such treatment may benefit from the combined effect of the different therapeutic agents.

[0153] The "therapeutic effective amount" or "therapeutic dose" of a drug or agent is the amount of drug or agent that will have the expected therapeutic effect when administered to a subject. A complete therapeutic effect may not necessarily be achieved with a single dose, but may only occur after a series of doses. Therefore, the therapeutic effective amount can be administered in one or more doses. The precise effective amount required by the subject will depend on factors such as the subject's body type, health, and age, as well as the nature and extent of the condition being treated, such as cancer or MDS. Technicians can readily determine the effective amount for a given situation through routine experiments.

[0154] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may or may not occur, and the description includes instances where the event or situation occurs as well as instances where it does not occur. For example, “optionally substituted alkyl” means that the alkyl group may be substituted as well as that the alkyl group is not substituted.

[0155] It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to produce chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods described below. If the substituent itself is substituted by more than one group, it should be understood that these multiple groups can be on the same carbon or different carbons, as long as a stable structure is produced.

[0156] As used herein, the term "optionally substituted" means that one to six hydrogen groups in a given structure are replaced by a group of a specified substituent, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2. Preferably, "optionally substituted" means that one to four hydrogen groups in a given structure are replaced by the aforementioned substituents. More preferably, one to three hydrogen groups are replaced by the substituents described above. It should be understood that the substituents may be further substituted.

[0157] As used herein, the term "alkyl" refers to a saturated aliphatic group, including but not limited to C1-C1 groups. 10 Straight-chain alkyl or C1-C 10Branched alkyl group. Preferably, the "alkyl" group refers to a C1-C6 straight-chain alkyl group or a C1-C6 branched alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight-chain alkyl group or a C1-C4 branched 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. The "alkyl" group may optionally be substituted.

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

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

[0161] The term "alkoxy group" refers to an alkyl group having an oxygen atom attached to it. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc.

[0162] The term "alkoxyalkyl" refers to an alkyl group that has been 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, including straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In a preferred embodiment, the straight-chain or branched alkyl group has 30 or fewer carbon atoms in its main chain (e.g., a straight chain of C16). 1-30 The branch is C 3-30 ), and more preferably 20 or less.

[0164] Furthermore, the term "alkyl" as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter referring to an alkyl moiety having a substituent of substituted hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0165] Term "C" xy "or "C x -C y"When used in conjunction with chemical motifs such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it is intended to include carbon atoms in the chain containing groups from x to y. C0 alkyl indicates a hydrogen atom at the terminal position of the group, or a bond if internal. For example, C..." 1-6 Alkyl groups contain one to six carbon atoms in their chains.

[0166] As used herein, the term "alkylamino" refers to an amino group that is substituted by 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 a group. , where R 9 and R 10 Each independently represents a hydrogen or hydrocarbon group, or R 9 and R 10 Together with the N atoms they are attached to, they form a heterocycle, which has 4 to 8 atoms in the ring structure.

[0169] The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines and their salts, for example, this part can be represented by the following formula: , where R 9 R 10 and R 10' Each independently represents a hydrogen or hydrocarbon group, or R 9 and R 10 Together with the N atoms they are attached to, they form a heterocycle, which has 4 to 8 atoms in the ring structure.

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

[0171] As used herein, the term "aralkyl" refers to an alkyl group that has been substituted with an aryl group.

[0172] As used herein, the term "aryl" includes a substituted or unsubstituted monocyclic aromatic group, wherein each atom of the ring is a carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes a polycyclic system having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is aromatic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0173] The term "carbamate" is recognized in the art and refers to a group. , where R 9 and R10 Independently represents a hydrogen or hydrocarbon group.

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

[0175] The term "carbocyclic ring" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. A carbocyclic ring includes a bicyclic molecule in which one, two, or three or more atoms are shared between two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, provided that the valence allows. Exemplary "carbocyclic rings" 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. Exemplary fused carbocyclic rings include naphthane, 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. The “carbocyclic ring” can be substituted at any one or more positions capable of carrying a hydrogen atom.

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

[0177] The term "carbonate" is recognized in the art and refers to the group -OCO2-.

[0178] As used herein, the term "carboxyl" refers to a group represented by the formula -CO2H.

[0179] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4-membered to 8-membered rings, more preferably 4-membered to 6-membered rings. The term "cycloalkyl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is a cycloalkyl group, and substituents (e.g., R...) are... 100 The ring is attached to a cycloalkyl ring; for example, other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, benzodioxane, tetrahydroquinoline, etc.

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

[0181] As used herein, the term "ether" refers to a hydrocarbon group connected to another hydrocarbon group via oxygen. Therefore, the ether substituent of the hydrocarbon group can be hydrocarbon-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocyclic-O-heterocycles and aryl-O-heterocycles. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0182] As used herein, the terms “halo” and “halogen” refer to halogens and include chlorine, fluorine, bromine, and iodine.

[0183] As used herein, the terms “heteroalkyl” and “heteroarylalkyl” refer to alkyl groups that have been substituted with heteroaryl groups.

[0184] The terms "heteroaryl" and "hetaryl" encompass substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is an aromatic heterocyclic ring; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

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

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

[0187] The terms "heterocyclic group," "heterocyclic," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclic group" and "heterocyclic" also include polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, and wherein at least one ring is heterocyclic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. For example, heterocyclic groups include piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc.

[0188] As used herein, the term "hydrocarbon group" refers to a group bonded by carbon atoms without =O or =S substituents, and typically has at least one carbon-hydrogen bond and is predominantly a carbon backbone, but may optionally include heteroatoms. Therefore, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbon groups, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked by oxygen rather than carbon) are not considered hydrocarbon groups. Hydrocarbon groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, ynyl, and combinations thereof.

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

[0190] When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "lower" is intended to include groups having ten or fewer atoms, preferably six or fewer, in the substituents. For example, "lower alkyl" refers to an alkyl group containing ten or fewer carbon atoms, preferably six or fewer. In some embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as hydroxyalkyl and aralkyl in the cited examples (in which case, for example, atoms in the aryl group are not counted when calculating carbon atoms in the alkyl substituents).

[0191] The terms "polycyclic," "polycyclic," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic) in which two or more atoms are shared by two adjacent rings; for example, the rings are "fused rings." Each ring of a polycyclic compound may be substituted or unsubstituted. In some embodiments, each ring of the polycyclic compound contains 3 to 10 atoms, preferably 5 to 7.

[0192] The term "sulfate" is recognized in the art and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0193] The term "sulfonamide" is recognized in the art and refers to a group represented by the following general formula. , where R 9 and R 10 It can independently represent either hydrogen or a hydrocarbon group.

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

[0195] The term "sulfonate" is recognized in the art and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

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

[0197] The term "substituted" refers to a portion having a substituent with a hydrogen substituted group on one or more carbons of the main chain. It should be understood that "substituted" or "replaced by" includes the implicit condition that such substitution is consistent with the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, which does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, permissible substituents can be one or more, the same or different. For the purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituent of the organic compounds described herein that satisfies the valence of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphates, phosphonates, hypophosphonates, amino groups, amide groups, amidines, imines, cyano groups, nitro groups, azides, mercapto groups, alkylthio groups, sulfates, sulfonates, sulfamoyl groups, sulfonamido groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or aromatic heterocyclic moieties. Those skilled in the art will understand that the substituted portion of the hydrocarbon chain may itself be substituted, if appropriate.

[0198] As used herein, the term "thioalkyl" refers to an alkyl group that has been replaced by a thiol group.

[0199] As used herein, the term "thioester" refers to the group -C(O)SR. 9 or -SC(O)R 9 Among them, R 9 Represents a hydrocarbon group.

[0200] As used in this article, the term "thioether" is equivalent to ether, in which oxygen is replaced by sulfur.

[0201] The term "urea" is recognized in the art and can be expressed by the following general formula. , where R 9 and R 10 It can independently represent either hydrogen or a hydrocarbon group.

[0202] As used herein, the term “regulation” includes inhibition or suppression of functions or activities (such as cell proliferation) as well as enhancement of functions or activities.

[0203] The phrase “pharmaceutically acceptable” is recognized in the art. In some embodiments, this term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0204] "Pharmaceutically acceptable salt" or "salt" in this article means an acid addition salt or base addition salt that is suitable for or compatible with the treatment of the patient.

[0205] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any base compound represented by Formula I. 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 monohydrogen phosphate and potassium hydrogen sulfate. 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. Monoacid salts or diacid salts can be formed, and such salts can exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts of Formula I compounds are more soluble in water and a variety of hydrophilic organic solvents and typically 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-pharmaceutical acceptable salts, such as oxalates, can be used to isolate Formula I compounds for laboratory use or for subsequent conversion into pharmaceutically acceptable acid addition salts.

[0206] As used herein, the term "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acid compound or any intermediate thereof represented by Formula I. Exemplary inorganic bases forming suitable salts include lithium hydroxide, sodium, potassium, calcium, magnesium, or barium. Exemplary organic bases forming 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 compounds that can be used in the methods and compositions of this disclosure have at least one stereocenter in their structure. This stereocenter may be present in an R or S configuration, and the use of the R and S designations is consistent with the rules described in Pure Appl. Chem. (1976), 45, 11-30. This disclosure covers all stereoisomers, such as enantiomers and diastereomers of compounds, salts, prodrugs, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO 01 / 062726.

[0208] Furthermore, some compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each case, this disclosure includes mixtures and individual isomers.

[0209] Some compounds may also exist in tautomeric forms. These forms, while not explicitly indicated in the formulas described herein, are intended to be included within the scope of this disclosure.

[0210] A “prodrug” or “pharmaceutically acceptable prodrug” is a compound that, upon administration, is metabolized (e.g., hydrolyzed or oxidized) in a host to form a compound of this disclosure (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds having a biologically unstable or cleavable (protective) group on the functional portion of an active compound. Prodrugs include compounds that can be oxidized, reduced, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation, or dephosphorylation to produce an active compound. Examples of prodrugs using esters or aminophosphates as biologically unstable or cleavable (protective) groups are disclosed in U.S. Patent Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce compounds of formula I. This disclosure includes prodrugs of the compounds described herein within its scope. The routine procedures for selecting and preparing suitable prodrugs are described, for example, in “Design of Prodrugs”, Ed.H. Bundgaard, Elsevier, 1985.

[0211] As used herein, the phrase “pharmaceutically acceptable carrier” refers to pharmaceutically acceptable materials, compositions, or carriers, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that can be used to formulate medicines for pharmaceutical or therapeutic purposes.

[0212] As used herein, the terms “logarithm of solubility,” “LogS,” or “logS” are used in the art to quantify the water solubility of compounds. The water solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility is generally accompanied by poor absorption. The LogS value is the unit logarithm of solubility measured in mol / L (base 10).

[0213] As used herein, “expression” refers, individually and / or cumulatively, to one or more biological processes that result in the production of a nucleic acid sequence according to the encoded agent. Expression specifically includes either or both of transcription and translation. For example, the expression of a DNA sequence can lead to the production of RNA and / or proteins. In another example, the expression of an RNA sequence leads to the production of a polypeptide (e.g., a protein). A cell, tissue, biological sample, or subject that produces the encoded agent can be said to express the encoded agent.

[0214] As used in this article, the phrase “expression product” refers to the product of expression. Specifically, expression products include transcription products (i.e., RNA) and translation products (i.e., polypeptides).

[0215] As used herein, the phrases “expression level” and “level of expression” refer to the level and / or prevalence of expression of an expression product. For example, expression level refers to the level and / or prevalence of an expression product and / or its precursor within a cell, tissue, biological sample, or subject. For example, the expression level of a gene can be measured by measuring the prevalence (i.e., presence) and / or level of its transcript (e.g., RNA) and / or measuring the prevalence and / or level of its translation product (e.g., polypeptide). For example, the expression level of a protein can be measured by measuring the prevalence (i.e., presence) and / or level of its precursor (e.g., mRNA) and / or measuring the prevalence and / or level of the protein and / or its components (e.g., peptide fragments).

[0216] As used in this article, the term "AZA" stands for azacitidine.

[0217] As used in this article, the term “VEN” stands for Venetok.

[0218] As used in this article, the term "BID" means twice-daily administration of the drug.

[0219] As used in this article, the term "QD" refers to daily administration of medication.

[0220] As used in this article, the term "CR" refers to a complete reaction.

[0221] As used in this article, the term "CRi" refers to a CR with incomplete hematologic recovery.

[0222] As used in this article, the term "CRh" refers to a CR with partial hematologic recovery.

[0223] As used in this article, the term "mCR" refers to complete bone marrow response.

[0224] As used in this article, the term "OS" refers to overall survival.

[0225] As used in this article, the term "PR" refers to a partial reaction.

[0226] As used in this article, the term "MTD" refers to the maximum tolerated dose.

[0227] As used in this article, the term "RP2D" refers to the recommended phase 2 dose.

[0228] As used in this article, the term “ANC” refers to the absolute neutrophil count.

[0229] The term "WBC" refers to the white blood cell count.

[0230] Example The invention will now be described in general terms and will be more readily understood by referring to the following embodiments, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0231] Exemplary methods and compounds relating to this disclosure can be found in U.S. Patent Nos. 10 / 160,753, 10 / 758,518 and 11 / 419,875; U.S. Application No. 17 / 680,995; and pending PCT patent applications Nos. US21 / 59668, US2021 / 030192, WO22 / 031330 and US23 / 21812, the contents of which are incorporated herein by reference in their entirety.

[0232] Example 1: Emavusertib in subjects with AML or MDS, whether or not they have received prior BCL-2 treatment. Exemplary performance in Goals and End Points Phase 1 (monotherapy) / Phase 1b (combination therapy) primary objectives • Phase 1: Based on safety and tolerability, dose-limiting toxicities, and pharmacokinetic and pharmacodynamic studies, determine the MTD and RP2D of emavusertib in patients with AML or intermediate, high, or very high-risk MDS (hrMDS). • Phase 1b: Based on safety and tolerability, dose-limiting toxicities, and pharmacokinetic and pharmacodynamic studies, determine the MTD and RP2D of emavusertib in combination with AZA in treatment-naïve patients with AML or hrMDS, or in combination with VEN in relapsed / refractory patients, after first-line treatment. Phase 1 (monotherapy) / Phase 1b (combination therapy) primary endpoint• MTD (defined as the highest dose with a dose-limiting toxicity rate of <33% in the first treatment cycle of at least 6 patients [time range: 28 days]) • RP2D (determined by the sponsor in consultation with the CSC, taking into account all aspects of safety, tolerability, bioactivity, pharmacokinetics, and preliminary efficacy in the trial population [time range: 24 months]) • Safety is measured by adverse events, ECG, chemical and hematological laboratory values, vital signs, and physical examination. Secondary goals for Phase 1 (monotherapy) / Phase 1b (combination therapy) • Use non-compartmental analysis and appropriate pharmacokinetic models to characterize the pharmacokinetic parameters of emavusertib. • Assess anticancer activity. Secondary endpoints for Phase 1 (monotherapy) / Phase 1b (combination therapy) • The pharmacokinetic parameters of emavusertib are obtained through C max C min T max AUC 0-24 AUC 0-inf and T 1 / 2 To measure (time range 24 months) • Clinical response assessment in AML or hrMDS is as follows: ○AML: The proportion of patients achieving CR+CRh The proportion of patients achieving CRi, CR, or CRh ○hrMDS: Overall response rate of CR+PR+mCR ○Infusion independence Phase 1 (monotherapy) / Phase 1b (combination therapy) Exploratory goals • Evaluate the potential association between target-related biomarkers, selected genetic mutations, gene expression profiles, cell origin, or other molecular taxonomic subtypes and antileukemic activity. • Evaluate the pharmacodynamic effects of emavusertib on selected biomarkers in peripheral blood and bone marrow. • Further evaluate the anticancer activity of RP2D. Phase 1 (monotherapy) / Phase 1b (combination therapy) exploratory endpoint • It can perform RNA expression profiling, DNA / RNA sequencing, protein profiling, IRAK4 / NF-KB pathway status, differentiation markers / apoptosis, etc. on peripheral blood and / or tumor samples to analyze changes induced by the investigational treatment and identify potential predictive biomarkers.

[0233] • Clinical response assessment in AML or hrMDS is as follows: ○ Duration of response (DOR) ○ Time to response ○ Overall survival (OS) Research Design This is a Phase 1, open-label, dose-escalation, and cohort-extension study of emavusertib, in patients with AML or MDS as monotherapy, in combination with AZA in treatment-naïve adult patients with AML or hrMDS after first-line treatment, or in combination with VEN in patients with relapsed / refractory AML or hrMDS.

[0234] Phase 1 dose escalation (monotherapy) is partially applicable to patients with AML and hrMDS.

[0235] In the phase 1b portion (combination therapy) of this study, patients with AML or hrMDS received emavusertib in combination with azacitidine (AZA) or venetoclax (VEN). Patients currently receiving combination therapy and benefiting from treatment should continue the study according to the protocol at a dose of 300 mg BID or lower.

[0236] This study employed a Clinical Safety Committee (CSC), whose task was to review all available safety information. The CSC was responsible for determining whether to increase the dose level or to initiate a new dose level. The CSC also defined whether a waiting period was required for any or all patients recruited into the new cohort.

[0237] Phase 1 dose escalation (monotherapy) The starting dose level is 200 mg BID, which has been determined to be safe, achieve the relevant drug exposure level, and demonstrate indications of biological activity and clinical efficacy in the emavusertib-101 study. Three patients with AML or MDS will be recruited at the specified dose. If none of the first three patients experience dose-limiting toxicities during the first cycle, the patient may be moved to the next higher dose level. If one of the first three patients experiences dose-limiting toxicities, the same dose level may be used on the other three patients.

[0238] If two or three of the first six patients experience dose-limiting toxicities, the dose level will be considered above the MTD, and further recruitment will be conducted at a lower dose level. Any adverse event leading to dose reduction or discontinuation is considered a dose-limiting toxicity unless the adverse event is clearly disease-related only. Provisional dose levels are summarized in Table 1.

[0239] Table 1: Provisional Dosage Levels of Emavusertib for AML and MDS *If the MTD is not achieved at dose level 2, higher dose levels may be tested. The CSC will determine these levels after reviewing all available data.

[0240] Phase 1b (Combination Therapy) Emavusertib+AZA The starting dose level for emavusertib will be 200 mg BID, administered over 21 days (days 1-21) in a 28-day cycle. Details of dose escalation are provided below. AZA 75 mg / m² 2 It will be administered intravenously (IV) or subcutaneously (SC) 7 times over a 28-day cycle (e.g., starting on day 1 and administered 7 times consecutively, or divided into several doses with a 5-2 break at the weekend), in accordance with local prescribing information (Table 2).

[0241] Notice• If toxicity occurs, reduce the AZA dose to 50 mg / m² according to the label. 2 Or lower.

[0242] • The expected dosage of emavusertib will be 200 mg, 300 mg, 400 mg BID; decreasing for DL-1 and DL-2; 150 mg, 100 mg, administered for 21 days in a 28-day cycle.

[0243] Table 2: Dosage levels of Emavusertib + Azacitidine .

[0244] The starting dose level for Emavusertib + VEN will be 200 mg BID, administered for 21 days out of a 28-day cycle (days 1-21). Dosage escalation details are provided below. According to the product label, VEN will be administered orally at the same time daily (day 1), increasing to 400 mg over 3 days, and continuing for 21 days out of a 28-day cycle. The second and subsequent cycles will begin at the target dose level (Table 3).

[0245] Notice • The expected dose of emavusertib will be 200 mg, 300 mg, and 400 mg BID; DL-1 and DL-2 will be reduced to 150 mg and 100 mg, respectively, for 21 days in a 28-day cycle. • VEN will be administered using a labeled dosing regimen, with the second and subsequent cycles starting at the target dose level.

[0246] ○ Bone marrow assessment and continuous safety assessment 2 weeks after administration can shorten the cycle length to 14 days. ○ Reduce the starting dose and target dose level according to the label to adjust for drug-drug interactions, and reduce the dose according to the label.

[0247] Table 3: Dosage levels of Emavusertib + Venetoclax .

[0248] Example 2: Exemplary results of RNA sequencing applied to clinical samples from a phase 1 / 2a trial. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid malignancies that exhibit a dynamic and diverse mutational landscape as the disease progresses. Mutations in spliceosomes (e.g., mutations in splicing factors SF3B1 and U2AF1) drive the overexpression of the highly active long isoform of interleukin-1 receptor-associated kinase 4 (IRAK4), upstream signaling activation of NFκB, triggering inflammation, tumorigenesis, and cancer cell survival. NFκB target genes CCL4, IL1B, and IER3 are highly expressed in patients with MDS and AML and are associated with poor prognosis. Emavusertib, a potent oral inhibitor of IRAK4 and FLT3 kinases, has demonstrated efficacy in preclinical models of leukemia.

[0249] In the Phase 1 / 2 trial of Example 1, patients with relapsed / refractory (R / R) AML or high-risk MDS were treated with emavusertib. Batch RNA sequencing of bone marrow or peripheral blood mononuclear cells from 26 AML patients and 16 MDS patients (including 24 paired samples) was performed at Tempus Laboratories (Chicago, IL) using the Illumina NGS platform (San Diego, CA). RNA-seq quality control was performed using FASTQC V0.11.8, and low-quality reads were removed using Trimgalore V0.6.3. Raw counts were normalized to total reads by calculating log2CPM (counts per million). Patients were classified as responders or non-responders based on actual response data, including changes in myeloblast counts.

[0250] Previous studies have shown significant differences between samples in NF-κB target genes (CCL4, IL1B, and IER3) associated with AML / MDS pathophysiology and prognosis.

[0251] As shown in Figures 1 and 2, high-risk MDS patients who responded to emavusertib showed decreased IL1B and IER3 expression levels (P≤0.01 and P≤0.01, respectively). As shown in Figures 3 and 4, AML patients who responded to emavusertib showed decreased IL1B and IER3 expression levels (P≤0.01 and P=0.57, respectively). On average, IL1B and IER3 expression were lower in responders than in non-responders before and during treatment for both AML and hrMDS, suggesting that low IL1B and / or low IER3 expression may predict response to emavusertib treatment. This suggests that IRAK4 inhibition may affect genes associated with the development and pathophysiology of AML / MDS. Previous clinical studies support the findings that IL1B and IER3 are important prognostic biomarkers for AML / MDS.

[0252] Therefore, if IL1B expression level is used as an auxiliary diagnostic criterion for AML or MDS, patients with low IL1B expression levels would be candidates for initial treatment with emavusertib, while patients with high IL1B expression levels would be candidates for combination therapy with emavusertib in combination with IL-1β inhibitors or degrading agents.

[0253] Additionally, as shown in Figure 5, CCL4, a chemokine known to be associated with the pathophysiology of heme malignancies, was expressed at higher levels in patients with MDS than in those with AML. In both baseline and treatment-treated patient samples, patients with MDS exhibited significantly higher CCL4 expression compared to those with AML (P ≤ 0.05). Other downstream chemokines associated with AML / MDS (e.g., CCL3) of IRAK4 showed similar differential expression patterns, as shown in Figure 6.

[0254] As shown in Figure 7, pathway analysis also revealed significant downregulation of the Hallmark G2M checkpoint (Figure 8), Hallmark E2F target (Figure 9), and Hallmark heme metabolism (Figure 10) pathways in treated samples from AML / MDS patients (all FDR p-values ​​<0.005, normalized enrichment fractions = -3.39, -1.97, and -2.17, respectively), indicating a reduction in cell cycle proliferation and metabolic markers. Notably, E2F2 was reduced in treated samples compared to baseline samples with a log2FC of approximately 1.3. These results suggest that emavusertib potentially downregulates pathways related to heme metabolism, proliferation, and cell cycle regulation, such as E2F-related genes. Additionally, pathway analysis revealed significant upregulation of TNF-α signaling via NF-κB, indicating increased apoptosis (Figure 11). In summary, MDS showed specific predictive biomarkers associated with clinical response to emavusertib, with non-responders exhibiting higher IL1B and IER3 expression compared to responders. Secondly, compared to AML, the chemokine CCL4 showed higher expression in hrMDS, reflecting an associated increase in inflammation. Furthermore, compared to baseline, AML / MDS patients treated with emavusertib showed negative enrichment of the G2M checkpoint, E2F target, and heme metabolism Hallmark pathways, indicating that these pathways were downregulated by emavusertib, while TNF-α / NF-κB signaling was upregulated, indicating increased apoptosis. The data presented in this paper demonstrate that emavusertib increases apoptosis / cell death and reduces cell proliferation and cell cycle. In conclusion, these data support the use of emavusertib to target the IRAK4 / NF-κB pathway in hematologic malignancies.

[0255] By incorporating via reference All publications and patents mentioned herein are incorporated herein by reference in their entirety as if each individual publication or patent were specifically and separately indicated to be incorporated by reference. In the event of conflict, this application (including any definitions herein) shall prevail.

[0256] Equivalent embodimentsAlthough specific embodiments of the invention have been discussed, the foregoing description is illustrative rather than restrictive. Many variations of the invention will become apparent to those skilled in the art upon reading this specification and the following claims. The full scope of the invention should be determined by referring to the full scope of the claims and their equivalents, as well as the description and such variations.

Claims

1. A method of treating a subject with cancer, the method comprising administering an IRAK4 modified compound to the subject, wherein the expression of interleukin-1β or immediate early response gene 3 in the subject is reduced.

2. The method according to claim 1, wherein the expression of interleukin-1β in the subject is reduced.

3. The method of claim 2, wherein the subject has reduced expression of interleukin-1β compared to a subject without cancer.

4. The method of claim 2, wherein the subject has reduced expression of interleukin-1β compared to a subject with cancer.

5. The method of claim 1, wherein the expression of the immediate early response gene 3 in the subject is reduced.

6. The method of claim 5, wherein the expression of the immediate early response gene 3 is reduced in the subject compared to a subject without cancer.

7. The method of claim 5, wherein the expression of the immediate early response gene 3 is reduced in the subject compared to the subject with cancer.

8. The method according to any one of claims 1-7, the method comprising: Biological samples are obtained from the subject; the expression level of interleukin-1β or immediate early response gene 3 in the biological samples is determined; the expression level of one or more genes is compared with a reference expression level; and if the expression level of one or more genes is lower than the reference expression level, the IRAK4 modified compound is administered.

9. The method of claim 8, wherein the method comprises determining the expression level of interleukin-1β in the biological sample.

10. The method of claim 8 or 9, wherein the method comprises determining the expression level of the immediate early response gene 3 in the biological sample.

11. The method according to any one of claims 8-10, wherein the biological sample comprises tissue (e.g., bone marrow).

12. The method according to any one of claims 8-11, wherein the biological sample comprises blood (e.g., a peripheral blood sample).

13. The method according to any one of claims 1-12, wherein the method further comprises administering an interleukin-1 blocker to the subject.

14. The method of claim 13, wherein the interleukin-1 blocker is an interleukin-1 receptor antagonist.

15. The method according to claim 13 or 14, wherein the interleukin-1 blocker is an interleukin-1 receptor antagonist protein or a homolog thereof.

16. The method according to any one of claims 13-15, wherein the interleukin-1 blocker is analytein.

17. The method of claim 13, wherein the interleukin-1 blocker is a soluble decoy receptor.

18. The method of claim 13 or 17, wherein the interleukin-1 blocker is a dimer fusion protein comprising a ligand-binding domain of the extracellular portion of a human interleukin-1 receptor component (IL-1R1) and an IL-1 receptor accessory protein (IL-1RAcP) linked to the Fc region of human IgG1.

19. The method according to any one of claims 13, 17 or 18, wherein the interleukin-1 blocker is linasip.

20. The method of claim 13, wherein the interleukin-1 blocker is an IL-1β neutralizing antibody.

21. The method according to claim 13 or 20, wherein the interleukin-1 blocker is kanamycin.

22. The method according to claim 13 or 20, wherein the interleukin-1 blocker is givozoline.

23. The method according to claim 13 or 20, wherein the interleukin-1 blocker is LY2189102.

24. The method of claim 13, wherein the interleukin-1 blocker is an IL-1α neutralizing antibody.

25. The method according to claim 13 or 24, wherein the interleukin-1 blocker is MABp1.

26. The method of claim 13, wherein the interleukin-1 blocker is an interleukin-1 receptor 1 blocking antibody.

27. The method according to claim 13 or 26, wherein the interleukin-1 blocker is MEDI-8968.

28. The method of claim 13, wherein the interleukin-1 blocker is a caspase-1 inhibitor.

29. The method according to any one of claims 1-28, wherein the method further comprises administering an agent that inhibits the activity of NF-KB.

30. The method according to any one of claims 1-29, wherein the IRAK4 modified compound is an IRAK4 inhibitor.

31. The method according to any one of claims 1-29, wherein the IRAK4 modified compound is an IRAK4 degrading agent.

32. The method according to claim 31, wherein the IRAK4 degrading agent is KT-474.

33. The method of claim 30, wherein the IRAK4 inhibitor has a structure represented by formula I: (I) or a pharmaceutically acceptable salt thereof; wherein X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2, or X3 is N; A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently halogenated or optionally substituted heterocyclic in each occurrence; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, hydroxyalkyl, or -NR. a R b R2 is hydrogen, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or -NR. a R b The substituents are alkyl, amino, halogen, or hydroxyl; R3 is alkyl or hydroxyl in each occurrence; R a and R b Independently hydrogen, alkyl, acyl or heterocyclic; "m" and "n" are independently 0, 1 or 2; and "p" is 0 or 1.

34. The method of claim 33, wherein A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; and R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogenated, or -NR group. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b "m" is 0; and "n" is 1.

35. The method of claim 33, wherein A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogen or hydroxyl groups; "m" and "n" are independently 0, 1 or 2; and "p" is 0 or 1.

36. The method according to any one of claims 33-35, wherein for: 。 37. The method according to any one of claims 33-36, wherein Z is an aryl, a 5-membered heterocyclic group, or a 6-membered heterocyclic group.

38. The method according to any one of claims 33-37, wherein Z is an optionally substituted heterocyclic group selected from: phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrazinyl, pyridazinyl, azacyclic butyl, oxacyclic butyl, imidazolyl, pyrrolyl Oxazoalkyl, thiazoalkyl, pyrazolalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanecycloyl, thiomorpholinyl dioxide, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl and azabicyclo[3.2.1]octyl; each of the heterocyclic groups is optionally surrounded by an alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl or -NR a R b Replace; and R a and R b It can be hydrogen, alkyl, or acyl on its own.

39. The method of claim 33, wherein the IRAK4 inhibitor has a structure represented by formula (IA): (IA) or its pharmaceutically acceptable salt.

40. The method of claim 39, wherein A is O or S; Y is -CH2- or O; and R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogenated, or -NR group. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b "m" is 0; and "n" is 1.

41. The method of claim 39, wherein A is O or S; Y is -CH2- or O; R1 is independently a halogen or optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogen or hydroxyl groups; and "m" and "n" are independently 0, 1 or 2.

42. The method of claim 33, wherein the IRAK4 inhibitor has a structure represented by formula (IB): (IB) or its pharmaceutically acceptable salt.

43. The method of claim 42, wherein A is O or S; Y is -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogen or hydroxyl groups; and "m" and "n" are independently 0, 1 or 2.

44. The method of claim 33, wherein the IRAK4 inhibitor has a structure represented by formula (IC): (IC) or its pharmaceutically acceptable salt.

45. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl, or -NR. a R b And R a and R b It can be hydrogen or acyl group independently.

46. ​​The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is an alkyl, aminoalkyl, halogen, or -NR. a R b And R a and R b It can be hydrogen or acyl group independently.

47. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; and said substituent is an alkyl, aminoalkyl, halogen, or -NR. a R b ;where R a and R b It can be hydrogen, alkyl, or heterocyclic group independently.

48. The method according to any one of claims 33-44, wherein R1 is an optionally substituted heterocyclic group; and said substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NR. a R b ;where R a and R b It can be hydrogen, alkyl, or heterocyclic group independently.

49. The method according to any one of claims 33-44, wherein R1 is pyridyl, pyrazolyl, pyrrolidinyl, or piperidinyl.

50. The method according to any one of claims 33-44, wherein R1 is an optionally substituted pyrazolyl group, wherein the substituent is an alkyl, hydroxyl, or -NR group. a R b .

51. The method according to any one of claims 33-44, wherein R1 is a halogen.

52. The method according to any one of claims 33-51, wherein R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b .

53. The method according to any one of claims 33-51, wherein R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogen or hydroxyl groups.

54. The method according to any one of claims 33-51, wherein R2 is an optionally substituted heterocyclic group selected from: piperidinyl, pyrrolidinyl, morpholinyl, piperazineyl, aziridine, pyrazolyl, furanyl or azirbicyclo[3.2.1]octyl; wherein the substituent is hydroxyl, halogen, alkyl or amino.

55. The method according to any one of claims 33-51, wherein R2 is piperidinyl, pyrrolidinyl, morpholinyl, or piperazineyl.

56. The method according to any one of claims 33-51, wherein R2 is hydrogen.

57. The method according to any one of claims 33-51, wherein R2 is a cycloalkyl group.

58. The method of claim 57, wherein R2 is cyclopropyl.

59. The method according to any one of claims 33-58, wherein R3 is an alkyl group.

60. The method according to any one of claims 33-59, wherein m is 0 and p is 1.

61. The method according to any one of claims 33-59, wherein m is 0 or 2, and p is 0 or 1.

62. The method of claim 30, wherein the IRAK4 inhibitor is selected from: Or their pharmaceutically acceptable salts or stereoisomers.

63. The method of claim 30, wherein the IRAK4 inhibitor is 。 64. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

65. The method of claim 30, wherein the IRAK4 inhibitor is 。 66. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

67. The method of claim 30, wherein the IRAK4 inhibitor is 。 68. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

69. The method of claim 30, wherein the IRAK4 inhibitor is 。 70. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

71. The method of claim 30, wherein the IRAK4 inhibitor is 。 72. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

73. The method of claim 30, wherein the IRAK4 inhibitor is 。 74. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

75. The method of claim 30, wherein the IRAK4 inhibitor is 。 76. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

77. The method of claim 30, wherein the IRAK4 inhibitor is 。 78. The method of claim 30, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

79. The method according to any one of claims 33-78, the method comprising administering 100 mg to 400 mg of the IRAK4 inhibitor to the subject twice daily.

80. The method according to any one of claims 33-78, the method comprising administering 200 mg to 400 mg of the IRAK4 inhibitor to the subject twice daily.

81. The method according to any one of claims 33-78, the method comprising administering 250 mg to 350 mg of the IRAK4 inhibitor to the subject twice daily.

82. The method according to any one of claims 33-78, the method comprising administering to the subject twice daily an IRAK4 inhibitor of 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.

83. The method according to any one of claims 33-78, the method comprising administering to the subject twice daily an IRAK4 inhibitor of 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.

84. The method according to any one of claims 33-78, the method comprising administering to the subject twice daily an IRAK4 inhibitor of about 100 mg, about 150 mg, about 200 mg, about 300 mg, or about 400 mg.

85. The method according to any one of claims 33-78, the method comprising administering about 100 mg of the IRAK4 inhibitor to the subject twice daily.

86. The method according to any one of claims 33-78, the method comprising administering about 150 mg of the IRAK4 inhibitor to the subject twice daily.

87. The method according to any one of claims 33-78, the method comprising administering about 200 mg of the IRAK4 inhibitor to the subject twice daily.

88. The method according to any one of claims 33-78, the method comprising administering about 225 mg of the IRAK4 inhibitor to the subject twice daily.

89. The method according to any one of claims 33-78, the method comprising administering about 250 mg of the IRAK4 inhibitor to the subject twice daily.

90. The method according to any one of claims 33-78, the method comprising administering about 275 mg of the IRAK4 inhibitor to the subject twice daily.

91. The method according to any one of claims 33-78, the method comprising administering about 300 mg of the IRAK4 inhibitor to the subject twice daily.

92. The method according to any one of claims 33-78, the method comprising administering about 325 mg of the IRAK4 inhibitor to the subject twice daily.

93. The method according to any one of claims 33-78, the method comprising administering about 350 mg of the IRAK4 inhibitor to the subject twice daily.

94. The method according to any one of claims 33-78, the method comprising administering about 375 mg of the IRAK4 inhibitor to the subject twice daily.

95. The method according to any one of claims 33-78, the method comprising administering about 400 mg of the IRAK4 inhibitor to the subject twice daily.

96. The method according to any one of claims 33-78, the method comprising administering to the subject once daily 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 of the IRAK4 inhibitor.

97. The method according to any one of claims 33-78, the method comprising administering about 25 mg of the IRAK4 inhibitor to the subject once daily.

98. The method according to any one of claims 33-78, the method comprising administering about 50 mg of the IRAK4 inhibitor to the subject once daily.

99. The method according to any one of claims 33-78, the method comprising administering about 75 mg of the IRAK4 inhibitor to the subject once daily.

100. The method according to any one of claims 33-78, the method comprising administering about 100 mg of the IRAK4 inhibitor to the subject once daily.

101. The method according to any one of claims 33-78, the method comprising administering about 125 mg of the IRAK4 inhibitor to the subject once daily.

102. The method according to any one of claims 33-78, the method comprising administering about 150 mg of the IRAK4 inhibitor to the subject once daily.

103. The method according to any one of claims 33-78, the method comprising administering about 175 mg of the IRAK4 inhibitor to the subject once daily.

104. The method according to any one of claims 33-78, the method comprising administering about 200 mg of the IRAK4 inhibitor to the subject once daily.

105. The method according to any one of claims 33-78, the method comprising administering about 225 mg of the IRAK4 inhibitor to the subject once daily.

106. The method according to any one of claims 33-78, the method comprising administering about 250 mg of the IRAK4 inhibitor to the subject once daily.

107. The method according to any one of claims 33-78, the method comprising administering about 275 mg of the IRAK4 inhibitor to the subject once daily.

108. The method according to any one of claims 33-78, the method comprising administering about 300 mg of the IRAK4 inhibitor to the subject once daily.

109. The method according to any one of claims 33-78, the method comprising administering about 325 mg of the IRAK4 inhibitor to the subject once daily.

110. The method according to any one of claims 33-78, the method comprising administering about 350 mg of the IRAK4 inhibitor to the subject once daily.

111. The method according to any one of claims 33-78, the method comprising administering about 375 mg of the IRAK4 inhibitor to the subject once daily.

112. The method according to any one of claims 33-78, the method comprising administering about 400 mg of the IRAK4 inhibitor to the subject once daily.

113. The method according to any one of claims 33-78, the method comprising administering about 425 mg of the IRAK4 inhibitor to the subject once daily.

114. The method according to any one of claims 33-78, the method comprising administering about 450 mg of the IRAK4 inhibitor to the subject once daily.

115. The method according to any one of claims 33-78, the method comprising administering about 475 mg of the IRAK4 inhibitor to the subject once daily.

116. The method according to any one of claims 33-78, the method comprising administering about 500 mg of the IRAK4 inhibitor to the subject once daily.

117. The method according to any one of claims 1-116, wherein the IRAK4 modified compound is administered orally to the subject.

118. The method according to any one of claims 33-78, the method comprising administering about 50 mg of the IRAK4 inhibitor to the subject once daily.

119. The method according to any one of claims 33-78, the method comprising administering about 75 mg of the IRAK4 inhibitor to the subject once daily.

120. The method according to any one of claims 33-78, the method comprising orally administering about 100 mg of the IRAK4 inhibitor to the subject twice daily.

121. The method according to any one of claims 33-78, the method comprising orally administering about 125 mg of the IRAK4 inhibitor to the subject twice daily.

122. The method according to any one of claims 33-78, the method comprising orally administering about 150 mg of the IRAK4 inhibitor to the subject twice daily.

123. The method according to any one of claims 33-78, the method comprising orally administering about 175 mg of the IRAK4 inhibitor to the subject twice daily.

124. The method according to any one of claims 33-78, the method comprising orally administering about 200 mg of the IRAK4 inhibitor to the subject twice daily.

125. The method according to any one of claims 33-78, the method comprising orally administering about 225 mg of the IRAK4 inhibitor to the subject twice daily.

126. The method according to any one of claims 33-78, the method comprising orally administering about 250 mg of the IRAK4 inhibitor to the subject twice daily.

127. The method according to any one of claims 33-78, the method comprising orally administering about 275 mg of the IRAK4 inhibitor to the subject twice daily.

128. The method according to any one of claims 33-78, the method comprising orally administering about 300 mg of the IRAK4 inhibitor to the subject twice daily.

129. The method according to any one of claims 33-78, the method comprising orally administering about 325 mg of the IRAK4 inhibitor to the subject twice daily.

130. The method according to any one of claims 33-78, the method comprising orally administering about 350 mg of the IRAK4 inhibitor to the subject twice daily.

131. The method according to any one of claims 33-78, the method comprising orally administering about 375 mg of the IRAK4 inhibitor to the subject twice daily.

132. The method according to any one of claims 33-78, the method comprising orally administering about 400 mg of the IRAK4 inhibitor to the subject twice daily.

133. The method according to any one of claims 1-132, the method comprising administering an additional 75 mg / m² to the subject once daily. 2 Azacitidine.

134. The method according to any one of claims 1-29, wherein the IRAK4 modified compound is PF-06650833.

135. The method according to any one of claims 1-29, wherein the IRAK4 modified compound is BAY1830839.

136. The method according to any one of claims 1-135, wherein the method further comprises administering a BCL-2 inhibitor to the subject in combination.

137. The method of claim 136, wherein the BCL-2 inhibitor is venetoc.

138. The method of claim 137, wherein the method comprises administering 400 mg of venetoc daily.

139. The method of claim 137, wherein the venetoc is administered orally.

140. The method of claim 137, wherein the method comprises oral administration of 400 mg of venetoclax daily.

141. The method according to any one of claims 1-140, wherein the method further comprises administering a BTK inhibitor to the subject in combination.

142. The method of claim 141, wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spetinib, or HM7 1224.

143. The method of claim 142, wherein the BTK inhibitor is acalabrutinib.

144. The method of claim 143, wherein the method comprises administering 200 mg of acalabrutinib daily.

145. The method of claim 143, wherein the acalatinib is administered orally.

146. The method of claim 143, wherein the method comprises oral administration of 200 mg of acalabrutinib daily.

147. The method of claim 142, wherein the BTK inhibitor is ibrutinib.

148. The method of claim 147, wherein the method comprises administering 420 mg of ibrutinib daily.

149. The method of claim 147, wherein the method comprises administering 560 mg of ibrutinib daily.

150. The method of claim 147, wherein the ibrutinib is administered orally.

151. The method of claim 147, wherein the method comprises oral administration of 420 mg of ibrutinib daily.

152. The method of claim 147, wherein the method comprises oral administration of 560 mg of ibrutinib daily.

153. The method of claim 142, wherein the BTK inhibitor is zanubrutinib.

154. The method of claim 153, wherein the method comprises administering 160 mg of zanubrutinib twice daily.

155. The method of claim 153, wherein the method comprises administering 320 mg of zanubrutinib once daily.

156. The method of claim 153, wherein the zanubrutinib is administered orally.

157. The method of claim 153, wherein the method comprises orally administering 160 mg of zanubrutinib twice daily.

158. The method of claim 153, wherein the method comprises oral administration of 320 mg of zanubrutinib once daily.

159. The method according to any one of claims 1-158, wherein the cancer is a hematologic malignancy.

160. The method of claim 159, wherein the hematologic malignancy is non-Hodgkin's lymphoma.

161. The method of claim 159, wherein the hematologic malignancy is leukemia.

162. The method of claim 159, wherein the hematologic malignancy is lymphoma.

163. The method according to any one of claims 159-162, wherein the hematologic malignancy is myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphocytic 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), Waldenström 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.

164. The method of claim 159, wherein the hematologic malignancy is myeloid leukemia.

165. The method of claim 159, wherein the hematologic malignancy is myeloid leukemia (e.g., acute myeloid leukemia).

166. The method of claim 159, wherein the hematologic malignancy is acute myeloid leukemia (e.g., AML).

167. The method of claim 166, wherein the AML is primary AML.

168. The method of claim 166, wherein the AML is secondary AML.

169. The method according to any one of claims 166-168, wherein the AML is treatment-related AML.

170. The method of claim 159, wherein the hematologic malignancy is myelodysplastic syndrome.

171. The method of claim 170, wherein the myelodysplastic syndrome is high-grade.

172. The method of claim 170, wherein the myelodysplastic syndrome is low-grade.

173. The method according to any one of claims 170-172, wherein the myelodysplastic syndrome is high-risk.

174. The method of claim 159, wherein the hematologic malignancy is lymphocytic leukemia (e.g., acute lymphoblastic leukemia).

175. The method of claim 159, wherein the hematologic malignancy is chronic lymphocytic leukemia (CLL).

176. The method of claim 175, wherein the CLL is a high-risk CLL.

177. The method of claim 159, wherein the hematologic malignancy is small lymphocytic lymphoma (SLL).

178. The method of claim 159, wherein the hematologic malignancy is follicular lymphoma.

179. The method of claim 159, wherein the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL).

180. The method of claim 159, wherein the hematologic malignancy is activated B-cell-like (ABC) DLBCL.

181. The method of claim 159, wherein the hematologic malignancy is germinal center B-cell-like (GCB) DLBCL.

182. The method according to any one of claims 179-181, wherein the DLBCL is external.

183. The method according to any one of claims 179-181, wherein the DLBCL is extranodal leg lymphoma, extranodal testicular lymphoma, or extranodal nonspecific (NOS) lymphoma.

184. The method of claim 159, wherein the hematologic malignancy is mantle cell lymphoma.

185. The method of claim 159, wherein the hematologic malignancy is Waldenström macroglobulinemia.

186. The method of claim 159, wherein the hematologic malignancy is multiple myeloma.

187. The method of claim 159, wherein the hematologic malignancy is marginal zone lymphoma.

188. The method of claim 159, wherein the hematologic malignancy is Burkitt lymphoma.

189. The method of claim 159, wherein the hematologic malignancy is a non-Burkett high-grade B-cell lymphoma.

190. The method of claim 159, wherein the hematologic malignancy is extranodal marginal zone B-cell lymphoma.

191. The method of claim 159, wherein the hematologic malignancy is a transformed high-grade B-cell lymphoma (HGBL).

192. The method of claim 159, wherein the hematologic malignancy is lymphoplasmacytic lymphoma (LPL).

193. The method of claim 159, wherein the hematologic malignancy is a CNS lymphoma.

194. The method of claim 193, wherein the CNS lymphoma is primary CNS lymphoma (PCNSL).

195. The method of claim 159, wherein the hematologic malignancy is MALT lymphoma.

196. The method according to any one of claims 159-195, wherein the hematologic malignancy is recurrent.

197. The method according to any one of claims 159-196, wherein the hematologic malignancy is refractory.

198. The method according to any one of claims 1-158, wherein the cancer is selected from: brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, stomach cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, melanoma, epidermal cancer, prostate cancer, and head and neck cancer.

199. The method according to any one of claims 1-158, wherein the cancer is pancreatic cancer.

200. The method according to any one of claims 1-158, wherein the cancer is colon cancer.

201. The method according to any one of claims 198-200, wherein the cancer is a solid tumor.

202. The method according to any one of claims 198-201, wherein the cancer is recurrent.

203. The method according to any one of claims 198-202, wherein the cancer is refractory.

204. The method according to any one of claims 1-203, wherein the cancer is resistant to treatment with a BTK inhibitor.

205. The method of claim 204, wherein the cancer is resistant to treatment with ibrutinib, acalatinib, zanubrutinib, evobrutinib, ONO-4059, spetinib, or HM7 1224.

206. The method of claim 205, wherein the cancer is resistant to treatment with ibrutinib.

207. The method of claim 205, wherein the cancer is resistant to treatment with acalabrutinib.

208. The method according to any one of claims 1-207, wherein the subject is an adult.

209. The method according to any one of claims 1-208, wherein the subject has previously received at least one anticancer therapy (e.g., anticancer therapy or anti-inflammatory therapy).

210. The method of claim 209, wherein the subject has previously received an anticancer therapy.

211. The method of claim 209, wherein the subject has previously received two anticancer therapies.

212. The method of claim 209, wherein the subject has previously received three anticancer therapies.

213. The method of claim 209, wherein the subject has previously received four anticancer therapies.

214. The method of claim 209, wherein the subject has previously received five anticancer therapies.

215. The method according to any one of claims 209-214, wherein the at least one anticancer therapy comprises: Anti-CD20 antibody, nitrogen mustard, steroid, purine analog, DNA topoisomerase inhibitor, DNA intercalating agent, microtubule inhibitor, BCL-2 inhibitor, proteasome inhibitor, Toll-like receptor inhibitor, kinase inhibitor, SRC kinase inhibitor, PI3K kinase inhibitor, BTK inhibitor, glutaminase inhibitor, steroid or methylating agent; or combinations thereof.

216. The method according to any one of claims 209-215, wherein the anticancer therapy comprises: Ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, opzomib, ixazomib, acalabrutinib, zanubrutinib, IMO-08400, ederaris, erblisse, CB-839, fludarabine, or thalidomide; or combinations thereof.

217. The method according to any one of claims 209-216, wherein the anticancer therapy comprises dexamethasone.

218. The method according to any one of claims 209-216, wherein the anticancer therapy comprises ibrutinib.

219. The method according to any one of claims 209-216, wherein the anticancer therapy comprises ibrutinib and rituximab.

220. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bendamustine.

221. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bendamustine and rituximab.

222. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bortezomib.

223. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bortezomib and dexamethasone.

224. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bortezomib and rituximab.

225. The method according to any one of claims 209-216, wherein the anticancer therapy comprises bortezomib, rituximab, and dexamethasone.

226. The method according to any one of claims 209-216, wherein the anticancer therapy comprises chlorambucil.

227. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cladribine.

228. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cladribine and rituximab.

229. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R).

230. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cyclophosphamide, prednisone, and rituximab (i.e., CPR).

231. The method according to any one of claims 209-216, wherein the anticancer therapy comprises fludarabine.

232. The method according to any one of claims 209-216, wherein the anticancer therapy comprises fludarabine and rituximab.

233. The method according to any one of claims 209-216, wherein the anticancer therapy comprises fludarabine, cyclophosphamide, and rituximab.

234. The method according to any one of claims 209-216, wherein the anticancer therapy comprises rituximab.

235. The method according to any one of claims 209-216, wherein the anticancer therapy comprises rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).

236. The method according to any one of claims 209-216, wherein the anticancer therapy comprises thalidomide.

237. The method according to any one of claims 209-216, wherein the anticancer therapy comprises thalidomide and rituximab.

238. The method according to any one of claims 209-216, wherein the anticancer therapy comprises venetoclax.

239. The method according to any one of claims 209-216, wherein the anticancer therapy comprises cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD).

240. The method according to any one of claims 209-216, wherein the anticancer therapy comprises a hypomethylating agent.

241. The method according to any one of claims 1-240, wherein the subject has previously received at least 6 cycles of a hypomethylating agent.

242. The method according to any one of claims 1-241, wherein the subject has previously received etoposide chemotherapy.

243. The method according to any one of claims 1-242, wherein the subject has previously received a bone marrow transplant.

244. The method according to any one of claims 1-243, wherein the subject has previously received a hematopoietic cell transplant.

245. The method according to any one of claims 1-244, wherein the subject has previously received a stem cell transplant.

246. The method according to any one of claims 1-245, wherein the subject has previously received an autologous stem cell transplant.

247. The method according to any one of claims 1-246, wherein the subject has previously received an allogeneic stem cell transplant.

248. The method according to any one of claims 1-247, wherein the subject has previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM conditioning).

249. The method according to any one of claims 1-248, wherein the subject has previously received re-induction therapy.

250. The method according to any one of claims 1-249, wherein the subject has previously achieved a partial response.

251. The method according to any one of claims 1-250, wherein the subject has previously achieved a good partial response.

252. The method according to any one of claims 1-251, wherein the subject has previously achieved a complete response.

253. The method according to any one of claims 1-252, wherein the subject has a mutation in the RICTOR.

254. The method of claim 253, wherein the subject has the N1065S mutation in the RICTOR.

255. The method according to any one of claims 1-254, wherein the subject has a mutation in MYD88.

256. The method of claim 255, wherein the subject has the L265P mutation in MYD88.

257. The method according to any one of claims 1-256, wherein the subject has a mutation in TET2.

258. The method according to any one of claims 1-257, wherein the subject does not have a mutation in CXCR4.

259. The method according to any one of claims 1-257, wherein the subject has a mutation in CXCR4.

260. The method according to any one of claims 1-259, wherein the subject has a mutation in SF3B1 (e.g., insertion, deletion, loss, or spliceosome mutation).

261. The method according to any one of claims 1-260, wherein the subject has a mutation in U2AF1 (e.g., insertion, deletion, loss, or spliceosome mutation).

262. The method according to any one of claims 1-261, wherein the subject has a mutation in FLT3 kinase (e.g., insertion, deletion, loss, or internal tandem duplication).

263. The method of claim 262, wherein the mutation of the FLT3 kinase is selected from: internal tandem repeat (ITD); mutations in D835, F691, K663, or N841; and combinations of ITD and mutations in D835, F691, K663, or N841.

264. The method of claim 263, wherein the mutation in the FLT3 kinase is D835H.

265. The method of claim 263, wherein the mutation in the FLT3 kinase is D835V.

266. The method of claim 263, wherein the mutation in the FLT3 kinase is D835Y.

267. The method of claim 263, wherein the mutation in the FLT3 kinase is K663Q.

268. The method of claim 263, wherein the mutation in the FLT3 kinase is N841I.

269. The method of claim 263, wherein the mutation in the FLT3 kinase is ITD and D835V.

270. The method of claim 263, wherein the mutation in the FLT3 kinase is ITD and F691L.

271. The method of claim 263, wherein the mutation in the FLT3 kinase is ITD and D835Y.

272. The method according to any one of claims 1-271, wherein the subject has a mutation in STAG2 (e.g., insertion, deletion, or loss).

273. The method according to any one of claims 1-272, wherein the subject has a mutation in DNMT3A (e.g., insertion, deletion, or loss).

274. The method according to any one of claims 1-273, wherein the subject has a mutation in BCOR (e.g., insertion, deletion, or loss).

275. The method according to any one of claims 1-274, wherein the subject has a mutation in WT1 (e.g., insertion, deletion, or loss).

276. The method according to any one of claims 1-275, wherein the subject has a mutation in NRAS (e.g., insertion, deletion, or loss).

277. The method according to any one of claims 1-276, wherein the subject shows early progress.

278. The method according to any one of claims 1-277, wherein the subject has not previously received a BTK inhibitor.

279. The method according to any one of claims 1-278, wherein the subject achieves a partial response after administration of the IRAK4 modified compound.

280. The method according to any one of claims 1-279, wherein the subject achieves a good partial response after administration of the IRAK4 modified compound.

281. The method according to any one of claims 1-279, wherein the subject achieves a complete response after administration of the IRAK4 modified compound.

282. The method according to any one of claims 1-281, wherein after administration of the IRAK4 modified compound, the subject's IL-1-induced signal transduction is reduced.

283. The method according to any one of claims 1-282, wherein the subject’s cytokine production is reduced after administration of the IRAK4 modified compound.

284. The method according to any one of claims 1-283, wherein the IRAK4 modified compound is administered until disease progression or unacceptable toxicity occurs.

285. The method according to any one of claims 209-284, wherein the subject has previously received a BTK inhibitor for cancer treatment.

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