A method for treating cancer in patients who have not previously received BCL2 inhibitor treatment.

Abstract

This disclosure relates to methods for treating specific diseases and disorders (e.g., IRAK4-related diseases and disorders).

Description

[Technical Field]

[0001] (Related applications) This application claims the interests of U.S. Provisional Patent Application No. 63 / 470,338, filed on 1 June 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 Toll / IL-1 receptor (TIR) ​​signaling. Diverse IRAK enzymes are important components in signaling pathways mediated by interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs) (Janssens, S., et al. Mol. Cell. 11, 2003, 293-302). The mammalian IRAK family consists of four members: IRAK1, IRAK2, IRAK3, and IRAK4. These proteins are characterized by a typical N-terminal death domain and a centrally located kinase domain that mediate interactions with MyD88 family adapter proteins. IRAK proteins, as well as MyD88, have been shown to play a role in the transmission of signals other than those derived from the IL-1R receptor, including signals induced by the activation of the IL-18 receptor (Kanakaraj, et al. Exp. Med. 189(7):1999, 1129-38) and 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 "master IRAK." Under overexpression conditions, all IRAKs can mediate the activation of the nuclear factor-κB (NF-κB) and stress-induced mitogen-activated protein kinase (MAPK) signaling cascades. However, only IRAK-1 and IRAK4 have been shown to possess active kinase activity.IRAK-1 kinase activity may not be essential for its function in IL-1-induced NF-κB activation (Kanakaraj et al, J.Exp.Med.187(12),1998,2073-2079) and (Xiaoxia Li, et al. Mol.Cell.Biol.19(7),1999,4643-4652), while IRAK4 requires its kinase activity for signal transduction (Li S, et al. Proc.Natl.Acad.Sci.USA 99(8),2002,5567-5572) and (Lye, E et al, J.Biol.Chem.279(39);2004,40653-8). Given the central role of IRAK4 in Toll-like / IL-1R signaling and immunological defense, IRAK4 inhibitors are considered beneficial therapeutic agents in inflammatory diseases, sepsis, and autoimmune disorders (Wietek C, et al, Mol. Interv. 2: 2002, 212-215).

[0003] Mice lacking IRAK4 are viable and exhibit complete suppression of inflammatory cytokine production in response to IL-1, IL-18, or LPS (Suzuki et al. Nature, 416(6882), 2002, 750-756). Similarly, human patients lacking IRAK4 are severely immunocompromised and do not respond to these cytokines (Medvedev et al. J.Exp.Med., 198(4), 2003, 521-531 and Picard et al. Science 299(5615), 2003, 2076-2079). Knock-in mice containing inactive IRAK4 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), demonstrating that IRAK4 kinase activity is essential for cytokine generation in response to TLR ligands, MAPK activation, and induction of NF-κB regulatory genes (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 EAEs due to a decrease in inflammatory cells infiltrating the CNS and a reduction 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 hematological malignancy in adults, with an estimated 80,000 new cases and 20,000 deaths in the United States in 2023. While the molecular pathologies driving NHL are diverse, a common theme is the activity of the NF-κB signaling pathway. Specific molecular changes driving this pathway have been identified in subsets of NHL. For example, diffuse large B-cell lymphoma (DLBCL) is an invasive lymphoma that can occur in lymph nodes or outside the lymphatic system, in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. DLBCL is a cancer of B cells, a type of white blood cell responsible for antibody production. It is the most common type of NHL among adults, with an annual incidence of 7-8 cases per 100,000 people. This cancer primarily occurs in older individuals, with a median age of diagnosis of approximately 70 years, although it can rarely occur in children and young adults. DLBCL is an invasive tumor, and the first sign of this disease is typically the observation of a rapidly growing mass. The five-year survival rate is only 58%. DLBCL is named according to the cells of their origin and has subtypes, including germinal center B-cell-like (GCB) and activated B-cell-like (ABC). These differ in that they have a poor prognosis and, in some cases, require a special approach to treatment.

[0005] Many DLBCL-related tumors contain genetic abnormalities in the BLC2 family of proteins that regulate apoptotic processes within these cells. Abnormal function and overexpression of BLC2 proteins can lead to tumor growth and cancer progression. Therefore, BLC2 inhibitors have become a therapeutic approach for treating lymphoid cancers, with venetoclax (VEN) emerging as the first FDA-approved orally administered BLC2 antagonist.

[0006] 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 demonstrated as a potential therapeutic target in human AML. Although AML is a heterogeneous disease, common features of leukemic blasts include high proliferative capacity within the mitotic pool, increased stem cell autoregeneration, and blockade of differentiation in a relatively immature state. It is also widely accepted that specific gene mutations present in AML cells can guide therapy and determine how long patients may survive.

[0007] Myelodysplastic syndromes are conditions that can occur when hematopoietic cells in the bone marrow become abnormal. The main clinical problems in these disorders are the pathological conditions caused by cytopenia and the possibility 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, with an IPSS score of ≥2.5, and immature blast cells may constitute more than 5% of the cells in the bone marrow. Low blood cell counts can lead to anemia, neutropenia, or thrombocytopenia. HrMDS has a greater risk of progression to AML and a shorter survival time; if patients are left untreated, the median survival time is only 0.8 years.

[0008] Another example of NHL is Waldenström macroglobulinemia (WM). WM is a non-Hodgkin lymphoma that affects two types of B cells: lymphoplasmacytoid cells and plasma cells. WM is characterized by high levels of circulating antibodies, immunoglobulin M (IgM), produced and secreted by the cells involved in the disease. WM is a rare disease, with only about 1,500 cases reported per year in the United States. There is no single acceptable treatment for WM, and clinical outcomes vary significantly due to gaps in knowledge regarding the molecular basis of the disease. The objective response rate is high (>80%), but the complete response rate is low (0-15%).

[0009] 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, including infectious agents (Epstein-Barr virus, hepatitis C virus, and human T-cell leukemia virus), radiation and chemotherapy, and autoimmune diseases. As a group, 2.1% of the U.S. population will be affected by non-Hodgkin lymphoma during their lifetime. The proportion of people who survive more than 5 years after diagnosis is 71%.

[0010] Considering the above, there is a clear and unmet need for additional therapies for the treatment of IRAK4-related cancers and other diseases. [Overview of the project]

[0011] In certain embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering an IRAK4 inhibitor or an IRAK4 degrader to the subject, wherein the subject has not previously received a BLC2 inhibitor for the treatment of cancer. [Brief explanation of the drawing]

[0012] [Figure 1A]This graph shows the results of a clinical trial on the efficacy of emabsearchib (compound 1) administration for the reduction of bone marrow (BM) blasts in patients with hematological malignancies. Blasts are immature white blood cells that are normally found in small numbers in healthy bone marrow. High levels of blasts circulating in the blood are associated with cancer. In this clinical trial, changes in blast levels were measured before and after treatment with compound 1. Here, the relative changes in blast levels before and after compound 1 are compared between patients who had previously received BLC2 inhibitors in prior treatment and patients who were BLC2 inhibitor inexperienced. The comparison groups included 22 patients with high-risk myelodysplastic syndromes (hrMDS) and 10 patients with acute myeloid leukemia (AML), respectively. Patients who were BLC2 inhibitor inexperienced (e.g., venetoclax) showed a significant reduction in blasts compared to patients who had been previously exposed to BLC2 inhibitors. Therefore, the significant difference in the best myeloblast count between baseline and post-baseline between subjects who had not been previously exposed to BLC2 inhibitors and subjects who had been exposed to BLC2 inhibitors suggests that subjects who had not been previously exposed to BLC2 inhibitors were more likely to respond to IRAK4 mediators such as compound 1. [Figure 1B] Figure 1A shows a graph illustrating baseline and best-post-treatment blast levels for the subjects. Subjects who had not been previously exposed to BLC2 inhibitors showed a significantly greater decrease in myeloblast count from baseline to best-post-baseline state compared to subjects who had been previously exposed to BLC2 inhibitors. Each patient is shaded according to their diagnosis, and high-risk myelodysplastic syndrome (MDS) patients tend to have lower blast levels than acute myeloid leukemia (AML) patients. [Modes for carrying out the invention]

[0013] Results from an ongoing Phase 1 trial demonstrated the clinical activity of the IRAK4 inhibitor emabsearchib (compound 1) in patients with relapsed / refractory AML and high-risk MDS. To support the development of effective treatment regimens with compound 1, a study was conducted to monitor bone marrow (BM) samples from AML and high-risk MDS patients with different treatment histories. Clinical response data showed that patients without prior treatment with BLC2 inhibitors had a higher response rate to compound 1 compared to patients who had previously been exposed to BLC2 inhibitors, as evidenced by a decrease in BM blast counts in hematology. This disclosure relates to a method for treating cancer using compound 1 and other IRAK4 inhibitors or degrading agents, wherein the subjects have not previously received treatment with BLC2 inhibitors.

[0014] In certain embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering an IRAK4 inhibitor or an IRAK4 degrader to the subject, wherein the cancer has not been exposed to a BLC2 inhibitor.

[0015] In certain embodiments, the subject has not previously received BLC2 inhibitors for cancer treatment.

[0016] In certain preferred embodiments, the BLC2 inhibitor is a BH3 mimetic.

[0017] In certain embodiments, the BLC2 inhibitor is venetoclax, navitoclax, ABT-737, or ovatoclax. In certain preferred embodiments, the BLC2 inhibitor is venetoclax.

[0018] In certain embodiments, the IRAK4-modified compound is an IRAK4 inhibitor. In other embodiments, the IRAK4-modified compound is an IRAK4 degrader.

[0019] Methods and compounds related to the content of this disclosure can be found, for example, in U.S. Patent Nos. 10,160,753, 9,732,095, 10,758,518, and 11,419,875; U.S. Patent Applications Nos. 17 / 680,995, 18 / 019,400, and 18 / 037,697, and the pending PCT Patent Application No. PCT / US23 / 21812. The content of these documents, in particular with respect to the IRAK4 inhibitors, therapeutic regimens, and disease indications disclosed herein, is fully incorporated herein by reference.

[0020] IRAK4 inhibitors In general, the methods disclosed herein may be carried out using any IRAK4 inhibitor. For example, the methods may be carried out using 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 above international applications, in particular with respect to the IRAK4 inhibitors disclosed therein, are fully incorporated herein by reference.

[0021] In certain embodiments, the IRAK4 inhibitor is of formula I:

[0022] [ka] It is represented as, or a pharmaceutically acceptable salt thereof, During the ceremony, X1 and X3 are independently CH or N, and X2 is CR2 or N, provided that one or only one of X1, X2, or X3 is N. A is either O or S, Y is either -CH2- or O. Z is an aryl or heterocyclyl, R1 is a heterocyclyl that, each instance, is independently substituted with a halo or optionally substituted with alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR substituents.a R b is, R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR a R b where the substituent is alkyl, amino, halo or hydroxyl, R3 is, each time it occurs, alkyl or hydroxyl, R a and R b are, independently, hydrogen, alkyl, acyl or heterocyclyl, "m" and "n" are, independently, 0, 1 or 2, "p" is 0 or 1.

[0023] In certain embodiments, A is O or S, Y is -CH2- or O, Z is aryl or heterocyclyl, R1 is, each time it occurs, independently halo or optionally substituted heterocyclyl, and the substituent is alkyl, aminoalkyl, halo, or -NR a R b where R a and R b are, independently, hydrogen, alkyl, or heterocyclyl, R2 is hydrogen, cycloalkyl, heterocyclyl or -NR a R b and "m" is 0 and "n" is 1.

[0024] In other embodiments, A is O or S, Y is -CH2- or O, Z is aryl or heterocyclyl, R1 is, each time it occurs, independently halo or optionally substituted heterocyclyl, and the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or -NR a R b where R a and R b are, independently, hydrogen, alkyl, or heterocyclyl, R2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl or -NR a Rb The substituent is selected from amino, halo, or hydroxyl, and "m" and "n" are independently 0, 1, or 2, and "p" is 0 or 1.

[0025] In a particular embodiment,

[0026] [ka] teeth

[0027] [ka] That is the case.

[0028] In certain embodiments, Z is an aryl or a 5-membered or 6-membered heterocyclyl. In certain embodiments, Z is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, The heterocyclils are optionally substituted heterocyclils selected from tetrahydropyranil, morpholinil, thiomorpholinil, 1,4-dioxanil, dioxidethiomorpholinil, oxapiperazinil, oxapiperidyl, tetrahydrofuryl, tetrahydropyranil, tetrahydrothiophenyl, dihydropyranil, and azabicyclo[3.2.1]octanil, each of which is alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or -NR. a R b Replaced by any choice, R a and R b These are independently hydrogen, alkyl, or acyl.

[0029] In certain embodiments, the IRAK4 inhibitor is defined by formula (IA):

[0030] [ka] Represented by or a pharmaceutically acceptable salt thereof. In certain embodiments, A is O or S, Y is -CH2- or O, and R1 is, each occurrence independently, a heterocycline substituted with a halo or optionally, alkyl, aminoalkyl, halo, or -NR a R b And R a and R b R2 is independently hydrogen, alkyl, or heterocycline, and R2 is hydrogen, cycloalkyl, heterocycline, or -NR a R b In this embodiment, "m" is 0 and "n" is 1. In other embodiments, A is O or S, Y is -CH2- or O, and R1 is, each occurrence, independently a halo or optionally substituted heterocycline, where the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or -NR a R b And R a and R b R2 is independently hydrogen, alkyl, or heterocycline, and R2 is hydrogen, cycloalkyl, optionally substituted heterocycline, or -NR a R b The substituent is selected from amino, halo, or hydroxyl, and "m" and "n" are independently 0, 1, or 2.

[0031] In certain embodiments, the IRAK4 inhibitor is defined by formula (IB):

[0032] [ka] Represented by or a pharmaceutically acceptable salt thereof. In certain embodiments, A is O or S, Y is -CH2- or O, and R1 is, each occurrence independently, a heterocycline substituted with a halo or optionally, alkyl, aminoalkyl, halo, or -NR a R bAnd R a and R b R2 is independently hydrogen, alkyl, or heterocycline, and R2 is hydrogen, cycloalkyl, heterocycline, or -NR a R b In other embodiments, A is O or S, Y is -CH2- or O, and R1 is, each occurrence, independently a halo or optionally substituted heterocycline, where the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or -NR a R b And R a and R b R2 is independently hydrogen, alkyl, or heterocycline, and R2 is hydrogen, cycloalkyl, optionally substituted heterocycline, or -NR a R b The substituent is selected from amino, halo, or hydroxyl, and "m" and "n" are independently 0, 1, or 2.

[0033] In certain embodiments, the IRAK4 inhibitor is of formula (IC):

[0034] [ka] It is represented by or a pharmaceutically acceptable salt thereof.

[0035] In certain embodiments, R1 is a heterocycline that is optionally substituted, and the substituents may be alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR a R b And R a and R b R1 is independently hydrogen or acyl. In other embodiments, R1 is optionally substituted heterocycline, and the substituents are alkyl, aminoalkyl, halo, or -NR a R b And R a and R bR1 is independently hydrogen or acyl. In yet another embodiment, R1 is an optionally substituted heterocycline, where the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR a R b And R a and R b R1 is independently hydrogen, alkyl, or heterocyclyl. In certain embodiments, R1 is pyridyl, pyrazolyl, pyrrolidinyl, or piperidinyl. In certain embodiments, R1 is optionally substituted pyrazolyl, and the substituent is alkyl, hydroxyl, or -NR a R b In other embodiments, R1 is a halo.

[0036] In certain embodiments, R2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR a R b The substituent is selected from amino, halo, or hydroxyl. In certain embodiments, R2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR a R b The substituent is selected from amino, halo, or hydroxyl. In certain embodiments, R2 is an optionally substituted heterocyclyl selected from piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanil, or azabicyclo[3.2.1]octanil, and the substituent is hydroxyl, halo, alkyl, or amino. In certain embodiments, R2 is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl. In other embodiments, R2 is hydrogen. In yet another embodiment, is cycloalkyl. In certain embodiments, R2 is cyclopropyl.

[0037] In certain embodiments, R3 is an alkyl group.

[0038] In certain embodiments, m is 0 and p is 1. In other embodiments, m is 0 or 2 and p is 0 or 1.

[0039] In certain embodiments, the IRAK4 inhibitor is selected from the following: 6'-amino-N-(2-morpholinoxazolo[4,5-b]pyridine-6-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-amino-N-(5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-[2,3'-bipyridine]-6-carboxamide hydrochloride; N-(5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide hydrochloride; N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-6-(1H-pyrazole-4-yl)picolinamide hydrochloride; N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-6-(1H-pyrazole-4-yl)picolinamide; 2-(2-methylpyridine-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 6-Chloro-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)picolinamide; N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-6-(1-methyl-1H-pyrazole-4-yl)picolinamide; 2-(2-chloropyridine-4-yl)-N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; (S)-2-(2-methylpyridine-4-yl)-N-(2-morpholino-5-(pyrrolidine-3-ylamino)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 6'-amino-N-(2-morpholinoxazolo[5,4-b]pyridine-5-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-amino-N-(2-morpholinothiazolo[4,5-c]pyridine-6-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-amino-N-(2-morpholinothiazolo[5,4-b]pyridine-5-yl)-[2,3'-bipyridine]-6-carboxamide; 2-(2-methylpyridine-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 6'-amino-N-(2-morpholinothiazolo[4,5-b]pyridine-6-yl)-[2,3'-bipyridine]-6-carboxamide; N-(2-morpholinothiazolo[4,5-b]pyridine-6-yl)-6-(1H-pyrazole-4-yl)picolinamide; 3-(4-(aminomethyl)piperidine-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridine-6-yl)benzamide; 2-(4-(aminomethyl)piperidine-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridine-6-yl)benzamide; 2-(2-methylpyridine-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-6-(1H-pyrazole-4-yl)picolinamide; N-(2,5-di(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-6-(1H-pyrazole-4-yl)picolinamide; N-(2,5-di(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(2,5-dimorpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(4-methylpiperazine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-2-(6-methoxypyridine-3-yl)oxazole-4-carboxamide; N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-3-yl)oxazole-4-carboxamide; N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-2-(2-hydroxypyridine-3-yl)oxazole-4-carboxamide; 2-(2-hydroxypyridine-3-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-2-(6-hydroxypyridine-3-yl)oxazole-4-carboxamide; 2-(2-methoxypyridine-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 2-(2-methylpyridine-3-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 2-(3-methylpyridine-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-2-(3-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(6-methylpyridine-3-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 6-(1-methyl-1H-pyrazole-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)picolinamide; N-(2,5-di(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-2-(6-methylpyridine-3-yl)oxazole-4-carboxamide; (S)-N-(5-(3-aminopyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (R)-N-(5-(3-aminopyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (S)-2-(3-aminopyrrolidine-1-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; (S)-6-(3-hydroxypyrrolidine-1-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)picolinamide; (S)-6-(3-aminopyrrolidine-1-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)picolinamide; (S)-2-(3-hydroxypyrrolidine-1-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(3-hydroxypyrrolidine-1-yl)oxazole-4-carboxamide; (S)-2-(3-aminopyrrolidine-1-yl)-N-(5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 2-(2-methylpyridine-4-yl)-N-(5-(piperidine-1-yl)-2-(pyrrolidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide hydrochloride; N-(2-(2,6-dimethylmorpholino)-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide hydrochloride; N-(2,5-di(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-6-(1-methyl-1H-pyrazole-4-yl)picolinamide hydrochloride; 6-(1-methyl-1H-pyrazole-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)picolinamide; N-(2,5-di(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-3-yl)oxazole-4-carboxamide hydrochloride; N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(2-methylpyridine-3-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 2-(2-hydroxypyridine-3-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; N-(2,5-di(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-2-(2-methoxypyridine-4-yl)oxazole-4-carboxamide; 2-(6-methoxypyridine-3-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 2-(2-methoxypyridine-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; (S)-N-(5-(3-fluoropiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(6-methylpyridine-3-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 2-(3-methylpyridine-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; (S)-6-(3-aminopyrrolidine-1-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)picolinamide; (S)-6-(3-hydroxypyrrolidine-1-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)picolinamide; (S)-6-(3-aminopyrrolidine-1-yl)-N-(2,5-di(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)picolinamide; (S)-N-(2,5-di(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-6-(3-hydroxypyrrolidine-1-yl)picolinamide; (S)-2-(3-aminopyrrolidine-1-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; (S)-N-(5-(3-aminopyrrolidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (S)-2-(3-aminopyrrolidine-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (S)-2-(3-hydroxypyrrolidine-1-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-6-(3-hydroxypyrrolidine-1-yl)picolinamide; (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(3-hydroxypyrrolidine-1-yl)oxazole-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazole-4-yl)picolinamide; (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazole-4-yl)oxazole-4-carboxamide; N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(6-methoxypyridine-3-yl)oxazole-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(6-methoxypyridine-3-yl)oxazole-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(6-methoxypyridine-3-yl)oxazole-4-carboxamide; (S)-N-(5-(azetidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-6-(3-hydroxypyrrolidine-1-yl)picolinamide; N-(5-(3-hydroxyazetidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)thiophene-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(4-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide (R)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(4-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)furan-2-carboxamide; N-(5-(azetidine-1-yl)-2-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(2-methylpyridine-4-yl)-N-(2-(piperidine-1-yl)-5-(pyrrolidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 2-(2-methylpyridine-4-yl)-N-(2-morpholino-5-(pyrrolidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 5-(2-methylpyridine-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)furan-2-carboxamide; N-(5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(2-aminopyridine-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide hydrochloride; N-(5-(azetidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (R)-N-(5-(3-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (R)-N-(5-(3-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)furan-2-carboxamide; (S)-6-(1-(2-hydroxypropyl)-1H-pyrazole-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)picolinamide N-(5-(4-fluoropiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)furan-2-carboxamide N-(5-(4-fluoropiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide hydrochloride N-(5-(1-methyl-1H-pyrazole-4-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(4-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)furan-2-carboxamide; N-(5-(3-fluoropiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(6-methoxypyridine-3-yl)oxazole-4-carboxamide; N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(6-methoxypyridine-3-yl)oxazole-4-carboxamide; N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(6-methoxypyridine-3-yl)oxazole-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)thiophene-2-carboxamide; N-(5-(azetidine-1-yl)-2-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(2-methylpyridine-4-yl)-N-(2-(piperidine-1-yl)-5-(pyrrolidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 5-(2-methylpyridine-4-yl)-N-(2-morpholino-5-(piperidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)furan-2-carboxamide; N-(5-(azetidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(2-methylpyridine-4-yl)-N-(2-morpholino-5-(pyrrolidine-1-yl)oxazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; N-(5-(4-hydroxypiperidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)furan-2-carboxamide; (R)-N-(5-(3-hydroxypiperidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-5-(2-methylpyridine-4-yl)furan-2-carboxamide; N-(5-(furan-3-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(3-fluoropiperidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(4-hydroxypiperidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(4-fluoropiperidine-1-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; (S)-N-(5-(3-aminopiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(2-methylpyridine-4-yl)-N-(2-morpholino-5-(1H-pyrazole-4-yl)thiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; N-(5-(6-fluoropyridine-3-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(2-(3-hydroxypiperidine-1-yl)-5-(piperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(2-acetamidopyridine-4-yl)-N-(5-(4-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; N-(2-(3-hydroxypiperidine-1-yl)-5-(4-hydroxypiperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; 2-(2-acetamidopyridine-4-yl)-N-(5-(3-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide; 2-(2-aminopyridine-4-yl)-N-(5-(3-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide hydrochloride; 5-(2-aminopyridine-4-yl)-N-(5-(4-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)furan-3-carboxamide hydrochloride; 2-(2-aminopyridine-4-yl)-N-(5-(4-hydroxypiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide hydrochloride; 2-(2-aminopyridine-4-yl)-N-(5-(4-fluoropiperidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)oxazole-4-carboxamide hydrochloride; N-(5-(2-fluoropyridine-4-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(4-fluoropiperidine-1-yl)-2-(3-hydroxypiperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide; N-(5-(4-aminopiperidine-1-yl)-2-(3-hydroxypiperidine-1-yl)thiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide hydrochloride; and N-(5-(2-hydroxypyridine-4-yl)-2-morpholinothiazolo[4,5-b]pyridine-6-yl)-2-(2-methylpyridine-4-yl)oxazole-4-carboxamide hydrochloride; or its pharmaceutically acceptable salts or stereoisomers.

[0040] In certain preferred embodiments, the IRAK4 inhibitor is

[0041] [ka] In other preferred embodiments, the IRAK4 inhibitor is

[0042] [ka] It is a pharmaceutically acceptable salt.

[0043] In certain preferred embodiments, the IRAK4 inhibitor is

[0044] [ka] In other preferred embodiments, the IRAK4 inhibitor is

[0045] [ka] It is a pharmaceutically acceptable salt.

[0046] In certain preferred embodiments, the IRAK4 inhibitor is

[0047] [ka] In other preferred embodiments, the IRAK4 inhibitor is

[0048] [ka] It is a pharmaceutically acceptable salt.

[0049] In certain preferred embodiments, the IRAK4 inhibitor is: In other preferred embodiments, the IRAK4 inhibitor is:

[0050] [ka] It is a pharmaceutically acceptable salt.

[0051] In certain preferred embodiments, the IRAK4 inhibitor is: In other preferred embodiments, the IRAK4 inhibitor is:

[0052] [ka] It is a pharmaceutically acceptable salt.

[0053] In certain preferred embodiments, the IRAK4 inhibitor is

[0054] [ka] In other preferred embodiments, the IRAK4 inhibitor is

[0055] [ka] It is a pharmaceutically acceptable salt.

[0056] In certain preferred embodiments, the IRAK4 inhibitor is

[0057] [ka] In other preferred embodiments, the IRAK4 inhibitor is

[0058] [ka] It is a pharmaceutically acceptable salt.

[0059] In certain preferred embodiments, the IRAK4 inhibitor is

[0060] [ka] In other preferred embodiments, the IRAK4 inhibitor is

[0061] [ka] It is a pharmaceutically acceptable salt.

[0062] In certain preferred embodiments, the IRAK4 inhibitor is

[0063] [ka] In other preferred embodiments, the IRAK4 inhibitor is

[0064] [ka] It is a pharmaceutically acceptable salt.

[0065] In general, the compounds described herein can be administered in any amount or manner that elicits a desired response in a subject. For example, 100 to 400 mg of an IRAK4 inhibitor selected from the compounds described herein can be administered to a subject twice daily, or 200 to 1000 mg of an IRAK4 inhibitor can be administered to a subject once daily. In certain embodiments, 100 to 400 mg of an IRAK4 inhibitor is administered to the subject twice daily. In certain embodiments, 200 to 400 mg of an IRAK4 inhibitor is administered to the subject twice daily. In certain preferred embodiments, 250 to 350 mg of an IRAK4 inhibitor is administered to the subject twice daily. In certain embodiments, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, or approximately 500 mg of the IRAK4 inhibitor is administered to the subject twice daily. In certain embodiments, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, or approximately 400 mg of the IRAK4 inhibitor is administered to the subject twice daily. In certain embodiments, approximately 50 mg, 100 mg, 200 mg, or 300 mg of the IRAK4 inhibitor is administered to the subject twice daily. In certain embodiments, approximately 50 mg of the IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 200 mg of the IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 225 mg of the IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 250 mg of the IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 275 mg of the IRAK4 inhibitor is administered to the subject twice daily. In a particularly preferred embodiment, approximately 300 mg of the IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 325 mg of the IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 350 mg of the IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 375 mg of the IRAK4 inhibitor is administered to the subject twice daily.In other embodiments, approximately 400 mg of the IRAK4 inhibitor is administered to the subject twice daily.

[0066] In certain embodiments, approximately 25 mg, 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 the IRAK4 inhibitor is administered to the subject once daily. In certain embodiments, approximately 50 mg of the IRAK4 inhibitor is administered to the subject once daily. In certain embodiments, approximately 75 mg of the IRAK4 inhibitor is administered to the subject once daily. In certain embodiments, approximately 100 mg of the IRAK4 inhibitor is administered to the subject once daily. In certain embodiments, approximately 125 mg of the IRAK4 inhibitor is administered to the subject once daily. In certain embodiments, approximately 150 mg of an IRAK4 inhibitor is administered to the subject once daily.

[0067] In certain preferred embodiments, the IRAK4 inhibitor or degrading agent is administered orally to the subject. In certain embodiments, about 50 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject twice daily. In other embodiments, about 200 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject twice daily. In other embodiments, about 250 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject twice daily. In particularly preferred embodiments, about 300 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject twice daily. In other embodiments, about 325 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject twice daily. In other embodiments, about 350 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject twice daily. In other embodiments, about 375 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject twice daily. In another embodiment, approximately 400 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject twice daily. In yet another embodiment, approximately 50 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject once daily. In yet another embodiment, approximately 75 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject once daily. In yet another embodiment, approximately 100 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject once daily. In yet another embodiment, approximately 125 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject once daily. In yet another embodiment, approximately 150 mg of the IRAK4 inhibitor or degrading agent is administered orally to the subject once daily.

[0068] In other embodiments, the IRAK4 inhibitor is PF-06650833 or BAY1830839.

[0069] IRAK4 Decomposing Agent In certain embodiments, the method includes administering an IRAK4 degrading agent. In certain embodiments, the IRAK4 degrading agent is KT-474.

[0070] Combination therapy In certain embodiments, the method further includes co-administration of a BTK inhibitor. In certain embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebratinib, or HM71224. In certain embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebratinib, or HM71224. In certain embodiments, the BTK inhibitor is acalabrutinib. In certain embodiments, the method includes administering 200 mg of acalabrutinib daily. In certain embodiments, acalabrutinib is administered orally. In certain embodiments, the method includes administering 200 mg of acalabrutinib orally daily. In certain preferred embodiments, the BTK inhibitor is ibrutinib. In certain embodiments, the method includes administering 420 mg of ibrutinib daily. In other embodiments, the method includes administering 420 mg of ibrutinib daily. In certain embodiments, ibrutinib is administered orally. In certain preferred embodiments, 420 mg of ibrutinib is administered orally daily. In other preferred embodiments, the method includes administering 560 mg of ibrutinib daily. In certain embodiments, the BTK inhibitor is zanubrutinib. In certain embodiments, the method involves administering 160 mg of zanubrutinib twice daily. In other embodiments, the method includes administering 320 mg of zanubrutinib once daily. In certain embodiments, zanubrutinib is administered orally. In certain 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 certain embodiments, the method further comprises co-administering one or more of the following: ABT-737, BAY-1143572, 5-fluorouracil, abiraterone acetate, acetylcholine, ad-trastuzumab emtansine, afatinib, aldesleukin, alectinib, alemtuzumab, alitretinoin, aminolevulinic acid, anastrozole, anastrozole, aprepitant, arsenic trioxide, asparaginase, erwinia chrysanthemis, atezolizumab, axitinib,Azacitidine, Bellinostat, Bendamustine, Benzylisothiocyanate, Bevacizumab, Bexarotene, Bicalutamide, Bleomycin, Blinatumomab, Bortezomib, Bosutinib, Brentuximab Vedotin, Busulfan, Cabazitaxel, Cabozantinib, Capecitabine, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Cetuximab, Chlorambucil, Cisplatin, Clofarabine, Cobimetinib, Copanlisib, Crizotinib, Cyclophosphamide, Cytarabine, Dabrafenib, Dacarbazine, Dacarbazine Dactinomycin, daratumumab, dasatinib, daunorubicin, decitabine, defibrotide sodium, degarelix, denileukin difutitox, denosumab, dexamethasone, dexrazoxane, dihydrotestosterone (DHT), dinutuximab, docetaxel, doxorubicin, elotuzumab, eltrombopag, enzalutamide, epirubicin, eribulin mesylate, erlotinib, etoposide, everolimus, exemestane, exemestane, filgrastim, fludarabine phosphate, flutamide, fulvestrant, fulvest Lanrant, gefitinib, gemcitabine, gemtuzumab, gemtuzumab-ozogamicin, glucarpidase, goserelin acetate, hydroxyurea, ibritumomab-tiuxetan, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, imiquimod, interferon alpha-2b, ipilimumab, irinotecan, ixabepyrone, ixazomib, lanreotide, lapatinib, lenalidomide, lenvatinib, letrozole, leucovorin, leuprolide, lomustine, mechloretamine, megestrol acetate, melphalan, mercapt Toprin, Mesna, Methotrexate, Mitomycin C, Mitoxantrone, Navitoclax, Necitumumab, Nelarabine, Netupitant, Nilotinib, Niltamide, Nivolumab, Obinutuzumab, Ofatumumab, Olaparib, Omasetaxin Mepesuccinate, Osimertinib, Oxaliplatin, Ozogamicin, Paclitaxel, Palbociclib, Palifermin, Pamidronate, Panitumumab, Panobinostat, Pazopanib, Pegaspargaze, Peginterferon Alpha-2b, Pembrolizumab, Pemetrexed, Pertuzumab,Prelixafor, pomalidomide, ponatinib, pralatrexate, prednisone, procarbazine, propranolol, radium-223 chloride, raloxifene, ramucirumab, rasburicase, regorafenib, rituximab, lorapitant, romidepsin, romiplostim, ruxolitinib, siltuximab, ciproisel-t, sonidecib, sorafenib, sunitinib, tarimogen / laherapelepbec, tamoxifen, temozolomide Temsirolimus, thalidomide, thioguanine, thiotepa, tipiracil, topotecan, toremifene, tositumomab, trabectidine, trametinib, trastuzumab, tretinoin, trifluridine, uridine triacetate, vandetanib, vemurafenib, vinblastine, vincristine, vinorelbine, bismodegib, vorinostat, ziv-aflibercept, zoledronic acid, and pharmaceutically acceptable salts thereof. In some embodiments, the second therapeutic agent is one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

[0071] Diseases and Disabilities The methods disclosed herein relate to the treatment of cancer. In certain embodiments, cancer is a hematological malignancy such as leukemia or lymphoma, e.g., non-Hodgkin lymphoma. In certain embodiments, hematological malignancies include myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphoblastic leukemia (e.g., acute lymphoblastic leukemia), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, follicular lymphoma, and diffuse large B-cell lymphoma (DLBCL) (e.g., DLBCL or ABC-DLBLC). These include 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. In certain embodiments, the hematological malignancy is myeloid leukemia. In other embodiments, the hematological malignancy is myeloid leukemia (e.g., acute myeloid leukemia). In certain embodiments, the hematological malignancy is acute myeloid leukemia (e.g., AML). In certain embodiments, AML is primary AML. In other embodiments, AML is secondary AML. In yet another embodiment, the hematological malignancy is myelodysplastic syndrome. In certain embodiments, myelodysplastic syndrome is high-grade. In other embodiments, myelodysplastic syndrome is low-grade. In specific embodiments, myelodysplastic syndrome is high-risk. In yet another embodiment, the hematological malignancy is lymphoblastic leukemia (e.g., acute lymphoblastic leukemia). In yet another embodiment, the hematological malignancy is chronic lymphocytic leukemia (CLL). In specific embodiments, the CLL is high-risk CLL. In yet another embodiment, the hematological malignancy is small lymphocytic lymphoma (SLL). In yet another embodiment, the hematological malignancy is follicular lymphoma. In yet another embodiment, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL). In yet another embodiment, the hematological malignancy is activated B-cell-like (ABC) DLBCL. In yet another embodiment, the hematological malignancy is germinal center B-cell-like (GCB) DLBCL.In certain embodiments, DLBCL is extranodal. In certain embodiments, DLBCL is extranodal limb lymphoma, extranodal testicular lymphoma, or extranodal unspecified (NOS) type lymphoma. In yet another embodiment, the hematological malignancy is mantle cell lymphoma. In yet another embodiment, the hematological malignancy is Waldenström macroglobulinemia. In yet another embodiment, the hematological malignancy is multiple myeloma. In yet another embodiment, the hematological malignancy is marginal zone lymphoma. In yet another embodiment, the hematological malignancy is Burkitt lymphoma. In yet another embodiment, the hematological malignancy is non-Burkitt high-grade B-cell lymphoma. In yet another embodiment, the hematological malignancy is extranodal marginal zone B-cell lymphoma. In yet another embodiment, the hematological malignancy is transformed high-grade B-cell lymphoma (HGBL). In yet another embodiment, the hematological malignancy is lymphoplasmacytic lymphoma (LPL). In yet another embodiment, the hematological malignancy is CNS lymphoma. In yet another embodiment, the CNS lymphoma is primary CNS lymphoma (PCNSL). In yet another embodiment, the hematological malignancy is MALT lymphoma. In certain embodiments, the hematological malignancy may be relapsed or refractory. In certain embodiments, the hematological malignancy is resistant to treatment with BTK inhibitors. In certain embodiments, the hematological malignancy is resistant to treatment with BTK inhibitors as monotherapy. In certain embodiments, the hematological malignancy is resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebratinib, or HM71224. In a certain preferred embodiment, the hematological malignancy is resistant to treatment with ibrutinib.

[0072] In certain embodiments, the cancer is selected from brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, epidermal cancer, prostate cancer, and head and neck cancer. In certain preferred embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is colon cancer. In certain embodiments, the cancer is a solid tumor. In various such embodiments, the cancer may be recurrent or refractory. In certain embodiments, the cancer is resistant to treatment with BTK inhibitors. In certain embodiments, the cancer is resistant to treatment with BTK inhibitors as monotherapy. In certain embodiments, the cancer is resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebratinib, or HM71224. In certain preferred embodiments, the cancer is resistant to treatment with ibrutinib.

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

[0074] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally once daily at a dose of approximately 50 mg, and the cancer is DLBCL. In certain embodiments, the DLBCL is recurrent or refractory.

[0075] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally once daily at a dose of approximately 50 mg, and the cancer is FL. In certain embodiments, the FL is recurrent or refractory.

[0076] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally once daily at a dose of approximately 300 mg, and the cancer is WM. In certain embodiments, the WM is recurrent or refractory.

[0077] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally twice daily at a dose of approximately 50 mg, and the cancer is DLBCL. In certain embodiments, the DLBCL is recurrent or refractory.

[0078] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally twice daily at a dose of approximately 300 mg, and the cancer is LPL. In certain embodiments, the LPL is recurrent or refractory.

[0079] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally twice daily at a dose of approximately 300 mg, and the cancer is GCB DLBCL. In certain embodiments, the GCB DLBCL is recurrent or refractory.

[0080] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally twice daily at a dose of approximately 400 mg, and the cancer is ABC DLBCL. In certain embodiments, the ABC DLBCL is recurrent or refractory.

[0081] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally twice daily at a dose of approximately 400 mg, and the cancer is MZL. In certain embodiments, the MZL is recurrent or refractory.

[0082] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally twice daily at a dose of approximately 300 mg, and the cancer is MZL. In certain embodiments, the MZL is recurrent or refractory.

[0083] In certain embodiments, an IRAK4 inhibitor or degrading agent is administered orally twice daily at a dose of approximately 300 mg, and the cancer is MALT. In certain embodiments, the MALT is recurrent or refractory.

[0084] In certain embodiments, the IRAK4 inhibitor or degrading agent is administered continuously (e.g., compound 1 is administered without a rest period). In other embodiments, the IRAK4 inhibitor or degrading agent is administered intermittently (e.g., compound 1 is administered continuously, interrupted by one or more rest periods). In certain embodiments, each rest period lasts for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In certain preferred embodiments, the rest period lasts for 7 days. In even more preferred embodiments, the IRAK4 inhibitor or degrading agent is administered daily for 3 weeks, followed by a 1-week rest period, and optionally, followed by 3 weeks of daily administration and a 1-week rest period, and this cycle may be repeated further. In certain embodiments, the aforementioned administration regimens are continued with alternating rest periods until a change in disease status is observed (e.g., complete response, partial response, or unacceptable toxicity). Methods for treating specific diseases and disorders using Compound 1 are disclosed in PCT / US2021 / 030192 and PCT / US23 / 21812, which are fully incorporated herein by reference.

[0085] Previous treatments The methods disclosed herein may be used as first-line therapies, or they may be applied to patients who have not been able to achieve either a partial or complete response with one or more prior anti-cancer or anti-inflammatory therapies. In certain embodiments, the subject has previously received at least one anti-cancer therapy. In certain embodiments, the patient has previously received one anti-cancer therapy. In other embodiments, the patient has previously received two anti-cancer therapies. In yet another embodiment, the patient has previously received three anti-cancer therapies. In yet another embodiment, the patient has previously received four anti-cancer therapies. In yet another embodiment, the patient has previously received five anti-cancer therapies. In certain embodiments, at least one anticancer therapy comprises an anti-CD20 antibody, nitrogen mustard, steroids, purine analogs, DNA topoisomerase inhibitors, DNA intercalators, tubulin inhibitors, proteasome inhibitors, Toll-like receptor inhibitors, kinase inhibitors, SRC kinase inhibitors, PI3K kinase inhibitors, BTK inhibitors, glutaminase inhibitors, PD-1 inhibitors, PD-L1 inhibitors, or methylating agents, or a combination thereof. In certain embodiments, the anticancer therapy includes ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, ifosfamide, prednisone, oprozomib, ixazomib, acalabrutinib, zanubrutinib, IMO-08400, idelalisib, umbralicib, CB-839, fludarabine, or thalidomide, or a combination thereof. In certain embodiments, the anticancer therapy includes ibrutinib. In certain embodiments, the anticancer therapy includes ibrutinib and rituximab. In certain embodiments, the anticancer therapy includes bendamustine. In certain embodiments, the anticancer therapy includes bendamustine and rituximab. In certain embodiments, the anticancer therapy includes bortezomib. In certain embodiments, the anticancer therapy includes bortezomib and dexamethasone. In certain embodiments, the anticancer therapy includes bortezomib and rituximab.In certain embodiments, the anticancer therapy includes bortezomib, rituximab, and dexamethasone. In certain embodiments, chlorambucil. In certain embodiments, the anticancer therapy includes cladribine. In certain embodiments, the anticancer therapy includes cladribine and rituximab. In certain embodiments, the anticancer therapy includes cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R). In certain embodiments, the anticancer therapy includes cyclophosphamide, prednisone, and rituximab (i.e., CPR). In certain embodiments, the anticancer therapy includes fludarabine. In certain embodiments, the anticancer therapy includes fludarabine and rituximab. In certain embodiments, the anticancer therapy includes fludarabine, cyclophosphamide, and rituximab. In certain preferred embodiments, the anticancer therapy includes rituximab. In certain preferred embodiments, the anticancer therapy comprises rituximab. In certain embodiments, the anticancer therapy comprises rituximab, cyclophosphamide, and dexamethasone (i.e., RCD). In certain embodiments, the anticancer therapy comprises thalidomide. In certain embodiments, the anticancer therapy comprises thalidomide and rituximab. In certain embodiments, the anticancer therapy comprises cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD). In certain embodiments, the anticancer therapy comprises a hypomethylating agent. In certain embodiments, the subject has previously received at least six cycles of a hypomethylating agent. In certain embodiments, the anticancer therapy comprises any of the aforementioned combinations, for example, the subject may first receive rituximab, and then at a later date, receive a combination of rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).

[0086] The subject may also have received or be prepared for other non-chemotherapy treatments, such as surgery, radiation, or bone marrow transplantation. In certain embodiments, the subject may have previously received etoposide chemomobilization therapy. In certain embodiments, the subject may have previously received bone marrow transplantation. In certain embodiments, the subject may have previously received stem cell transplantation. In certain embodiments, the subject may have previously received autologous cell transplantation. In certain embodiments, the subject may have previously received allogeneic stem cell transplantation. In certain embodiments, the subject may have previously received hematopoietic stem cell transplantation. In certain embodiments, the subject may have previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM pretreatment). In certain embodiments, the subject may have previously received reinduction therapy.

[0087] The subjects may also have previously shown a favorable outcome to previous therapy and may require additional treatment at a later date. In certain embodiments, the subjects have previously achieved a partial response. In certain embodiments, the subjects have previously achieved a good partial response. In certain embodiments, the subjects have previously achieved a complete response. In certain embodiments, the cancer is recurrent. In certain embodiments, the cancer is refractory.

[0088] The subjects may also have or have developed one or more gene mutations that either make the target cancer more resistant to treatment or less resistant. In certain embodiments, the subjects have a mutation in RICTOR. In certain embodiments, the subjects have an N1065S mutation in RICTOR. In certain preferred embodiments, the subjects have a mutation in MYD88. In certain even more preferred embodiments, the subjects have an L265P mutation in MYD88. In certain embodiments, the subjects have a mutation in TET2. In certain embodiments, the subjects do not have a mutation in CXCR4. In other embodiments, the subjects have a mutation in CXCR4. In certain preferred embodiments, the subjects have a mutation in SF3B1 (e.g., an insertion, deletion, loss, or spliceosome mutation). In certain preferred embodiments, the subjects have a mutation in U2AF1 (e.g., an insertion, deletion, loss, or spliceosome mutation). In certain preferred embodiments, the subjects have a mutation in FLT3. In some embodiments, the FLT3 kinase mutation is selected from one or more of the following: internal tandem duplication (ITD), mutation at D835, mutation at F691, mutation at K663, and / or mutation at N841. In some embodiments, the FLT3 kinase mutation includes the D835H mutation. In some embodiments, the FLT3 kinase mutation includes the D835V mutation. In some embodiments, the FLT3 kinase mutation includes the D835Y mutation. In some embodiments, the FLT3 kinase mutation includes the K663Q mutation. In some embodiments, the FLT3 kinase mutation includes the N841I mutation. In some embodiments, the FLT3 kinase mutation includes the ITD and D835V mutations. In some embodiments, the FLT3 kinase mutation includes the ITD and F691L mutation. In some embodiments, the FLT3 kinase mutation includes the ITD and D835Y mutation. In certain embodiments, the subject has a mutation at STAG2. In certain embodiments, the subject has a mutation in DNMT3A. In certain embodiments, the subject has a mutation in BCOR. In certain embodiments, the subject has a mutation in WT1. In certain embodiments, the subject has a mutation in NRAS.In certain embodiments, the subjects exhibit early progression. In certain embodiments, the subjects have not previously received BTK inhibitors.

[0089] In certain embodiments, the subject achieves a partial response after administration of the compound. In certain 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 certain embodiments, the subject achieves a partial response within 7 days of receiving the compound. In certain embodiments, the subject achieves a good partial response within 7 days of being administered the compound. In certain embodiments, the subject achieves a complete response within 7 days of being administered the compound. In certain embodiments, the tumor volume of the subject is reduced 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 certain embodiments, the tumor volume of the subject is reduced by 5 percent. In certain embodiments, the tumor volume of the subject is reduced by 10 percent. In certain embodiments, the target tumor volume is reduced by 15 percent. In certain embodiments, the target tumor volume is reduced by 20 percent. In certain embodiments, the target tumor volume is reduced by 25 percent. In certain embodiments, the target tumor volume is reduced by 30 percent. In certain embodiments, the target tumor volume is reduced by 35 percent. In certain embodiments, the target tumor volume is reduced by 40 percent. In certain embodiments, the target tumor volume is reduced by 45 percent. In certain embodiments, the target tumor volume is reduced by 50 percent. In certain embodiments, the target tumor volume is reduced by 55 percent. In certain embodiments, the target tumor volume is reduced by 60 percent. In certain embodiments, the target tumor volume is reduced by 65 percent. In certain embodiments, the target tumor volume is reduced by 70 percent. In certain embodiments, the target tumor volume is reduced by 80 percent. In certain embodiments, the target tumor volume is reduced by 85 percent. In certain embodiments, the target tumor volume is reduced by 90 percent. In certain embodiments, the target tumor volume is reduced by 95 percent.

[0090] Pharmaceutical composition The compositions and methods of the present invention may be used to treat individuals in need. In certain embodiments, the individuals are mammals, such as humans or non-human mammals. When administered to animals such as humans, the compositions or compounds are 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 physiological buffer saline, or oils such as glycols, glycerols, olive oil, or other solvents or vehicles such as injectable organic esters. In preferred embodiments, if such a pharmaceutical composition is for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion across the epithelial barrier), the aqueous solution is pyrogenic or substantially pyrogenic. Excipients may be selected, for example, to result in delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in unit dosage forms such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized reconstituted products, powders, liquids, syrups, suppositories, and injections. The composition may also be present in transdermal delivery systems, such as skin patches. Furthermore, the composition may be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0091] A pharmaceutically acceptable carrier may contain a physiologically acceptable agent that acts to stabilize, increase the solubility of, or increase the absorption of a compound, such as the compound of the present invention. Examples of such physiologically acceptable agents include carbohydrates (e.g., glucose, sucrose, or dextran), antioxidants (e.g., ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may be, for example, a liposome or other polymer matrix in which the compound of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0092] The term "pharmaceutically acceptable" is used herein to mean a compound, substance, composition, and / or dosage form that is suitable for use in contact with human and animal tissues in proportion to a reasonable benefit-to-risk ratio, without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of sound medical judgment.

[0093] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulant. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of substances that may function 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, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) p (11) Glycols such as polypropylene glycol; (12) Polyols such as glycerin, 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) Alginic acid; (17) Water that does not contain pyrogens; (18) Isotonic saline solution; (19) Ringer's solution; (20) Ethyl alcohol; (21) Phosphate buffer; (22) Other non-toxic, suitable substances used in pharmaceutical formulations.

[0094] A pharmaceutical composition (preparation) may be administered to a subject by any of several routes of administration, including, for example, the following: Oral (e.g., aqueous or non-aqueous solution or suspension, such as a liquid drug, tablets, capsules (including sprinkle capsules and gelatin capsules), bolus, powder, granules, paste for application to the tongue); Absorption through the oral mucosa (e.g., sublingual); Subcutaneous; Transdermal (e.g., as a patch applied to the skin); Topical (e.g., as a cream, ointment or spray applied to the skin). The compound may further be formulated for inhalation. In certain embodiments, the compound may simply be dissolved or suspended in sterile water. Details of suitable administration routes and compositions thereof can be found, for example, in U.S. Patents 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and the patents cited herein.

[0095] The formulation may be conveniently provided in unit dosage forms, or it may be prepared by any method well known in the field of pharmacy. The amount of active ingredient that can be combined with a carrier to produce a single dosage form varies depending on the host being treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Generally, this amount is in the range of about 1% to about 99% of 100% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0096] Methods for preparing these formulations or compositions involve combining an active compound, such as the compound of the present invention, with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by uniformly and closely combining the compound of the present invention with a liquid carrier, a fine powder solid carrier, or both, and then, if necessary, shaping the product.

[0097] Formulations of the present invention suitable for oral administration may consist of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using flavoring agents, usually sucrose and acacia or tragacanth), lyophilized products, 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 flavored tablets (using inert agents such as gelatin and glycerin, or sucrose and acacia), and / or as mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The composition or compound may further be administered as a bolus, lick, or paste.

[0098] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, sugar-coated tablets, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) Fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) Binders, e.g., carboxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) Humectants, e.g., glycerol; (4) Disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) Dissolution retarders, e.g., paraffin; (6) Absorption enhancers, e.g., quaternary ammonium compounds; (7) Wetting agents, e.g., cetyl alcohol and glycerol monostearate; (8) Absorbents, e.g., kaolin, bentonite clay; (9) Lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) Complexing agents, e.g., modified and unmodified cyclodextrins; (11) Colorants. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also include a buffer. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0099] Tablets may be prepared by compression or molding, with one or more optional auxiliary components. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), a surfactant, or a dispersant. Molded tablets can be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine.

[0100] Tablets, as well as other solid dosage forms of pharmaceutical compositions such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical field. They may further be formulated to provide sustained or controlled release of the active ingredient therein, for example, by using various proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or microspheres to provide a desired release profile. They may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injection medium immediately before use. These compositions may further optionally contain an opacifying agent and may optionally release only the active ingredient, or preferentially the active ingredient, in a delayed manner in a specific part of the gastrointestinal tract. Examples of embedding compositions that can be used include polymer substances and waxes. The active ingredient may further, where appropriate, be in microencapsulated form together with one or more of the above excipients.

[0101] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof.

[0102] In addition to inert diluents, oral compositions may also contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances and preservatives.

[0103] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, crystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0104] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0105] In addition to the active compound, ointments, pastes, creams, and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0106] In addition to the active compound, the powder and spray formulations may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The spray formulations may further contain common propellants such as chlorofluoro hydrocarbons and volatile unsubstituted hydrocarbons (e.g., butane and propane).

[0107] Transdermal patches offer the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate of such flow can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0108] As used herein, the terms “parenteral administration” and “administered parenterally” mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intrathecal, and intrasternal injections and infusions. Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injection solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostatic agents, solutes that are isotonic with the blood of the recipient to whom the formulation is intended, or suspending agents or thickeners.

[0109] 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, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of a coating substance such as lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of a surfactant.

[0110] These compositions may further contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. Furthermore, long-term absorption of injectable pharmaceutical forms can be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

[0111] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with low water solubility. The absorption rate of a drug depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0112] Injectable depot formulations are prepared by creating a microencapsulation matrix of the target compound within a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injection formulations can also be prepared by encapsulating the drug in liposomes or microemulsions compatible with body tissues.

[0113] For use in the method of the present invention, the active compound may be given by itself or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0114] The delivery method may further be provided by a refillable or biodegradable device. In recent years, various sustained-release polymer devices have been developed and tested in vivo for the controlled delivery of drugs, including protein-based biopharmaceuticals. Various biocompatible polymers (including hydrogels), including both biodegradable and non-biodegradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0115] The actual dose level of the active ingredient in a pharmaceutical composition can be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient.

[0116] The selected dosage level depends on a variety of factors, including the activity of the specific compound or combination of compounds used, or its ester, salt, or amide; the route of administration; the time of administration; the elimination rate of the specific compound used; the duration of treatment; other drugs, compounds, and / or substances used in combination with the specific compound used; the age, sex, weight, condition, overall health, and medical history of the patient being treated; and similar factors well known in the medical field.

[0117] A physician or veterinarian with ordinary art in the art can easily determine and prescribe the therapeutically effective dose of the required pharmaceutical composition. For example, a physician or veterinarian can start with a dose of the pharmaceutical composition or compound at a level lower than the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. "Therapeutic dose" means a concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective dose of a compound varies depending on the subject's weight, sex, age, and medical history. Other factors that may affect the effective dose include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, other types of therapeutic agents administered with the compound of the present invention. Larger total doses may be delivered by multiple administrations of the drug. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0118] Generally, the preferred daily dose of the active compound used in the compositions and methods of the present invention is the minimum amount of the compound that is effective in producing a therapeutic effect. Such an effective dose generally depends on the factors mentioned above.

[0119] If desired, the effective daily dose of the active compound may be administered in unit dosage form as one, two, three, four, five, six or more subdoses, administered separately at appropriate intervals throughout the day. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound is administered once daily.

[0120] Patients receiving this treatment include primates (especially humans), as well as any animals in need, including other mammals such as horses, cattle, pigs, sheep, cats, and dogs, poultry, and pets in general.

[0121] In certain embodiments, the compounds of the present invention may be used alone or in combination with other types of therapeutic agents.

[0122] This disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in compositions and methods of the present invention. In certain embodiments, the salts intended for the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, the salts intended for the present invention include, but are not limited to, L-arginine, benetamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydravamin, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, the salts intended for the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In certain embodiments, the salts intended for the present invention include, but are not limited to, the following:1-Hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptone Acids, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 1-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, 1-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenate.

[0123] Pharmacopoecially acceptable acid addition salts can also exist as various solvates with water, methanol, ethanol, dimethylformamide, and others. Mixtures of such solvates can also be prepared. The source of such solvates may be from the crystallization solvent, may be inherent to the preparation or crystallization solvent, or may be associated with such solvent.

[0124] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the composition.

[0125] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bicarbonate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0126] definition Unless otherwise defined herein, scientific and technical terms used in this application have meanings that are generally understood by those skilled in the art. In general, the nomenclature and techniques used in relation to chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are well known and commonly used in the art.

[0127] The methods and techniques described herein are generally carried out in accordance with conventional methods well known in the art, unless otherwise indicated, and as described in the various general and more specific references cited and discussed throughout this specification. See, for example, the following: "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 ed.", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0128] Chemical terms used herein, unless otherwise defined, are defined below: "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0129] All of the foregoing references made in this application, as well as any other publications, patents, and published patent applications, are incorporated herein by reference. In the event of any conflict, this specification shall prevail, including its specific definitions.

[0130] The term “agent” is used herein to refer to chemical compounds (e.g., organic or inorganic compounds, mixtures of chemical compounds), biological macromolecules (e.g., nucleic acids, antibodies, parts thereof, and humanized, chimeric and human antibodies and monoclonal antibodies, proteins or parts thereof, e.g., peptides, lipids, carbohydrates), or extracts made from biological substances such as bacterial, plant, fungal, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known and agents whose structure is unknown. The ability of such agents to inhibit or promote AR degradation may make them suitable as “therapeutic agents” in the methods and compositions of this disclosure.

[0131] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, domestic animals (including cattle and pigs), companion animals (e.g., dogs and cats), and rodents (e.g., mice and rats).

[0132] "Treating" a condition or patient means taking steps to obtain a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, whether detectable or undetectable; reduction of disease severity; stabilization (i.e., non-exacerbating) of the disease; prevention of disease progression; delay or slowing of disease progression; improvement or alleviation of the disease state; and remission (partial or total), whether detectable or undetectable. "Treatment" may further mean extending survival compared to the survival expected without treatment.

[0133] The term “prevention” is recognized in the art and, when used in relation to a condition such as local recurrence (e.g., pain), a disease such as cancer, a syndrome such as heart failure, or any other medical condition, is well understood in the art and includes the administration of a composition that reduces the frequency of symptoms of a medical condition in a subject or delays its onset compared to a subject not administered the composition. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population (e.g., by a statistically and / or clinically significant amount) compared to an untreated control population.

[0134] "Administering" or "dosing" a substance, compound, or drug can be carried out using one of various methods known to those skilled in the art. For example, a compound or drug can be administered intravenously, intra-arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, orally, sublingually, orally (by ingestion), intranasally (by inhalation), intrathecally, intracerebrally, and transdermally (e.g., by absorption through the skin canal). The compound or drug may further be appropriately introduced by a refillable or biodegradable polymer device or other device (e.g., a patch and a pump) or formulation that provides sustained release, sustained release, or controlled release of the compound or drug. Dosage may further be carried out, for example, once, multiple times, and / or over a period of time.

[0135] The appropriate method for administering a substance, compound, or drug to a subject also depends, for example, on the subject's age and / or physical condition, as well as the chemical and biological properties of the compound or drug (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In certain embodiments, the compound or drug is administered orally to the subject (e.g., by oral ingestion). In certain embodiments, the orally administered compound or drug is in a sustained-release or extended-release formulation, or is administered using a device for such sustained-release or extended-release.

[0136] As used herein, the term “co-administration” refers to any form of administration of two or more different therapeutic agents such that a second agent is administered while a previously administered therapeutic agent is still effective in the body (for example, the two agents may be effective simultaneously in the patient and may include a synergistic effect of the two agents). For example, different therapeutic compounds may be administered simultaneously or sequentially, in the same formulation or in separate formulations. Thus, an individual receiving such treatment may benefit from the combined effect of different therapeutic agents.

[0137] The "therapeutic effective dose" of a drug or medication is the amount of the drug or medication that, when administered to a subject, produces the intended therapeutic effect. Complete therapeutic effect is not necessarily achieved by a single dose, but may only occur after a series of doses. Therefore, the therapeutic effective dose may be administered in one or more doses. The exact effective dose required for a subject depends, for example, on the subject's size, health, and age, as well as the nature and severity of the condition being treated, such as cancer or MDS. Those skilled in the art can readily determine the effective dose for a given situation through conventional experimentation.

[0138] As used herein, the terms “optional” or “optionally” mean that the event or situation described therein may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, “optionally substituted alkyl” means that the alkyl may be substituted as it is in cases in which the alkyl is not substituted.

[0139] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art to yield chemically stable compounds that can be readily synthesized from readily available starting materials by art known in the art and by the methods described below. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon or different carbons, as long as a stable structure is obtained.

[0140] As used herein, the term “optionally substituted” refers to the substitution of 1 to 6 hydrogen radicals in a given structure with specific substituents, including but not limited to hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the substitution of 1 to 4 hydrogen radicals in a given structure with the above substituents. More preferably, 1 to 3 hydrogen radicals are substituted with the above substituents. It is understood that substituents may be further substituted.

[0141] As used herein, the term "alkyl" refers to C1-C 10 Linear alkyl groups or C1-C 10 This refers to saturated aliphatic groups, including but not limited to branched alkyl groups. Preferably, the "alkyl" group refers to a C1-C6 linear alkyl group or a C1-C6 branched alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 linear 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 be optionally substituted.

[0142] The term "acyl" is recognized in the field and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0143] The term "acylamino" is recognized in the relevant technical field and refers to an amino group substituted with an acyl group, which can be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0144] The term "acyloxy" is recognized in the field and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0145] The term "alkoxy" refers to an alkyl group to which oxygen is bonded. Representative alkoxy groups include methoxy, ethoxy, propoxy, and tert-butoxy.

[0146] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, and can be represented by the general formula alkyl-O-alkyl.

[0147] The term "alkyl" refers to saturated aliphatic groups, including linear alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, linear or branched alkyl groups have 30 or fewer carbon atoms in their skeleton (for example, in a linear group, C 1~30 In branched chains, C 3~30 ), more preferably having 20 or fewer carbon atoms.

[0148] Furthermore, as used herein, in the examples and claims, the term “alkyl” is intended to include both unsubstituted alkyl groups and substituted alkyl groups, the latter of which refers to an alkyl moiety having substituents that substitute hydrogens on one or more carbons of a hydrocarbon skeleton, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0149] The term “C x-y " or "C x -C yWhen used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it means that the chain contains a group with x to y carbon atoms. C0 alkyl indicates hydrogen when the group is at the terminal position and a bond when it is in the middle. 1-6 Alkyl groups, for example, contain 1 to 6 carbon atoms in their chain.

[0150] As used herein, the term "alkylamino" refers to an amino group that is substituted with at least one alkyl group.

[0151] 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-.

[0152] As used herein, the term "amide" refers to the following groups:

[0153] [ka] In the formula, R 9 and R 10 Each of these independently represents either a hydrogen atom or a hydrocarbyl group, or R 9 and R 10 These atoms, together with the N atoms to which they are bonded, complete a heterocycle with 4 to 8 atoms in the ring structure.

[0154] The terms "amine" and "amino" are recognized in the field and refer to both unsubstituted and substituted amines, as well as their salts (for example, the parts that may be represented below).

[0155] [ka] In the formula, R 9 , R 10 , and R 10 Each of the ' represents either a hydrogen atom or a hydrocarbyl group, or R 9 and R 10These atoms, together with the N atoms to which they are bonded, complete a heterocycle with 4 to 8 atoms in the ring structure.

[0156] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0157] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0158] As used herein, the term “aryl” includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” further includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is aromatic (for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl). Examples of aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline.

[0159] The term "carbamate" is recognized in the relevant technical field and refers to the following groups:

[0160] [ka] In the formula, R 9 and R 10 This independently represents a hydrogen atom or a hydrocarbyl group.

[0161] As used herein, the term "carbocykrylalkyl" refers to an alkyl group substituted with a carbocyclic group.

[0162] The term "carbocyclic ring" includes monocyclic rings with 5 to 7 members and bicyclic rings with 8 to 12 members. Each ring in a bicyclic carbocyclic ring may 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 the two rings. The term "condensed carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring in a condensed carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring (e.g., phenyl) may be condensed with 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, as long as the valence allows. Examples of “carbocyclic rings” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octo-3-ene, naphthalene, and adamantane. Examples of condensed carbocyclic rings include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hepta-3-ene. The “carbocyclic rings” may be substituted at any one or more positions where hydrogen atoms may be present.

[0163] As used herein, the term "carbocykrylalkyl" refers to an alkyl group substituted with a carbocyclic group.

[0164] The term "carbonate" is recognized in the relevant technical field and refers to the group -OCO2-.

[0165] As used herein, the term "carboxy" refers to the group represented by the formula -CO2H.

[0166] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term "cycloalkyl" further includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is cycloalkyl, and substituents (e.g., R) 100 The group is bonded to a cycloalkyl ring, and for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, and tetrahydroquinoline.

[0167] As used herein, the term "ester" refers to the group -C(O)OR 9 It refers to, and in the formula, R 9 This represents a hydrocarbyl group.

[0168] As used herein, the term “ether” refers to a hydrocarbyl group bonded to another hydrocarbyl group via oxygen. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocyclic-O-heterocyclic and aryl-O-heterocyclic groups. Ethers also include “alkoxyalkyl” groups, which can be represented by the general formula alkyl-O-alkyl.

[0169] As used herein, the terms “halo” and “halogen” mean halogen, and include chloro, fluoro, bromo, and iodine.

[0170] As used herein, the terms “hetallalkyl” and “hetallalkyl” refer to alkyl groups substituted with hetalil groups.

[0171] The terms "heteroaryl" and "hetalil" include substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, wherein the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetalil" further include polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings, and at least one of the rings is heteroaromatic, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0172] As used herein, the term “heteroatom” means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0173] As used herein, the term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclic group.

[0174] The terms "heterocyclyl," "heterocycle," and "heterocyclic formula" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, the ring structure containing at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic formula" further include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is a heterocyclic formula, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of heterocyclyl groups include piperidine, piperazine, pyrrolidine, morpholine, lactone, and lactam.

[0175] As used herein, the term "hydrocarbyl" refers to a group that is bonded through a carbon atom having no =O or =S substituents, typically having at least one carbon-hydrogen bond and mainly a carbon skeleton, and optionally may contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for the purposes of this application, but substituents such as acetyl (having an =O substituent on the bonded carbon) and ethoxy (bonded through oxygen rather than carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

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

[0177] The term "lower", when used with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, means including a group having 10 or fewer, preferably 6 or fewer, atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are each lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, and these may occur alone or in combination with other substituents, for example, in the description of hydroxyalkyl and aralkyl (in which case, for example, the atoms within an aryl group are not counted when counting the carbon atoms in an alkyl substituent).

[0178] The terms "polysicyclic", "polycyclic", and "polycyclic ring system" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) where two or more atoms are common to two adjacent rings (e.g., the rings are "fused rings"). Each of the rings of the polycyclic ring system may or may not be substituted. In certain embodiments, each ring of the polycyclic ring system contains 3 to 10 atoms, preferably 5 to 7 atoms, in the ring.

[0179] The term "sulfate" is recognized in the art and refers to the group -OSO3H or a pharmaceutically acceptable salt thereof.

[0180] The term "sulfonamide" is recognized in the art and has the general formula:

[0181]

Chemical formula

[0182] The term "sulfoxide" is recognized in the art and refers to the group -S(O)-.

[0183] The term "sulfonate" is recognized in the art and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

[0184] The term "sulfone" is recognized in the art and refers to the group -S(O)2-.

[0185] The term "substituted" refers to a moiety having a substituent that replaces one or more hydrogens on one or more carbons of a skeleton. "Substitution" or "substituted with" is understood to include the implicit condition that such substitution results in a stable compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc., in accordance with the valences of the substituted atom and the substituent. As used herein, the term "substituted" is intended to include all acceptable substituents of an organic compound. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. There may be one or more acceptable substituents for a suitable organic compound, which may be the same or different. For the purposes of the present invention, a heteroatom such as nitrogen may have any acceptable substituent of the organic compounds described herein that satisfies the valence of the hydrogen substituent and / or the heteroatom. Substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that a moiety substituted on a hydrocarbon chain may itself be substituted where appropriate.

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

[0187] As used herein, the term "thioester" refers to the group -C(O)SR 9 or -SC(O)R 9 where R 9 represents a hydrocarbyl.

[0188] As used herein, the term "thioether" is equivalent to an ether in which oxygen is replaced by sulfur.

[0189] The term "urea" is recognized in the relevant technical field, and its general formula is:

[0190] [ka] It can be expressed as, In the formula, R 9 and R 10 This independently represents hydrogen or hydrocarbyl.

[0191] As used herein, the term “modulate” includes inhibition or suppression of function or activity (such as cell proliferation), as well as enhancement of function or activity.

[0192] The phrase "pharmaceutically acceptable" is recognized in the art. In certain embodiments, this term includes compositions, excipients, adjuvants, polymers and other substances and / or dosage forms that, within the bounds of sound medical judgment, are suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0193] In this specification, “pharmaceutically acceptable salt” or “salt” is used to mean an acid addition salt or base addition salt that is suitable or appropriate for the treatment of a patient.

[0194] As used herein, the term “pharmaceutically acceptable acid addition salt” means any non-toxic organic or inorganic salt of any base compound represented by formula I. Exemplary inorganic acids that constitute a suitable salt include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium bisulfate. Exemplary organic acids that constitute a suitable salt include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Either monoate or diate salts can be formed, and such salts may exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts of compounds of formula I are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The selection of appropriate salts is known to those skilled in the art. Other pharmaceutically unacceptable salts (e.g., oxalates) may be used, for example, in the isolation of compounds of formula I for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0195] As used herein, the term “pharmaceutically acceptable base addition salt” means any non-toxic organic or inorganic base addition salt relating to any acid compound represented by Formula I or any intermediate thereof. Exemplary inorganic bases that form suitable salts include hydroxides of lithium, sodium, potassium, calcium, magnesium, or barium. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines (e.g., methylamine, trimethylamine, and picoline) or ammonia. The selection of suitable salts is known to those skilled in the art.

[0196] Many of the compounds useful in the methods and compositions of the present disclosure have at least one stereocenter in their structure. This stereocenter may be present in the R or S configuration, and the R and S notations are used in accordance with the rules described below. Pure Appl.Chem. (1976), 45, 11-30. The present disclosure contemplates all stereoisomeric forms, including enantiomeric and diastereomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO 01 / 062726.

[0197] Furthermore, certain compounds containing an alkenyl group may exist as Z (zusammen) or E (entgegen) isomers. In each case, the present disclosure includes both mixtures and separated individual isomers.

[0198] Some of the compounds may further exist in tautomeric forms. Such forms are not explicitly shown in the formulas described herein but are intended to be included within the scope of the present disclosure.

[0199] A “prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that, after administration, is metabolized in the host, for example, by hydrolysis or oxidation, to constitute a compound of the Disclosure (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds having a biologically unstable group or a cleavable (protecting) group in the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce an active compound. Examples of prodrugs using esters or phosphoramides as biologically unstable or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, which are incorporated herein by reference. The prodrugs of the Disclosure are metabolized to produce compounds of formula I. The Disclosure includes, within its scope, prodrugs of the compounds described herein. Conventional procedures for selecting and preparing suitable prodrugs are, for example, seen in "Design of Prodrugs" (Ed. H. Bundgaard, Elsevier, 1985).

[0200] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filter, diluent, excipient, solvent, or encapsulant, that is useful for formulating a drug for pharmaceutical or therapeutic use.

[0201] As used herein, the terms “logarithm of solubility,” “LogS,” or “logS” are used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility is often associated with poor absorption. The LogS value is the unit strip logarithm (base 10) of solubility measured in moles / liter.

[0202] As used herein, the term “expression level” refers to the level of expression and / or prevalence of an expression product within a sample. For example, the expression level of a protein can be measured by staining a tissue sample (e.g., multiple cells) and measuring the prevalence (i.e., occurrence) and / or level of the protein across one or more cells (preferably multiple cells) in the tissue, or across the entire tissue sample.

[0203] As used herein, the term "AZA" refers to azacitidine.

[0204] As used herein, the term "BID" refers to the administration of the drug twice daily.

[0205] As used herein, the term "QD" refers to a daily dose of the drug.

[0206] As used herein, the term "CR" refers to complete response.

[0207] As used herein, the term "CRi" refers to complete complete remission (CR) with incomplete hematological recovery.

[0208] As used herein, the term "CRh" refers to complete remission with partial hematological recovery.

[0209] As used herein, the term "mCR" refers to complete myelorebrospinal response.

[0210] As used herein, the term "OS" refers to overall survival.

[0211] As used herein, the term "PR" indicates a partial response.

[0212] As used herein, the term "MTD" refers to the maximum tolerated dose.

[0213] As used herein, the term "RP2D" refers to the recommended Phase 2 dose.

[0214] As used herein, the term "ANC" refers to the absolute number of neutrophils.

[0215] The term "WBC" refers to the white blood cell count. [Examples]

[0216] The present invention will be more readily understood by referring to the following examples, which are described herein in general terms and included solely for illustrative purposes of specific aspects and embodiments of the invention, and are not intended to limit the invention.

[0217] Exemplary methods and compounds relating to the content of this disclosure can be found, for example, in U.S. Patent Nos. 10 / 160,753, 09 / 732,095, 10 / 758,518, and 11 / 419,875, U.S. Patent Application No. 17 / 680995, and pending PCT Patent Applications Nos. U.S. 21 / 59668, U.S. 2021 / 030192, WO22 / 031330, and U.S. 23 / 21812, the content of which is fully incorporated herein by reference.

[0218] Example 1: Exemplary performance of Compound 1 in subjects with AML or MDS who have previously received BLC2 therapy or not. Exemplary initial clinical results from this trial are reported in Figures 1A and 1B.

[0219] Purpose and endpoints Phase 1 (monotherapy) / Phase 1b (combination therapy) Main objective ● Phase 1: Determine the MTD and RP2D of Compound 1 in patients with AML or intermediate-risk, high-risk, or very high-risk MDS (hrMDS) based on safety and tolerability, dose-limiting toxicity, and pharmacokinetic and pharmacodynamic findings. ● Phase 1b: Determine the MTD and RP2D of Compound 1 in combination with AZA in treatment-naive patients with AML or hrMDS after first-line treatment, based on safety and tolerability, dose-limiting toxicity, and pharmacokinetic and pharmacodynamic findings.

[0220] Phase 1 (monotherapy) / Phase 1b (combination therapy) primary endpoint ● MTD (defined as the highest dose with < 33% dose-limiting toxicity rate in the first treatment cycle in at least 6 patients [time frame: 28 days]) ● RP2D (determined by the sponsor in consultation with the CSC considering all aspects of safety, tolerability, biological activity, pharmacokinetics and preliminary efficacy in the trial population [time frame: 24 months]) ● Safety measured by adverse events, ECG, chemical and hematological test values, vital signs, and physical examinations

[0221] Phase 1 (monotherapy) / Phase 1b (combination therapy) secondary objectives ● Characterize the pharmacokinetic parameters of Compound 1 using non-compartmental analysis and appropriate pharmacokinetic models ● Evaluate anti-cancer activity

[0222] Phase 1 (monotherapy) / Phase 1b (combination therapy) secondary endpoints ● C max 、C min 、T max 、AUC 0-24 、AUC 0-inf 、and T 1 / 2 Pharmacokinetic parameters of Compound 1 measured by (time frame: 24 months) ● Clinical response in AML or hrMDS evaluated as follows: ○ AML: ■ Proportion of patients achieving CR+CRh ■ Proportion of patients achieving CRi, or CR or CRh ○ hrMDS: Overall response rate of CR+PR+mCR ○ Transfusion independence

[0223] Phase 1 (monotherapy) / Phase 1b (combination therapy) exploratory objectives ● Evaluate the potential association between target-related biomarkers, selected gene mutations, gene expression signatures, cell of origin, or other molecular classification subtypes and anti-leukemia activity ● To evaluate the pharmacodynamic effects of compound 1 on selected biomarkers in peripheral blood and bone marrow. ● Further evaluation of anticancer activity in RP2D

[0224] Phase 1 (monotherapy) / Phase 1b (combination therapy) exploratory endpoints ● By performing RNA expression profiling, DNA / RNA sequencing, protein profiling, IRAK4 / NF-κB pathway status analysis, differentiation markers / apoptosis, etc., on peripheral blood and / or tumor samples, it is possible to analyze changes induced by research treatments and identify potential predictive biomarkers. ●Clinical responses in AML or hrMDS evaluated as follows: ○ Response duration (DOR) ○ Response time ○Overall survival (OS)

[0225] research design This is a Phase 1 open-label dose-escalation and cohort expansion study of Compound 1 as a monotherapy in patients with AML or MDS after first-line therapy, and in combination with AZA in untreated adult patients with AML or hrMDS.

[0226] The Phase 1 dose escalation (single therapy) portion was conducted in patients with AML and hrMDS.

[0227] In the Phase 1b portion of the study (combination therapy), patients with AML or hrMDS are administered compound 1 in combination with azacitidine (AZA). Patients currently receiving combination therapy and benefiting from it should continue the study according to the protocol at doses of 300 mg BID or less.

[0228] This study will utilize a Clinical Safety Committee (CSC) tasked with reviewing all available safety information. The CSC will be responsible for determining whether dose levels should be extended or whether new dose levels should be opened. The CSC will also define whether a wait period is required for any or all patients enrolled in the new cohort.

[0229] Phase 1 dose escalation (monotherapy) The starting dose level was 200 mg BID, which was determined to be safe, capable of achieving the relevant level of drug exposure, and demonstrating signs of bioactivity and clinical efficacy in test compound 1-101. Three patients with AML or MDS were enrolled at the specified dose. If none of the first three patients experienced dose-limiting toxicity during the first cycle, the patient may be enrolled at the next higher dose level. If one of the first three patients experienced dose-limiting toxicity, the dose level may be increased for an additional three patients.

[0230] If two or three of the initial six patients experience dose-limiting toxicity, this dose level is considered above the MTD, and additional enrollment will proceed at a lower dose level. Any adverse event leading to dose reduction or discontinuation is considered dose-limiting toxicity unless the adverse event is clearly and independently disease-related. Provisional dose levels are outlined in Table 1.

[0231] [Table 1]

[0232] Phase 1b (combination therapy) Compound 1+AZA The starting dose level for compound 1 is 200 mg BID over 21 days (days 1-21) of a 28-day cycle. Details of dose escalation are provided below. AZA 75 mg / m² 2The drug is administered intravenously (IV) or subcutaneously (SC) in seven doses over a 28-day cycle (for example, starting on day 1 and administered seven consecutive times or in divided doses with weekend breaks 5-2), according to local prescribing information (Table 2).

[0233] Note: ● 50 mg / m² per label 2 Reduce AZA dose in the following cases of toxicity. ●The expected dosage of compound 1 is 200, 300, 400 mg BID, DL-1 and DL-2 tapering, followed by 150 mg, 100 mg, administered over 21 days in a 28-day cycle.

[0234] [Table 2]

[0235] Built-in by reference All publications and patents referenced herein are incorporated herein by reference in whole, as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In case of any conflict, the present application, including any definitions herein, shall prevail.

[0236] Equivalents While specific embodiments of the present invention have been described, the above specification is illustrative and not limiting. Many variations of the present invention will become apparent to those skilled in the art by examining this specification and the following claims. The full scope of the present invention should be determined by referring to the claims together with the full scope of their equivalents, and the specification together with such variations.

Claims

1. A method for treating cancer in a subject, comprising administering an IRAK4 inhibitor or an IRAK4 degrading agent to the subject, wherein the cancer has not been exposed to a BLC2 inhibitor.

2. The method according to claim 1, wherein the subject has not previously received a BLC2 inhibitor for the treatment of the cancer.

3. The method according to claim 1 or 2, wherein the BLC2 inhibitor is a BH3 mimetic.

4. The method according to any one of claims 1 to 3, wherein the BLC2 inhibitor is venetoclax (i.e., ABT-199), navitoclax (i.e., ABT-263), ABT-737, or ovatoclax (i.e., GX15-070).

5. The method according to claim 4, wherein the BLC2 inhibitor is venetoclax (i.e., ABT-199).

6. The method according to any one of claims 1 to 5, wherein the IRAK4-modified compound is an IRAK4 inhibitor.

7. The method according to any one of claims 1 to 5, wherein the IRAK4-modified compound is an IRAK4 degrading agent.

8. The aforementioned IRAK4 inhibitor is given by formula I: 【Chemistry 1】 Having a structure represented by or a pharmaceutically acceptable salt thereof, During the ceremony, X １ and X ３ Independently, CH or N, and X ２ CR ２ or N, where X １ , X ２ or X ３ One of them and only one of them are N, A is either O or S, Y is -CH ２ - or O, Z is an aryl or heterocyclyl, R １ is, each time it appears, independently, a halo or a heterocyclyl optionally substituted, said substituent being alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NR ａ R ｂ and R ２ is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR ａ R ｂ The substituent is alkyl, amino, halo, or hydroxyl, R ３ Each instance is alkyl or hydroxyl, R ａ and R ｂ These are independently hydrogen, alkyl, acyl, or heterocyclyl. "m" and "n" are independently 0, 1, or 2. The method according to any one of claims 1 to 6, wherein "p" is 0 or 1.

9. A is either O or S, Y is -CH ２ - or O, Z is an aryl or heterocyclyl, R １ Each instance is a heterocyclyl that is independently substituted with a halo or optionally substituted, wherein the substituent is alkyl, aminoalkyl, halo, or -NR ａ R ｂ And R ａ and R ｂ These are independently hydrogen, alkyl, or heterocyclyl, R ２ is hydrogen, cycloalkyl, heterocyclyl or -NR ａ R ｂ And, "m" is 0, The method according to claim 8, wherein "n" is 1.

10. A is either O or S, Y is -CH ２ - or O, Z is an aryl or heterocyclyl, R １ Each instance is a heterocyclyl that is independently substituted with a halo or of any choice, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ And R ａ and R ｂ These are independently hydrogen, alkyl, or heterocyclyl, R ２ is a hydrogen, cycloalkyl, optionally substituted heterocyclyl or -NR ａ R ｂ The substituent is selected from amino, halo, or hydroxyl, "m" and "n" are independently 0, 1, or 2. The method according to claim 8, wherein "p" is 0 or 1. 【Request Item 11】 【Chemistry 2】 teeth 【Transformation 3】 The method according to any one of claims 8 to 10.

12. The method according to any one of claims 8 to 11, wherein Z is an aryl or a five-membered or six-membered heterocycline.

13. Z stands for phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydrofuranyl A heterocycline that is optionally substituted, selected from ropyranil, morpholinil, thiomorpholinil, 1,4-dioxanil, dioxidethiomorpholinil, oxapiperazinil, oxapiperidyl, tetrahydrofuryl, tetrahydropyranil, tetrahydrothiophenyl, dihydropyranil, and azabicyclo[3.2.1]octanil, each of which is alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or -NR ａ R ｂ Replaced by choice, R ａ and R ｂ The method according to any one of claims 8 to 12, wherein is independently hydrogen, alkyl, or acyl.

14. The aforementioned IRAK4 inhibitor is given by formula (IA): 【Chemistry 4】 The method according to claim 8, having a structure represented by or a pharmaceutically acceptable salt thereof.

15. A is either O or S, Y is -CH ２ - or O, R １ Each instance is a heterocyclyl that is independently substituted with a halo or optionally substituted, wherein the substituent is alkyl, aminoalkyl, halo, or -NR ａ R ｂ And R ａ and R ｂ These are independently hydrogen, alkyl, or heterocyclyl, R ２ is hydrogen, cycloalkyl, heterocyclyl or -NR ａ R ｂ And, "m" is 0, The method according to claim 14, wherein "n" is 1.

16. A is either O or S, Y is -CH ２ - or O, R １ Each instance is a heterocyclyl that is independently substituted with a halo or of any choice, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ And R ａ and R ｂ These are independently hydrogen, alkyl, or heterocyclyl, R ２ is a hydrogen, cycloalkyl, optionally substituted heterocyclyl or -NR ａ R ｂ The substituent is selected from amino, halo, or hydroxyl, The method according to claim 14, wherein "m" and "n" are independently 0, 1, or 2.

17. The aforementioned IRAK4 inhibitor is given by formula (IB): 【Transformation 5】 The method according to claim 8, having a structure represented by or a pharmaceutically acceptable salt thereof.

18. A is either O or S, Y is -CH ２ - or O, R １ Each instance is a heterocyclyl that is independently substituted with a halo or of any choice, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ And R ａ and R ｂ These are independently hydrogen, alkyl, or heterocyclyl, R ２ is a hydrogen, cycloalkyl, optionally substituted heterocyclyl or -NR ａ R ｂ The substituent is selected from amino, halo, or hydroxyl, The method according to claim 17, wherein "m" and "n" are independently 0, 1, or 2.

19. The aforementioned IRAK4 inhibitor is of formula (IC) 【Transformation 6】 The method according to claim 8, having a structure represented by or a pharmaceutically acceptable salt thereof.

20. R １ is a heterocycline that is optionally substituted, wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NR ａ R ｂ And R ａ and R ｂ The method according to any one of claims 8 to 19, wherein is independently hydrogen or acyl.

21. R １ is a heterocycline that is optionally substituted, wherein the substituent is alkyl, aminoalkyl, halo, or -NR ａ R ｂ And R ａ and R ｂ The method according to any one of claims 8 to 19, wherein is independently hydrogen or acyl.

22. R １ is a heterocycline that is optionally substituted, wherein the substituent is alkyl, aminoalkyl, halo, or -NR ａ R ｂ And R ａ and R ｂ The method according to any one of claims 8 to 19, wherein is independently hydrogen, alkyl, or heterocyclyl.

23. R １ is a heterocycline that is optionally substituted, and the substituents are alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ And R ａ and R ｂ The method according to any one of claims 8 to 19, wherein is independently hydrogen, alkyl, or heterocyclyl.

24. R １ The method according to any one of claims 8 to 19, wherein is pyridyl, pyrazolyl, pyrrolidinil, or piperidinil.

25. R １ is a pyrazolyl optionally substituted, said substituent being alkyl, hydroxyl or -NR ａ R ｂ and is the method according to any one of claims 8 to 19.

26. R １ The method according to any one of claims 8 to 19, wherein is a halo.

27. R ２ is hydrogen, cycloalkyl, heterocyclyl or -NR ａ R ｂ The method according to any one of claims 8 to 26.

28. R ２ is hydrogen, cycloalkyl, optionally substituted heterocyclyl or -NR ａ R ｂ where the substituent is selected from amino, halo or hydroxyl, the method according to any one of claims 8 to 26.

29. R ２ The method according to any one of claims 8 to 26, wherein is an optionally substituted heterocyclyl selected from piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanil, or azabicyclo[3.2.1]octanil, wherein the substituent is hydroxyl, halo, alkyl, or amino.

30. R ２ The method according to any one of claims 8 to 26, wherein is piperidinil, pyrrolidinil, morpholinil, or piperazinil.

31. R ２ The method according to any one of claims 8 to 26, wherein is hydrogen.

32. R ２ The method according to any one of claims 8 to 26, wherein is a cycloalkyl group.

33. R ２ The method according to claim 32, wherein is cyclopropyl.

34. R ３ The method according to any one of claims 8 to 33, wherein is alkyl.

35. The method according to any one of claims 8 to 34, wherein m is 0 and p is 1.

36. The method according to any one of claims 8 to 34, wherein m is 0 or 2 and p is 0 or 1.

37. The aforementioned IRAK4 inhibitors are as follows: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 The method according to any one of claims 1 to 6, or selected from pharmaceutically acceptable salts thereof.

38. The aforementioned IRAK4 inhibitor is 【Transformation 7】 The method according to any one of claims 1 to 6.

39. The aforementioned IRAK4 inhibitor is 【Transformation 8】 The method according to any one of claims 1 to 6, wherein the salt is pharmaceutically acceptable.

40. The aforementioned IRAK4 inhibitor is 【Chemistry 9】 The method according to any one of claims 1 to 6.

41. The aforementioned IRAK4 inhibitor is 【Chemistry 10】 The method according to any one of claims 1 to 6, wherein the salt is pharmaceutically acceptable.

42. The aforementioned IRAK4 inhibitor is 【Chemistry 11】 The method according to any one of claims 1 to 6.

43. The aforementioned IRAK4 inhibitor is 【Chemistry 12】 The method according to any one of claims 1 to 6, wherein the salt is pharmaceutically acceptable.

44. The aforementioned IRAK4 inhibitor is 【Chemistry 13】 The method according to any one of claims 1 to 6.

45. The aforementioned IRAK4 inhibitor is 【Chemistry 14】 The method according to any one of claims 1 to 6, wherein the salt is pharmaceutically acceptable.

46. The aforementioned IRAK4 inhibitor is 【Chemistry 15】 The method according to any one of claims 1 to 6.

47. The aforementioned IRAK4 inhibitor is 【Chemistry 16】 The method according to any one of claims 1 to 6, wherein the salt is pharmaceutically acceptable.

48. The aforementioned IRAK4 inhibitor is 【Chemistry 17】 The method according to any one of claims 1 to 6.

49. The aforementioned IRAK4 inhibitor is [Chemistry 18] The method according to any one of claims 1 to 6, wherein the salt is pharmaceutically acceptable.

50. The aforementioned IRAK4 inhibitor is 【Chemistry 19】 The method according to any one of claims 1 to 6.

51. The aforementioned IRAK4 inhibitor is 【Chemistry 20】 The method according to any one of claims 1 to 6, wherein the salt is pharmaceutically acceptable.

52. The aforementioned IRAK4 inhibitor is 【Chemistry 21】 The method according to any one of claims 1 to 6.

53. The aforementioned IRAK4 inhibitor is 【Chemistry 22】 The method according to any one of claims 1 to 6, wherein the salt is pharmaceutically acceptable.

54. The method according to any one of claims 8 to 53, comprising administering 100 to 400 mg of the IRAK4 inhibitor to the subject twice daily.

55. The method according to any one of claims 8 to 53, comprising administering 200 to 400 mg of the IRAK4 inhibitor to the subject twice daily.

56. The method according to any one of claims 8 to 53, comprising administering 250 to 350 mg of the IRAK4 inhibitor to the subject twice daily.

57. The method according to any one of claims 8 to 53, comprising administering the IRAK4 inhibitor in an amount of approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, or approximately 500 mg to the subject twice daily.

58. The method according to any one of claims 8 to 53, comprising administering the IRAK4 inhibitor in an amount of approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, or approximately 400 mg to the subject twice daily.

59. The method according to any one of claims 8 to 53, comprising administering approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 300 mg, or approximately 400 mg of the IRAK4 inhibitor to the subject twice daily.

60. The method according to any one of claims 8 to 53, comprising administering approximately 100 mg of the IRAK4 inhibitor to the subject twice daily.

61. The method according to any one of claims 8 to 53, comprising administering approximately 150 mg of the IRAK4 inhibitor to the subject twice daily.

62. The method according to any one of claims 8 to 53, comprising administering approximately 200 mg of the IRAK4 inhibitor to the subject twice daily.

63. The method according to any one of claims 8 to 53, comprising administering approximately 225 mg of the IRAK4 inhibitor to the subject twice daily.

64. The method according to any one of claims 8 to 53, comprising administering approximately 250 mg of the IRAK4 inhibitor to the subject twice daily.

65. The method according to any one of claims 8 to 53, comprising administering approximately 275 mg of the IRAK4 inhibitor to the subject twice daily.

66. The method according to any one of claims 8 to 53, comprising administering approximately 300 mg of the IRAK4 inhibitor to the subject twice daily.

67. The method according to any one of claims 8 to 53, comprising administering approximately 325 mg of the IRAK4 inhibitor to the subject twice daily.

68. The method according to any one of claims 8 to 53, comprising administering approximately 350 mg of the IRAK4 inhibitor to the subject twice daily.

69. The method according to any one of claims 8 to 53, comprising administering approximately 375 mg of the IRAK4 inhibitor to the subject twice daily.

70. The method according to any one of claims 8 to 53, comprising administering approximately 400 mg of the IRAK4 inhibitor to the subject twice daily.

71. The method according to any one of claims 8 to 53, comprising administering the IRAK4 inhibitor in an amount of approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, or approximately 500 mg to the subject once daily.

72. The method according to any one of claims 8 to 53, comprising administering approximately 25 mg of the IRAK4 inhibitor to the subject once daily.

73. The method according to any one of claims 8 to 53, comprising administering approximately 50 mg of the IRAK4 inhibitor to the subject once daily.

74. The method according to any one of claims 8 to 53, comprising administering approximately 75 mg of the IRAK4 inhibitor to the subject once daily.

75. The method according to any one of claims 8 to 53, comprising administering approximately 100 mg of the IRAK4 inhibitor to the subject once daily.

76. The method according to any one of claims 8 to 53, comprising administering approximately 125 mg of the IRAK4 inhibitor to the subject once daily.

77. The method according to any one of claims 8 to 53, comprising administering approximately 150 mg of the IRAK4 inhibitor to the subject once daily.

78. The method according to any one of claims 8 to 53, comprising administering approximately 175 mg of the IRAK4 inhibitor to the subject once daily.

79. The method according to any one of claims 8 to 53, comprising administering approximately 200 mg of the IRAK4 inhibitor to the subject once daily.

80. The method according to any one of claims 8 to 53, comprising administering approximately 225 mg of the IRAK4 inhibitor to the subject once daily.

81. The method according to any one of claims 8 to 53, comprising administering approximately 250 mg of the IRAK4 inhibitor to the subject once daily.

82. The method according to any one of claims 8 to 53, comprising administering approximately 275 mg of the IRAK4 inhibitor to the subject once daily.

83. The method according to any one of claims 8 to 53, comprising administering approximately 300 mg of the IRAK4 inhibitor to the subject once daily.

84. The method according to any one of claims 8 to 53, comprising administering approximately 325 mg of the IRAK4 inhibitor to the subject once daily.

85. The method according to any one of claims 8 to 53, comprising administering approximately 350 mg of the IRAK4 inhibitor to the subject once daily.

86. The method according to any one of claims 8 to 53, comprising administering approximately 375 mg of the IRAK4 inhibitor to the subject once daily.

87. The method according to any one of claims 8 to 53, comprising administering approximately 400 mg of the IRAK4 inhibitor to the subject once daily.

88. The method according to any one of claims 8 to 53, comprising administering approximately 425 mg of the IRAK4 inhibitor to the subject once daily.

89. The method according to any one of claims 8 to 53, comprising administering approximately 450 mg of the IRAK4 inhibitor to the subject once daily.

90. The method according to any one of claims 8 to 53, comprising administering approximately 475 mg of the IRAK4 inhibitor to the subject once daily.

91. The method according to any one of claims 8 to 53, comprising administering approximately 500 mg of the IRAK4 inhibitor to the subject once daily.

92. The method according to any one of claims 1 to 74, wherein the IRAK4 inhibitor or IRAK4 degrading agent is administered orally to the subject.

93. The method according to any one of claims 8 to 53, comprising administering approximately 50 mg of the IRAK4 inhibitor to the subject once daily.

94. The method according to any one of claims 8 to 53, comprising administering approximately 75 mg of the IRAK4 inhibitor to the subject once daily.

95. The method according to any one of claims 8 to 53, comprising orally administering approximately 100 mg of the IRAK4 inhibitor to the subject twice a day.

96. The method according to any one of claims 8 to 53, comprising orally administering approximately 125 mg of the IRAK4 inhibitor to the subject twice daily.

97. The method according to any one of claims 8 to 53, comprising orally administering approximately 150 mg of the IRAK4 inhibitor to the subject twice daily.

98. The method according to any one of claims 8 to 53, comprising orally administering approximately 175 mg of the IRAK4 inhibitor to the subject twice daily.

99. The method according to any one of claims 8 to 53, comprising orally administering approximately 200 mg of the IRAK4 inhibitor to the subject twice daily.

100. The method according to any one of claims 8 to 53, comprising orally administering approximately 225 mg of the IRAK4 inhibitor to the subject twice daily.

101. The method according to any one of claims 8 to 53, comprising orally administering approximately 250 mg of the IRAK4 inhibitor to the subject twice daily.

102. The method according to any one of claims 8 to 53, comprising orally administering approximately 275 mg of the IRAK4 inhibitor to the subject twice daily.

103. The method according to any one of claims 8 to 53, comprising orally administering approximately 300 mg of the IRAK4 inhibitor to the subject twice a day.

104. The method according to any one of claims 8 to 53, comprising orally administering approximately 325 mg of the IRAK4 inhibitor to the subject twice daily.

105. The method according to any one of claims 8 to 53, comprising orally administering approximately 350 mg of the IRAK4 inhibitor to the subject twice daily.

106. The method according to any one of claims 8 to 53, comprising orally administering approximately 375 mg of the IRAK4 inhibitor to the subject twice daily.

107. The method according to any one of claims 8 to 53, comprising orally administering approximately 400 mg of the IRAK4 inhibitor to the subject twice a day.

108. 75 mg / m² ２ The method according to any one of claims 8 to 107, further comprising administering azacitidine to the subject once daily.

109. The method according to any one of claims 1 to 7, wherein the IRAK4-modified compound is PF-06650833 or BAY1830839.

110. The method according to claim 7, wherein the IRAK4 decomposing agent is KT-474.

111. The method according to any one of claims 1 to 110, further comprising co-administering a BTK inhibitor to the subject.

112. The method according to claim 111, wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebralutinib, or HM71224.

113. The method according to claim 112, wherein the BTK inhibitor is acalabrutinib.

114. The method according to claim 113, comprising administering 200 mg of acalabrutinib daily.

115. The method according to claim 113, wherein the acalabrutinib is administered orally.

116. The method according to claim 113, comprising administering 200 mg of acalabrutinib orally on a daily basis.

117. The method according to claim 112, wherein the BTK inhibitor is ibrutinib.

118. The method according to claim 117, comprising administering 420 mg of ibrutinib daily.

119. The method according to claim 117, comprising administering 560 mg of ibrutinib daily.

120. The method according to claim 117, wherein the ibrutinib is administered orally.

121. The method according to claim 117, comprising administering 420 mg of ibrutinib orally on a daily basis.

122. The method according to claim 117, comprising administering 560 mg of ibrutinib orally on a daily basis.

123. The method according to claim 112, wherein the BTK inhibitor is zanubrutinib.

124. The method according to claim 123, comprising administering 160 mg of zanubrutinib twice daily.

125. The method according to claim 123, comprising administering 320 mg of zanubrutinib once daily.

126. The method according to claim 123, wherein zanubrutinib is administered orally.

127. The method according to claim 123, comprising administering 160 mg of zanubrutinib orally twice daily.

128. The method according to claim 123, comprising administering 320 mg of zanubrutinib orally once daily.

129. The method according to any one of claims 1 to 128, wherein the cancer is a hematological malignancy.

130. The method according to claim 129, wherein the hematological malignancy is a non-Hodgkin lymphoma.

131. The method according to claim 129, wherein the hematological malignancy is leukemia.

132. The method according to claim 129, wherein the hematological malignancy is lymphoma.

133. The aforementioned hematological malignancies include myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia, myelodysplastic syndrome), lymphoblastic leukemia (e.g., acute lymphoblastic leukemia), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., DLBCL or ABC-DLBLC), and mantle cell lymphoma (MCL). The method according to any one of claims 129 to 132, wherein the lymphoma is 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.

134. The method according to claim 129, wherein the hematological malignancy is myeloid leukemia.

135. The method according to claim 129, wherein the hematological malignancy is myeloid leukemia (for example, acute myeloid leukemia).

136. The method according to claim 129, wherein the hematological malignancy is acute myeloid leukemia (e.g., AML).

137. The method according to claim 136, wherein the AML is primary AML.

138. The method according to claim 136, wherein the AML is a secondary AML.

139. The method according to any one of claims 136 to 138, wherein the AML is a therapeutic AML.

140. The method according to claim 129, wherein the hematological malignancy is myelodysplastic syndrome.

141. The method according to claim 140, wherein the myelodysplastic syndrome is of high malignancy.

142. The method according to claim 140, wherein the myelodysplastic syndrome is of low grade.

143. The method according to any one of claims 140 to 142, wherein the myelodysplastic syndrome is at high risk.

144. The method according to claim 129, wherein the hematological malignancy is lymphoblastic leukemia (for example, acute lymphoblastic leukemia).

145. The method according to claim 129, wherein the hematological malignancy is chronic lymphocytic leukemia (CLL).

146. The method according to claim 145, wherein the CLL is a high-risk CLL.

147. The method according to claim 129, wherein the hematological malignancy is small lymphocytic lymphoma (SLL).

148. The method according to claim 129, wherein the hematological malignancy is follicular lymphoma.

149. The method according to claim 129, wherein the hematological malignancy is diffuse large B-cell lymphoma (DLBCL).

150. The method according to claim 129, wherein the hematological malignancy is activated B-cell-like (ABC) DLBCL.

151. The method according to claim 129, wherein the hematological malignancy is germinal center B-cell-like (GCB) DLBCL.

152. The method according to any one of claims 149 to 151, wherein the DLBCL is extranodal.

153. The method according to any one of claims 149 to 152, wherein the DLBCL is extranodal limb lymphoma, extranodal testicular lymphoma, or extranodal unspecified (NOS) type lymphoma.

154. The method according to claim 129, wherein the hematological malignancy is mantle cell lymphoma.

155. The method according to claim 129, wherein the hematological malignancy is Waldenström macroglobulinemia.

156. The method according to claim 129, wherein the hematological malignancy is multiple myeloma.

157. The method according to claim 129, wherein the hematological malignancy is marginal zone lymphoma.

158. The method according to claim 129, wherein the hematological malignancy is Burkitt lymphoma.

159. The method according to claim 129, wherein the hematological malignancy is a non-Burkitt high-grade B-cell lymphoma.

160. The method according to claim 129, wherein the hematological malignancy is an extranodal marginal zone B-cell lymphoma.

161. The method according to claim 129, wherein the hematological malignancy is transformed high-grade B-cell lymphoma (HGBL).

162. The method according to claim 129, wherein the hematological malignancy is lymphoplasmacytic lymphoma (LPL).

163. The method according to claim 129, wherein the hematological malignancy is CNS lymphoma.

164. The method according to claim 163, wherein the CNS lymphoma is primary CNS lymphoma (PCNSL).

165. The method according to claim 129, wherein the hematological malignancy is MALT lymphoma.

166. The method according to any one of claims 129 to 165, wherein the hematological malignancy is recurrent.

167. The method according to any one of claims 129 to 166, wherein the hematological malignancy is refractory.

168. The method according to any one of claims 1 to 128, 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, epidermal cancer, prostate cancer, and head and neck cancer.

169. The method according to any one of claims 1 to 128, wherein the cancer is pancreatic cancer.

170. The method according to any one of claims 1 to 128, wherein the cancer is colon cancer.

171. The method according to any one of claims 168 to 170, wherein the cancer is a solid tumor.

172. The method according to any one of claims 168 to 171, wherein the cancer is recurrent.

173. The method according to any one of claims 168 to 172, wherein the cancer is intractable.

174. The method according to any one of claims 1 to 173, wherein the cancer is resistant to treatment with a BTK inhibitor.

175. The method according to claim 174, wherein the cancer is resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebralutinib, or HM71224.

176. The method according to claim 175, wherein the cancer is resistant to treatment with ibrutinib.

177. The method according to claim 175, wherein the cancer is resistant to treatment with acalabrutinib.

178. The method according to any one of claims 1 to 177, wherein the subject is an adult.

179. The method according to any one of claims 1 to 177, wherein the subject has previously received at least one anti-cancer therapy (e.g., anti-cancer therapy or anti-inflammatory therapy).

180. The method according to claim 179, wherein the subject has previously received one anti-cancer therapy.

181. The method according to claim 179, wherein the subject has previously received two anti-cancer therapies.

182. The method according to claim 179, wherein the subject has previously received three anti-cancer therapies.

183. The method according to claim 179, wherein the subject has previously received four anti-cancer therapies.

184. The method according to claim 179, wherein the subject has previously received five anti-cancer therapies.

185. The method according to any one of claims 179 to 184, wherein the at least one anticancer therapy comprises an anti-CD20 antibody, nitrogen mustard, a steroid, a purine analog, a DNA topoisomerase inhibitor, a DNA intercalator, a tubulin 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, a steroid, a PD-1 inhibitor, a PD-L1 inhibitor, or a methylating agent, or a combination thereof.

186. The method according to any one of claims 179 to 185, wherein the anticancer therapy comprises ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, ifosfamide, prednisone, oprozomib, ixazomib, acalabrutinib, zanubrutinib, IMO-08400, idelalisib, umbralicib, CB-839, fludarabine, or thalidomide, or a combination thereof.

187. The anticancer therapy according to any one of claims 179 to 186, wherein the anticancer therapy comprises dexamethasone.

188. The anticancer therapy according to any one of claims 179 to 186, wherein the anticancer therapy comprises ibrutinib.

189. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises ibrutinib and rituximab.

190. The anti-cancer therapy according to any one of claims 179 to 186, comprising bendamustine.

191. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises bendamustine and rituximab.

192. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises bortezomib.

193. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises bortezomib and dexamethasone.

194. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises bortezomib and rituximab.

195. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises bortezomib, rituximab, and dexamethasone.

196. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises chlorambucil.

197. The anticancer therapy according to any one of claims 179 to 186, wherein the anticancer therapy comprises cladribine.

198. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises cladribine and rituximab.

199. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R).

200. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises cyclophosphamide, prednisone, and rituximab (i.e., CPR).

201. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises fludarabine.

202. The method according to any one of claims 161 to 186, wherein the anticancer therapy comprises fludarabine and rituximab.

203. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises fludarabine, cyclophosphamide, and rituximab.

204. The anticancer therapy according to any one of claims 179 to 186, wherein the anticancer therapy comprises rituximab.

205. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).

206. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises thalidomide.

207. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises thalidomide and rituximab.

208. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD).

209. The method according to any one of claims 179 to 186, wherein the anticancer therapy comprises a hypomethylating agent.

210. The method according to any one of claims 1 to 209, wherein the subject has previously received at least six cycles of a low-methylating agent.

211. The method according to any one of claims 1 to 210, wherein the subject has previously received etoposide chemomobilization therapy.

212. The method according to any one of claims 1 to 211, wherein the subject has previously undergone a bone marrow transplant.

213. The method according to any one of claims 1 to 212, wherein the subject has previously undergone hematopoietic stem cell transplantation.

214. The method according to any one of claims 1 to 213, wherein the subject has previously undergone stem cell transplantation.

215. The method according to any one of claims 1 to 214, wherein the subject has previously undergone autologous stem cell transplantation.

216. The method according to any one of claims 1 to 215, wherein the subject has previously undergone allogeneic stem cell transplantation.

217. The method according to any one of claims 1 to 216, wherein the subject has previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM pretreatment).

218. The method according to any one of claims 1 to 217, wherein the subject has previously received reinduction therapy.

219. The method according to any one of claims 1 to 218, wherein the subject has previously achieved a partial response.

220. The method according to any one of claims 1 to 219, wherein the subject has previously achieved a good partial response.

221. The method according to any one of claims 1 to 220, wherein the subject has previously achieved a complete response.

222. The method according to any one of claims 1 to 221, wherein the subject has a mutation in RICTOR.

223. The method according to any one of claims 1 to 222, wherein the subject has the N1065S mutation in RICTOR.

224. The method according to any one of claims 1 to 223, wherein the subject has a mutation in MYD88.

225. The method according to any one of claims 1 to 224, wherein the subject has the L265P mutation in MYD88.

226. The method according to any one of claims 1 to 225, wherein the subject has a mutation in TET2.

227. The method according to any one of claims 1 to 226, wherein the subject does not have a mutation in CXCR4.

228. The method according to any one of claims 1 to 226, wherein the subject has a mutation in CXCR4.

229. The method according to any one of claims 1 to 228, wherein the subject has a mutation in SF3B1 (e.g., insertion, deletion, loss, or spliceosome mutation).

230. The method according to any one of claims 1 to 229, wherein the subject has a mutation in U2AF1 (e.g., insertion, deletion, loss, or spliceosome mutation).

231. The method according to any one of claims 1 to 230, wherein the subject has a mutation in FLT3 (e.g., insertion, deletion, or loss).

232. The method according to claim 231, wherein the mutation in the FLT3 kinase is selected from one or more of the following: internal tandem duplication (ITD), a mutation at D835, a mutation at F691, a mutation at K663, and / or a mutation at N841.

233. The method according to claim 231 or 232, wherein the mutation in FLT3 kinase includes the D835H mutation.

234. The method according to any one of claims 231 to 233, wherein the mutation in FLT3 kinase includes the D835V mutation.

235. The method according to any one of claims 231 to 234, wherein the mutation in the FLT3 kinase includes the D835Y mutation.

236. The method according to any one of claims 231 to 235, wherein the mutation in the FLT3 kinase includes the K663Q mutation.

237. The method according to any one of claims 231 to 236, wherein the mutation in the FLT3 kinase includes the N841I mutation.

238. The method according to any one of claims 231 to 237, wherein the mutation in FLT3 kinase includes the ITD and D835V mutations.

239. The method according to any one of claims 231 to 238, wherein the mutation in FLT3 kinase includes the ITD and F691L mutations.

240. The method according to any one of claims 231 to 239, wherein the mutation in FLT3 kinase includes the ITD and D835Y mutations.

241. The method according to any one of claims 1 to 240, wherein the subject has a mutation in STAG2 (e.g., insertion, deletion, or loss).

242. The method according to any one of claims 1 to 241, wherein the subject has a mutation in DNMT3A (e.g., insertion, deletion, or loss).

243. The method according to any one of claims 1 to 242, wherein the subject has a mutation in BCOR (e.g., insertion, deletion, or loss).

244. The method according to any one of claims 1 to 243, wherein the subject has a mutation in WT1 (e.g., insertion, deletion, or loss).

245. The method according to any one of claims 1 to 244, wherein the subject has a mutation in the NRAS (e.g., insertion, deletion, or loss).

246. The method according to any one of claims 1 to 245, wherein the subject exhibits early progression.

247. The method according to any one of claims 1 to 246, wherein the subject has not previously received a BTK inhibitor.

248. The method according to any one of claims 1 to 247, wherein the subject achieves a partial response after administration of the IRAK4 inhibitor.

249. The method according to any one of claims 1 to 248, wherein the subject achieves a good partial response after administration of the IRAK4 inhibitor.

250. The method according to any one of claims 1 to 249, wherein the subject achieves a complete response after administration of the IRAK4 inhibitor.

251. The method according to any one of claims 1 to 250, wherein the target IL-1-induced signaling is reduced after administration of the IRAK4 inhibitor.

252. The method according to any one of claims 1 to 251, wherein the production of the target cytokine decreases after administration of the IRAK4 inhibitor.

253. The method according to any one of claims 1 to 252, wherein the IRAK4 inhibitor is administered until disease progression or unacceptable toxicity occurs.

Images