Methods of treating cancer in a subject having prior immune checkpoint inhibitor exposure

Abstract

The present disclosure relates to the use of an IRAK4 inhibitor or IRAK4 degrader in the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration to a subject who has previously received one or more immune checkpoint inhibitors for the treatment of the cancer.

Description

[0001] This application is a divisional application of patent application No. 202480035800.9 entitled "Method for treating cancer in a subject with prior exposure to immune checkpoint inhibitors", filed on May 31, 2024.

[0002] Related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 470,361, filed June 1, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] 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) ​​signal transduction. Various IRAK enzymes are key components in signal transduction pathways mediated by interleukin-1 receptor (IL-1R) and Toll-like receptors (TLRs) (Janssens, S. et al., Mol. Cell. 11, 2003, 293-302). The mammalian IRAK family has four members: IRAK1, IRAK2, IRAK3, and IRAK4. These proteins are characterized by a typical N-terminal death domain mediating interactions with MyD88 family adaptor proteins and a centrally located kinase domain. IRAK proteins, including MyD88, have been shown to play roles in transducing signals other than those derived from the IL-1R receptor, including signals triggered by activation of the IL-18 receptor (Kanakaraj et al., J. Exp. Med., J. Immunol. 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 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. While IRAK-1 kinase activity may be dispensable 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), 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 immune protection, IRAK4 inhibitors have been considered valuable therapeutic agents for inflammatory diseases, sepsis and autoimmune disorders (Wietek C et al., Mol. Interv. 2:2002, 212-215).

[0004] Mice lacking IRAK4 are viable and show complete elimination of the production of inflammatory cytokines in response to IL-1, IL-18, or LPS (Suzuki et al., Nature, 416(6882), 2002, 750-756). Similarly, human patients lacking IRAK4 have severely impaired immune function and are unresponsive to these cytokines (Medvedev et al., J. Exp. Med., 198(4), 2003, 521-531 and Picard et al., Science 299(5615), 2003, 2076-2079). Knock-in mice containing inactive IRAK4 exhibit complete resistance 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 production, MAPK activation, and the induction of NF-κB-regulated genes in response to TLR ligands (Koziczak-Holbro M et al., J Biol Chem; 282(18):2007;13552-13560). Inactivation of IRAK4 kinase (IRAK4 KI) in mice leads to resistance to EAE due to reduced infiltrating inflammatory cells entering the CNS and reduced production of IL-17 mediated by antigen-specific CD4+ T cells (Kirk A et al., The Journal of Immunology, 183(1), 2009, 568-577).

[0005] Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in adults, with an estimated 80,000 new cases and 20,000 deaths in the United States in 2023. The molecular pathology driving NHL is diverse, although a common theme is the overactivity of the NF-κB signaling pathway. Specific molecular changes driving this pathway have been identified in subgroups of NHL. For example, diffuse large B-cell lymphoma (hereinafter also referred to as “DLBCL”) is an aggressive lymphoma that can occur in or outside the lymphatic system, in the gastrointestinal tract, testes, thyroid gland, skin, breast, bone, or brain. DLBCL is a B-cell cancer, a type of white blood cell responsible for producing antibodies. It is the most common type of non-Hodgkin lymphoma in adults, with an annual incidence of 7–8 cases per 100,000 people per year. This cancer primarily occurs in older adults, with a median age of diagnosis of approximately 70 years, but it can also occur in children and young adults in rare cases. DLBCL is an aggressive tumor, and the first sign of the disease is usually the observation of a rapidly growing mass. The five-year survival rate is only 58%. DLBCL has subtypes named after their cells of origin and includes germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes. They differ in that they have a worse prognosis and, in some cases, require specific treatments.

[0006] Acute myeloid leukemia (AML), one of the most common forms of leukemia in adults, sees approximately 20,000 new cases diagnosed each year. AML remains a highly fatal disease, with a five-year survival rate of only 28.3%. Interleukin-1 receptor-associated kinase 4 (IRAK4) has been shown to be a potential therapeutic target in human AML. Although AML is a heterogeneous disease, common characteristics of leukemia blasts include high proliferative potential, increased stem cell self-renewal, and differentiation arrest in a relatively immature state within the cell pool. It is also generally believed that specific gene mutations present in AML cells can guide treatment and determine how long a patient may survive.

[0007] Myelodysplastic syndromes (MDS) are conditions that can occur when hematopoietic cells in the bone marrow become abnormal. The main clinical problems in these conditions are the morbidity due to cytopenia and the likelihood of MDS progressing to AML. In the general population, the incidence of MDS is approximately 4.9 per 100,000 people per year. High-risk MDS (hrMDS) is defined as having a high risk, an IPSS score ≥ 2.5, and immature blasts potentially comprising more than 5% of the cells in the bone marrow. Low blood cell counts can lead to anemia, neutropenia, or thrombocytopenia. HrMDS carries a greater risk of developing AML and has a shorter survival rate; the median survival is only 0.8 years when patients do not receive treatment.

[0008] Another example of NHL is Waldenstrom's macroglobulinemia (WM). WM is a non-Hodgkin's lymphoma that affects two types of B cells: lymphoplasmacytic-like cells and plasma cells. WM is characterized by high levels of circulating antibodies, immunoglobulin M (IgM), which are produced and secreted by cells involved in the disease. WM is a rare disease, with only about 1,500 cases diagnosed annually in the United States. Due to gaps in knowledge about the molecular basis of the disease, there is no single acceptable treatment for WM and significant differences in clinical outcomes. Objective response rates are high (>80%), but complete response rates are low (0–15%).

[0009] Other types of non-Hodgkin's 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's lymphoma can be caused by a variety of factors, such as infectious agents (Epstein-Barr virus, hepatitis C virus, and human T-cell leukemia virus), radiation and chemotherapy treatments, and autoimmune diseases. Overall, non-Hodgkin's lymphoma affects 2.1% of the U.S. population in their lifetime. The percentage of people who survive more than five years after diagnosis is 71%.

[0010] Targeting intratumoral immune cells with immune checkpoint inhibitors has enabled novel treatment options for many cancers. While several other targets are under development, major clinically approved therapies focus on the programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways. These therapies have proven effective in treating both Hodgkin's lymphoma and non-Hodgkin's lymphoma, although not all patients respond to these treatments.

[0011] In light of the above, there is a clear and unmet need for alternative therapies for the treatment of cancer and other IRAK4-related diseases. Summary of the Invention

[0012] In some respects, this disclosure provides a method for treating cancer in a subject, the method comprising administering an IRAK4 inhibitor or an IRAK4 degrader to the subject, wherein the subject has previously received an immune checkpoint inhibitor for the treatment of cancer. Attached Figure Description

[0013] Figure 1AThis is a graph illustrating the results of a clinical study demonstrating the efficacy of emavusertib (compound 1) in reducing bone marrow (BM) blasts in patients with blood cancer. Blasts are immature white blood cells that are normally present in small numbers in healthy bone marrow. High levels of blasts circulating in the blood are associated with cancer. This clinical study measured changes in blast levels 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 an immune checkpoint inhibitor in their prior treatment and those who had not. Each comparison group contained at least 5 patients with high-risk myelodysplastic syndromes (hrMDS) and 1 patient with acute myeloid leukemia (AML). Patients who had previously been exposed to immune checkpoint inhibitors (e.g., magrolimab, ipilimumab, or a combination of nivolumab and ipilimumab) showed a significant reduction in blasts compared to those who had not previously been exposed to immune checkpoint inhibitors. Therefore, the significant difference in baseline and post-optimal baseline bone marrow blast counts between subjects with prior immune checkpoint inhibitor exposure and those without suggests that subjects with prior immune checkpoint inhibitor exposure are more likely to respond to IRAK4 mediators such as compound 1.

[0014] Figure 1B It shows Figure 1A A graph showing the baseline and post-optimal treatment blast cell levels of the subjects. Subjects with prior immune checkpoint inhibitor exposure exhibited a greater decrease in bone marrow blast cell count from baseline to optimal baseline compared to those without prior exposure. Patients were shaded according to their diagnosis. Detailed Implementation

[0015] Results from an ongoing Phase 1 study demonstrated the clinical activity of the IRAK4 inhibitor imaseti (compound 1) in patients with relapsed / refractory AML and high-risk MDS. To support the development of an effective treatment regimen with compound 1, a study was conducted to monitor bone marrow (BM) samples obtained from AML and high-risk MDS patients with varying prior treatment histories. Clinical response data showed that patients with a history of treatment with immune checkpoint inhibitors had a higher response rate to compound 1 compared to patients who had not previously been exposed to immune checkpoint inhibitors, as demonstrated by a reduction in BM blast cell counts in hematology. This disclosure relates to methods of treating cancer with compound 1 and other IRAK4 inhibitors or degraders, wherein the subjects have a history of treatment with immune checkpoint inhibitors.

[0016] In some aspects, this disclosure provides a method for treating cancer in a subject, the method comprising administering an IRAK4 inhibitor or an IRAK4 degrader to the subject, wherein the subject has previously received one or more immune checkpoint inhibitors for the treatment of cancer.

[0017] In some embodiments, one or more immune checkpoint inhibitors include programmed cell death protein (PD-1) inhibitors. In some preferred embodiments, the PD-1 inhibitor is an antibody. In some embodiments, the PD-1 inhibitor is a small molecule.

[0018] In some embodiments, one or more immune checkpoint inhibitors include programmed cell death ligand 1 (PD-L1) inhibitors. In some preferred embodiments, the PD-L1 inhibitor is an antibody. In some embodiments, the PD-L1 inhibitor is a small molecule.

[0019] In some embodiments, one or more immune checkpoint inhibitors include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. In some preferred embodiments, the CTLA-4 inhibitor is an antibody. In some embodiments, the CTLA-4 inhibitor is a small molecule.

[0020] In some embodiments, one or more immune checkpoint inhibitors include CD47 inhibitors. In some preferred embodiments, the CD47 inhibitor is an antibody. In some embodiments, the CD47 inhibitor is a small molecule.

[0021] In some embodiments, one or more immune checkpoint inhibitors include LAG-3 inhibitors. In some embodiments, the LAG-3 inhibitor is an antibody. In some embodiments, the LAG-3 inhibitor is a small molecule.

[0022] In some embodiments, one or more immune checkpoint inhibitors include 4-IBB inhibitors. In some embodiments, the 4-IBB inhibitor is an antibody. In some embodiments, the 4-IBB inhibitor is a small molecule.

[0023] In some embodiments, one or more immune checkpoint inhibitors include CD27 inhibitors. In some embodiments, the CD27 inhibitor is an antibody. In some embodiments, the CD27 inhibitor is a small molecule.

[0024] In some embodiments, one or more immune checkpoint inhibitors include CD40 inhibitors. In some embodiments, the CD40 inhibitor is an antibody. In some embodiments, the CD40 inhibitor is a small molecule.

[0025] In some embodiments, one or more immune checkpoint inhibitors include CD80 inhibitors. In some embodiments, the CD80 inhibitor is an antibody. In some embodiments, the CD80 inhibitor is a small molecule.

[0026] In some embodiments, one or more immune checkpoint inhibitors include OX-40 inhibitors. In some embodiments, the OX-40 inhibitor is an antibody. In some embodiments, the OX-40 inhibitor is a small molecule.

[0027] In some embodiments, the subject has previously received one immune checkpoint inhibitor. In some embodiments, the subject has previously received two immune checkpoint inhibitors. In some embodiments, the subject has previously received three immune checkpoint inhibitors. In some embodiments, the subject has previously received four immune checkpoint inhibitors. In some embodiments, the subject has previously received five immune checkpoint inhibitors.

[0028] In some implementations, one or more immune checkpoint inhibitors include molotovicillin, ipilimumab, nivolumab, atezolizumab, avelumab, camrelizumab, cemiplimab, dacetuzumab, dostarlimab, durvalumab, galiximab, lucarumumab, pembrolizumab, relatlimab, retifanlimab, selicrelumab, sintilimab, and sparidalizumab. (rtalizumab), torilizumab, tislelizumab, toripalimab, tremelimumab, urelumab, utomilumab, varlilumab, MGD013, SHR-1701, IMC-001, MCLA-145, CA-170, INCAGN02385, IMP701, MK-4280, ADG106, ISF35, CDX-1140, SEA-CD40, TTI-621, TJC4, TTI-622, ALX148, TG-1801, MEDI6469, BMS-986178 or PF-04518600; or combinations thereof.

[0029] In some preferred embodiments, one or more immune checkpoint inhibitors include molotovicillin.

[0030] In some preferred embodiments, one or more immune checkpoint inhibitors include ipilimumab.

[0031] In some preferred embodiments, one or more immune checkpoint inhibitors include nivolumab.

[0032] In some preferred embodiments, one or more immune checkpoint inhibitors include ipilimumab and nivolumab.

[0033] In some embodiments, one or more immune checkpoint inhibitors include atezolizumab. In some embodiments, one or more immune checkpoint inhibitors include avelumab. In some embodiments, one or more immune checkpoint inhibitors include camrelizumab. In some embodiments, one or more immune checkpoint inhibitors include cimiprimab. In some embodiments, one or more immune checkpoint inhibitors include dasizumab. In some embodiments, one or more immune checkpoint inhibitors include dotalimab. In some embodiments, one or more immune checkpoint inhibitors include durvalumab. In some embodiments, one or more immune checkpoint inhibitors include galiximab. In some embodiments, one or more immune checkpoint inhibitors include rucamimumab. In some embodiments, one or more immune checkpoint inhibitors include pembrolizumab. In some embodiments, one or more immune checkpoint inhibitors include renalalimab. In some embodiments, one or more immune checkpoint inhibitors include rivanol. In some embodiments, one or more immune checkpoint inhibitors include celumab. In some embodiments, one or more immune checkpoint inhibitors include sintilimab. In some embodiments, one or more immune checkpoint inhibitors include spartazolizumab. In some embodiments, one or more immune checkpoint inhibitors include toripalimab. In some embodiments, one or more immune checkpoint inhibitors include tislelizumab. In some embodiments, one or more immune checkpoint inhibitors include toripalimab. In some embodiments, one or more immune checkpoint inhibitors include trimemumab. In some embodiments, one or more immune checkpoint inhibitors include uroselumab. In some embodiments, one or more immune checkpoint inhibitors include utorumab. In some embodiments, one or more immune checkpoint inhibitors include varigramab.

[0034] In some preferred embodiments, the subject has previously received an immune checkpoint inhibitor, and the immune checkpoint inhibitor is an anti-CD47 antibody. In some preferred embodiments, the anti-CD47 antibody is molotovicillin.

[0035] In some preferred embodiments, the subject has previously received an immune checkpoint inhibitor, and the immune checkpoint inhibitor is an anti-CTLA-4 antibody. In some preferred embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0036] In some preferred embodiments, the subject has previously received two immune checkpoint inhibitors, and the immune checkpoint inhibitors are an anti-CTLA-4 antibody and an anti-PD-1 antibody. In some preferred embodiments, the anti-CTLA antibody is ipilimumab. In some preferred embodiments, the anti-PD-1 antibody is nivolumab. In some preferred embodiments, both the anti-CTLA antibody and the anti-PD-1 antibody are nivolumab.

[0037] In some embodiments, the IRAK4-modifying compound is an IRAK4 inhibitor. In other embodiments, the IRAK4-modifying compound is an IRAK4 degrader.

[0038] Methods and compounds relating to the present disclosure can be found, for example, in U.S. Patents 10,160,753, 9,732,095, 10,758,518, and 11,419,875; U.S. Applications 17 / 680,995, 18 / 019,400, and 18 / 037,697; and pending PCT patent application PCT / US23 / 21812; the contents of these applications are incorporated herein by reference in their entirety, particularly the IRAK4 inhibitors, treatment regimens, and indications disclosed therein.

[0039] IRAK4 inhibitors In a broad sense, the methods disclosed herein can be performed using any IRAK4 inhibitor. For example, these methods can be performed using the IRAK4 inhibitors disclosed in PCT / IB 15 / 050119, PCT / IB 15 / 050217, PCT / IB 15 / 0054620, PCT / IB 16 / 054203 and / or PCT / IB16 / 054229. The contents of each of the foregoing international applications, particularly the IRAK4 inhibitors disclosed therein, are fully incorporated herein by reference.

[0040] In some implementations, IRAK4 inhibitors are represented by Formula I: Or its pharmaceutically acceptable salt; in X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2 or X3 is N; A is O or S; Y is -CH2- or O; Z is an aryl or heterocyclic group; R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogroup, hydroxy, hydroxyalkyl, or -NR group. a R b ; R2 is hydrogen, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or -NR. a R b The substituents thereon are alkyl, amino, halogroups or hydroxyl groups; R3 is either an alkyl or hydroxyl group each time it appears; R a and R b It can be independently hydrogen, alkyl, acyl, or heterocyclic; 'm' and 'n' are independently 0, 1, or 2; 'p' is 0 or 1.

[0041] In some embodiments, A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently a halogroup or optionally substituted heterocyclic group each time it appears, wherein the substituent is alkyl, aminoalkyl, halogroup or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b ; 'm' is 0; and 'n' is 1.

[0042] In other embodiments, A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic; R1 is independently a halogroup or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituents are selected from amino, halogenated or hydroxyl groups; 'm' and 'n' are independently 0 and 1.

[0043] In some implementations, yes or .

[0044] In some implementations, Z is an aryl or a 5- or 6-membered heterocyclic group. In some embodiments, Z is an optionally substituted heterocyclic group selected from phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azacyclic butyl, oxacyclic butyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxyl, dioxothiomorpholinyl, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophene, dihydropyranyl, and azabicyclo[3.2.1]octyl; each of the foregoing groups is optionally substituted with an alkyl, alkoxy, haloyl, hydroxy, hydroxyalkyl, or -NR group. a R b Replace; and R a and R b It can be hydrogen, alkyl, or acyl on its own.

[0045] In some implementations, IRAK4 inhibitors are represented by formula (IA): Or a pharmaceutically acceptable salt thereof. In some embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogroup or optionally substituted heterocyclic group each time it appears, wherein said substituent is an alkyl, aminoalkyl, halogroup or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b 'm' is 0; and 'n' is 1. In other embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogroup or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituent is selected from amino, halogenated or hydroxyl groups; and 'm' and 'n' are independently 0, 1 or 2.

[0046] In some implementations, IRAK4 inhibitors are represented by formula (IB): Or a pharmaceutically acceptable salt thereof. In some embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogroup or optionally substituted heterocyclic group each time it appears, wherein said substituent is an alkyl, aminoalkyl, halogroup or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b And 'n' is 1. In other embodiments, A is O or S; Y is -CH2- or O; R1 is independently a halogroup or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl, or -NR. a R b ;where R a and R b R2 is independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituent is selected from amino, halogenated or hydroxyl groups; and 'm' and 'n' are independently 0, 1 or 2.

[0047] In some implementations, IRAK4 inhibitors are represented by formula (IC): Or its pharmaceutically acceptable salt.

[0048] In some embodiments, R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxy, hydroxyalkyl, or -NR. a R b And R a and R b It can be hydrogen or acyl independently. In other embodiments, R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, aminoalkyl, halogroup, or -NR. a R b And R a and R b It is independently hydrogen or acyl. In yet another embodiment, R1 is an optionally substituted heterocyclic group; and said substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl, or -NR. a R b ;where R a and Rb R1 is independently hydrogen, alkyl, or heterocyclic. In some embodiments, R1 is pyridinyl, pyrazolyl, pyrrolidinyl, or piperidinyl. In some embodiments, R1 is an optionally substituted pyrazolyl group, wherein the substituent is alkyl, hydroxyl, or -NR. a R b In other implementations, R1 is a halogenated group.

[0049] In some embodiments, R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogenated, or hydroxyl groups. In some embodiments, R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic, or -NR. a R b The substituent is selected from amino, halogroup, or hydroxyl. In some embodiments, R2 is an optionally substituted heterocyclic group selected from piperidinyl, pyrrolyl, morpholinyl, piperazine, aziridine, pyrazolyl, furanyl, or azirbicyclo[3.2.1]octyl; wherein the substituent is hydroxyl, halogroup, alkyl, or amino. In some embodiments, R2 is piperidinyl, pyrrolyl, morpholinyl, or piperazine. In other embodiments, R2 is hydrogen. In yet another embodiment, it is cycloalkyl. In some embodiments, R2 is cyclopropyl.

[0050] In some embodiments, R3 is an alkyl group.

[0051] In some implementations, m is 0 and p is 1. In other implementations, m is 0 or 2, and p is 0 or 1.

[0052] In some implementations, the IRAK4 inhibitor is selected from: 6'-Amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-Amino-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide hydrochloride; N-(5-Cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide hydrochloride; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6-Chloro-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide; 2-(2-chloropyridin-4-yl)-N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6'-Amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-Amino-N-(2-morpholinothiazo[4,5-c]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-Amino-N-(2-morpholinothiazo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6'-Amino-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide; N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; 3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)benzamide; 2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)benzamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2,5-Dimorpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-yl)oxazolo-4-carboxamide; 2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-hydroxypyridin-3-yl)oxazol-4-carboxamide; 2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-yl)oxazolo-4-carboxamide; 2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopyrrolidone-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-aminopyrrolidone-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)pyridineamide; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidine-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide hydrochloride; 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazol-4-carboxamide hydrochloride; N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methoxypyridin-4-yl)oxazol-4-carboxamide; 2-(6-methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; (S)-N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)pyridineamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopyrrolidone-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(5-Cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidone-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(azacyclobutan-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; N-(5-(3-hydroxyazacyclobutane-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(azacyclobutan-1-yl)-2-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidine-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidine-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)furan-2-carboxamide; N-(5-(azacycloheptane-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(5-(azacyclobutan-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride N-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-fluorophenyl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidone-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide; N-(5-(azacyclobutan-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidine-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide; N-(5-(azacyclobutan-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidone-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; 5-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)furan-3-carboxamide hydrochloride; 2-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; 2-(2-aminopyridin-4-yl)-N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; and N-(5-(2-hydroxypyridin-4-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; Or its pharmaceutically acceptable salts or stereoisomers.

[0053] In some preferred embodiments, the IRAK4 inhibitor is (Compound 1). In other preferred embodiments, the IRAK4 inhibitor is Pharmaceutically acceptable salts.

[0054] In some preferred embodiments, the IRAK4 inhibitor is In other preferred embodiments, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0055] In some preferred embodiments, the IRAK4 inhibitor is In other preferred embodiments, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0056] In some preferred embodiments, the IRAK4 inhibitor is [specifically, a specific component]. In other preferred embodiments, the IRAK4 inhibitor is [specifically, a specific component]. Pharmaceutically acceptable salts.

[0057] In some preferred embodiments, the IRAK4 inhibitor is [specifically, a specific component]. In other preferred embodiments, the IRAK4 inhibitor is [specifically, a specific component]. Pharmaceutically acceptable salts.

[0058] In some preferred embodiments, the IRAK4 inhibitor is In other preferred embodiments, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0059] In some preferred embodiments, the IRAK4 inhibitor is In other preferred embodiments, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0060] In some preferred embodiments, the IRAK4 inhibitor is In other preferred embodiments, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0061] In some preferred embodiments, the IRAK4 inhibitor is In other preferred embodiments, the IRAK4 inhibitor is... Pharmaceutically acceptable salts.

[0062] Generally, the compounds described herein can be administered in any amount or manner that elicits the desired response in a subject. For example, a 100 mg to 400 mg IRAK4 inhibitor selected from the compounds described herein can be administered to a subject twice daily, or a 200 mg to 1000 mg IRAK4 inhibitor can be administered to a subject once daily. In some embodiments, a 100 mg to 400 mg IRAK4 inhibitor is administered to a subject twice daily. In some embodiments, a 200 mg to 400 mg IRAK4 inhibitor is administered to a subject twice daily. In some preferred embodiments, a 250 mg to 350 mg IRAK4 inhibitor is administered to a subject twice daily. In some implementations, an IRAK4 inhibitor is administered to the subject twice daily in doses 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. In some implementations, an IRAK4 inhibitor is administered to the subject twice daily in doses 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. In some embodiments, a subject is given about 50 mg, about 100 mg, about 200 mg, or about 300 mg of an IRAK4 inhibitor twice daily. In some embodiments, a subject is given about 50 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 200 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 225 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 250 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 275 mg of an IRAK4 inhibitor twice daily. In a particularly preferred embodiment, a subject is given about 300 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 325 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 350 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 375 mg of an IRAK4 inhibitor twice daily. In other embodiments, a subject is given about 400 mg of an IRAK4 inhibitor twice daily.

[0063] In some embodiments, a subject is given 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 an IRAK4 inhibitor once daily. In some embodiments, a subject is given approximately 50 mg of an IRAK4 inhibitor once daily. In some embodiments, a subject is given approximately 75 mg of an IRAK4 inhibitor once daily. In some embodiments, a subject is given approximately 100 mg of an IRAK4 inhibitor once daily. In some embodiments, a subject is given approximately 125 mg of an IRAK4 inhibitor once daily. In some embodiments, a subject is given approximately 150 mg of an IRAK4 inhibitor once daily.

[0064] In some preferred embodiments, the IRAK4 inhibitor or degrader is administered orally to the subject. In some embodiments, about 50 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 200 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 250 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In a particularly preferred embodiment, about 300 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 325 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 350 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 375 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 400 mg of the IRAK4 inhibitor or degrader is administered orally to the subject twice daily. In other embodiments, about 50 mg of the IRAK4 inhibitor or degrader is administered orally to the subject once daily. In yet another embodiment, approximately 75 mg of an IRAK4 inhibitor or degrader is administered orally to the subject once daily. In yet another embodiment, approximately 100 mg of an IRAK4 inhibitor or degrader is administered orally to the subject once daily. In yet another embodiment, approximately 125 mg of an IRAK4 inhibitor or degrader is administered orally to the subject once daily. In yet another embodiment, approximately 150 mg of an IRAK4 inhibitor or degrader is administered orally to the subject once daily.

[0065] In other implementations, the IRAK4 inhibitor is PF-06650833 or BAY 1830839.

[0066] IRAK4 Degrading Agent In some embodiments, the method includes applying an IRAK4 degrading agent. In some embodiments, the IRAK4 degrading agent is KT-474.

[0067] combination therapy In some embodiments of the method disclosed herein, the method further includes co-administering a BCL-2 inhibitor to the subject. In some preferred embodiments, the BCL-2 inhibitor is venetoclax. In some embodiments, the method further includes administering 400 mg of venetoclax daily. In some embodiments, venetoclax is administered orally. In some preferred embodiments, the method further includes administering 400 mg of venetoclax orally daily.

[0068] In other embodiments, the method further includes co-administering a BTK inhibitor to the subject. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM7 1224. In some embodiments, the BTK inhibitor is acalabrutinib. In some embodiments, the method includes administering 200 mg of acalabrutinib daily. In some embodiments, acalabrutinib is administered orally. In some embodiments, the method includes administering 200 mg of acalabrutinib orally daily. In some preferred embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the method includes administering 420 mg of ibrutinib daily. In other embodiments, the method includes administering 420 mg of ibrutinib daily. In some embodiments, ibrutinib is administered orally. In some preferred embodiments, 420 mg of ibrutinib is administered orally daily. In other preferred embodiments, the method includes administering 560 mg of ibrutinib daily. In some embodiments, the BTK inhibitor is zanubrutinib. In some embodiments, the method includes administering 160 mg of zanubrutinib twice daily. In other embodiments, the method includes administering 320 mg of zanubrutinib once daily. In some embodiments, zanubrutinib is administered orally. In some embodiments, the method includes administering 160 mg of zanubrutinib orally twice daily. In other embodiments, the method includes administering 320 mg of zanubrutinib orally once daily. In some embodiments, the method further includes the combined administration of ABT-737, BAY-1143572, 5-fluorouracil, abiraterone acetate, acetylcholine, ado-trastuzumab emtansine, afatinib, aldesleukin, alectinib, alemtuzumab, alitretinoin, aminolevulinic acid, anastrozole, aprepitant, arsenic trioxide, and Erwinia asparaginase.Chrysanthemi, Atezolizumab, Axitinib, Azacitidine, Belinostat, Bendamustine, Benzyl isothiocyanate, Bevacizumab, Bexarotene, Bicalutamide, Bleomycin, Blinatumomab, Bortezomib, Bosutinib, Brentuximab Vedotin, Busulfan, Cabazitaxel, Cabozantinib, Capecitabine, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Cetuximab, Chloramic acid mustard, Cisplatin, Clofarabine, Cobimetinib Copanlisib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin D, daratumumab, dasatinib, daunorubicin, decitabine, and defibrotide are also mentioned. sodium, degarelix, denileukin diftitox, denosumab, dexamethasone, dexrazoxane, dihydrotestosterone (DHT), dinutuximab, docetaxel, doxorubicin, elotuzumab, eltrombopag, enzalutamide, epirubicin, eribulin mesylatemesylate, erlotinib, etoposide, everolimus, exemestane, filgrastim, fludarabine phosphate, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab, gemtuzumab ozogamicin, glucarpidase, goserelin acetate, hydroxyurea, ibritumomab Tiuxetan, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, imiquimod, interferon alpha-2b, ipilimumab, irinotecan, ixabepilone, ixazomib, lanreotide, lapatinib, lenalidomide, lenvatinib, letrozole, leucovorin, leuprolide, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, mesna, methotrexate, mitomycin CC) Mitoxantrone, Navitoclax, Necitumumab, Nilarabine, Netupitant, Nilotinib, Nilutamide, Nivolumab, Obinutuzumab, Ofatumumab, Olaparib, Omacetaxine Mepesuccinat e), osimertinib, oxaliplatin, ozogamicin, paclitaxel, palbociclib, palifermin, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pegylated interferon alpha-2b, pembrolizumab, pemetrexed ( Pemetrexed, pertuzumab, plerixafor, pomalidomide, ponatinib, pralatrexate, prednisone, procarbazine, propranolol, radium-223 dichloride, raloxifene, ramucirumab, rasburicase se), regorafenib, rituximab, rolapitant, romidepsin, romiplostim, ruxolitinib, siltuximab, sipuleucel-t, sonidegib, sorafenib, sunitinib, talimogenelaherparepvec, tamoxifen, temozolomide, temsirolimus, thalidomide, thioguanine, thiotepa, tipiracil, topotecan, toremifene, toremifene, tositumomab, trabectedin, trametinib, trastuzumab (t The second therapeutic agent is one or more of rastuzumab, tretinoin, trifluridine, uridine triacetate, vandetanib, vemurafenib, venetoc, vinblastine, vincristine, vinorelbine, vismodegib, 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.

[0069] Diseases and symptoms The methods disclosed herein relate to the treatment of cancer. In some implementations, the cancer is a blood malignancy, such as leukemia or lymphoma, for example, non-Hodgkin's lymphoma. In some implementations, the hematologic malignancy is 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), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt's 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 some embodiments, the hematologic malignancy is myeloid leukemia. In other embodiments, the hematologic malignancy is myeloid leukemia (e.g., acute myeloid leukemia). In some embodiments, the hematologic malignancy is acute myeloid leukemia (e.g., AML). In some embodiments, the AML is primary AML. In other embodiments, the AML is secondary AML. In still other embodiments, the hematologic malignancy is myelodysplastic syndrome. In some embodiments, the myelodysplastic syndrome is high-grade. In other embodiments, the myelodysplastic syndrome is low-grade. In some embodiments, the myelodysplastic syndrome is high-risk. In still other embodiments, the hematologic malignancy is lymphoblastic leukemia (e.g., acute lymphoblastic leukemia). In still other embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, the CLL is high-risk CLL. In still other embodiments, the hematologic malignancy is small lymphocytic lymphoma (SLL). In still other embodiments, the hematologic malignancy is follicular lymphoma. In yet another embodiment, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In yet another embodiment, the hematologic malignancy is activated B-cell-like (ABC) DLBCL. In yet another embodiment, the hematologic malignancy is germinal center B-cell-like (GCB) DLBCL. In some embodiments, the DLBCL is extranodal. In some embodiments, the DLBCL is extranodal leg lymphoma, extranodal testicular lymphoma, or extranodal nonspecific (NOS) lymphoma. In yet another embodiment, the hematologic malignancy is mantle cell lymphoma. In another embodiment, the hematologic malignancy is Waldenström macroglobulinemia. In yet another embodiment, the hematologic malignancy is multiple myeloma.In another embodiment, the hematologic malignancy is marginal zone lymphoma. In yet another embodiment, the hematologic malignancy is Burkitt's lymphoma. In yet another embodiment, the hematologic malignancy is non-Burkitt high-grade B-cell lymphoma. In another embodiment, the hematologic malignancy is extranodal marginal zone B-cell lymphoma. In yet another embodiment, the hematologic malignancy is transformed high-grade B-cell lymphoma (HGBL). In yet another embodiment, the hematologic malignancy is lymphoplasmacytic lymphoma (LPL). In yet another embodiment, the hematologic malignancy is CNS lymphoma. In yet another embodiment, the CNS lymphoma is primary CNS lymphoma (PCNSL). In yet another embodiment, the hematologic malignancy is MALT lymphoma. In some embodiments, the hematologic malignancy may be relapsed or refractory. In some embodiments, the hematologic malignancy is resistant to treatment with a BTK inhibitor. In some embodiments, the hematologic malignancy is resistant to treatment with a BTK inhibitor as monotherapy. In some embodiments, the hematologic malignancies are resistant to treatment with ibrutinib, acalatinib, zanubrutinib, evobrutinib, ONO-4059, sipebrutinib, or HM71224. In some preferred embodiments, the hematologic malignancies are resistant to treatment with ibrutinib.

[0070] In some embodiments, the cancer is selected from brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, gastric cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, epidermal cancer, prostate cancer, and head and neck cancer. In some preferred embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is colon cancer. In some embodiments, the cancer is a solid tumor. In various such embodiments, the cancer may be recurrent or refractory. In some embodiments, the above-mentioned cancers are resistant to treatment with BTK inhibitors. In some embodiments, the above-mentioned cancers are resistant to treatment with BTK inhibitors as monotherapy. In some embodiments, the cancers are resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, sipebrutinib, or HM7 1224. In some preferred embodiments, the cancers are resistant to treatment with ibrutinib.

[0071] In some implementations, the subjects are adults.

[0072] In some implementations, an IRAK4 inhibitor or degrader is administered orally once daily at a dose of approximately 50 mg; and the cancer is DLBCL. In some implementations, the DLBCL is relapsed or refractory.

[0073] In some implementations, an IRAK4 inhibitor or degrader is administered orally once daily at a dose of approximately 50 mg; and the cancer is FL. In some implementations, the FL is relapsed or refractory.

[0074] In some embodiments, an IRAK4 inhibitor or degrader is administered orally once daily at a dose of approximately 300 mg; and the cancer is WM. In some embodiments, the WM is relapsed or refractory.

[0075] In some implementations, an IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 50 mg; and the cancer is DLBCL. In some implementations, the DLBCL is relapsed or refractory.

[0076] In some implementations, an IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 300 mg; and the cancer is LPL. In some implementations, the LPL is relapsed or refractory.

[0077] In some implementations, an IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 300 mg; and the cancer is GCB DLBCL. In some implementations, GCB DLBCL is relapsed or refractory.

[0078] In some implementations, an IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 400 mg; and the cancer is ABC DLBCL. In some implementations, ABC DLBCL is relapsed or refractory.

[0079] In some embodiments, an IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 400 mg; and the cancer is MZL. In some embodiments, the MZL is relapsed or refractory.

[0080] In some embodiments, an IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 300 mg; and the cancer is MZL. In some embodiments, the MZL is relapsed or refractory.

[0081] In some implementations, an IRAK4 inhibitor or degrader is administered orally twice daily at a dose of approximately 300 mg; and the cancer is MALT. In some implementations, MALT is relapsed or refractory.

[0082] In some embodiments, the IRAK4 inhibitor or degrader is administered continuously (e.g., compound 1 is administered without a drug holiday). In other embodiments, the IRAK4 inhibitor or degrader is administered intermittently (e.g., continuous administration of compound 1 is interrupted by one or more drug holidays). In some embodiments, each drug holiday lasts for periods of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some preferred embodiments, the drug holiday lasts for 7 days. In a further preferred embodiment, the IRAK4 inhibitor or degrader is administered daily for three weeks, followed by a one-week drug holiday, optionally followed by three weeks of daily administration and a one-week drug holiday, and this cycle may be repeated further. In some embodiments, the aforementioned dosing regimen continues, with administration periods alternating with holidays, until a change in disease status is observed (e.g., until complete remission, partial remission, or unacceptable toxicity is observed). Methods of treating certain diseases and conditions with compound 1 are disclosed in PCT / US2021 / 030192 and PCT / US23 / 21812, the contents of which are incorporated herein by reference in their entirety.

[0083] Previous treatment The methods disclosed herein can be used as first-line therapy, or they can be applied to patients who have failed to achieve partial or complete remission using one or more prior anticancer or anti-inflammatory therapies. In some embodiments, the subject has previously received at least one anticancer therapy. In some embodiments, the patient has previously received one anticancer therapy. In other embodiments, the patient has previously received two anticancer therapies. In still other embodiments, the patient has previously received three anticancer therapies. In still other embodiments, the patient has previously received four anticancer therapies. In still other embodiments, the patient has previously received five anticancer therapies. In some embodiments, at least one anticancer therapy comprises an antiCD20 antibody, nitrogen mustard, a steroid, a purine analog, a DNA topoisomerase inhibitor, a DNA intercalating agent, a tubulin inhibitor, a BCL-2 inhibitor, a proteasome inhibitor, a Toll-like receptor inhibitor, a kinase inhibitor, an SRC kinase inhibitor, a PI3K kinase inhibitor, a BTK inhibitor, a glutaminase inhibitor, a steroid, or a methylating agent; or a combination thereof. In some embodiments, the anticancer therapy includes ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, oprozomib, ixazomib, acalatinib, zanubrutinib, IMO-08400, ederaglixide, umbrelasib, CB-839, fludarabine, or thalidomide; or combinations thereof. In some embodiments, the anticancer therapy includes ibrutinib. In some embodiments, the anticancer therapy includes ibrutinib and rituximab. In some embodiments, the anticancer therapy includes bendamustine. In some embodiments, the anticancer therapy includes bendamustine and rituximab. In some embodiments, the anticancer therapy includes bortezomib. In some embodiments, the anticancer therapy includes bortezomib and dexamethasone. In some embodiments, the anticancer therapy includes bortezomib and rituximab. In some embodiments, the anticancer therapy includes bortezomib, rituximab, and dexamethasone. In some embodiments, chlorambucil. In some embodiments, the anticancer therapy includes cladribine. In some embodiments, the anticancer therapy includes cladribine and rituximab. In some embodiments, the anticancer therapy includes cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R). In some embodiments, the anticancer therapy includes cyclophosphamide, prednisone, and rituximab (i.e., CPR). In some embodiments, the anticancer therapy includes fludarabine. In some embodiments, the anticancer therapy includes fludarabine and rituximab. In some embodiments, the anticancer therapy includes fludarabine, cyclophosphamide, and rituximab. In some preferred embodiments, the anticancer therapy includes rituximab.In some preferred embodiments, the anticancer therapy includes rituximab. In some embodiments, the anticancer therapy includes rituximab, cyclophosphamide, and dexamethasone (i.e., RCD). In some embodiments, the anticancer therapy includes thalidomide. In some embodiments, the anticancer therapy includes thalidomide and rituximab. In some embodiments, the anticancer therapy includes venetoclax. In some embodiments, the anticancer therapy includes cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD). In some embodiments, the anticancer therapy includes a hypomethylating agent. In some embodiments, the subject has previously received at least 6 cycles of a hypomethylating agent. In some embodiments, the anticancer therapy includes a combination of any of the foregoing, 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).

[0084] Subjects may have already received or be prepared to receive other non-chemotherapy treatments, such as surgery, radiation, or bone marrow transplantation. In some implementations, subjects have previously received etoposide chemomobilization therapy. In some implementations, subjects have previously received a bone marrow transplant. In some implementations, subjects have previously received a stem cell transplant. In some implementations, subjects have previously received an autologous cell transplant. In some implementations, subjects have previously received an allogeneic stem cell transplant. In some implementations, subjects have previously received a hematopoietic cell transplant. In some implementations, subjects have previously received carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM conditioning). In some implementations, subjects have previously received re-induction therapy.

[0085] The subject may have previously shown good results with prior therapy and only require further treatment later. In some implementations, the subject has previously achieved partial remission. In some implementations, the subject has previously achieved a good partial remission. In some implementations, the subject has previously achieved a complete remission. In some implementations, the cancer is recurrent. In some implementations, the cancer is refractory.

[0086] Subjects may also have one or more pre-existing or developed gene mutations that make their cancer more or less resistant to the therapy. In some embodiments, the subject has a mutation in RICTOR. In some embodiments, the subject has an N1065S mutation in RICTOR. In some preferred embodiments, the subject has a mutation in MYD88. In some even more preferred embodiments, the subject has an L265P mutation in MYD88. In some embodiments, the subject has a mutation in TET2. In some embodiments, the subject does not have a mutation in CXCR4. In other embodiments, the subject has a mutation in CXCR4. In some preferred embodiments, the subject has a mutation in SF3B1 (e.g., insertion, deletion, loss, or splice mutation). In some preferred embodiments, the subject has a mutation in U2AF1 (e.g., insertion, deletion, loss, or splice mutation). In some preferred embodiments, the subject has a mutation in FLT3. In some embodiments, the FLT3 kinase mutation is selected from one or more of the following: internal tandem repeat (ITD), mutation in D835, mutation in F691, mutation in K663, and / or mutation in N841. In some embodiments, the 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 both ITD and D835V mutations. In some embodiments, the FLT3 kinase mutation includes both ITD and F691L mutations. In some embodiments, the FLT3 kinase mutation includes both ITD and D835Y mutations. In some embodiments, the subject has a mutation in STAG2. In some embodiments, the subject has a mutation in DNMT3A. In some embodiments, the subject has a mutation in BCOR. In some implementations, the subject has a mutation in WT1. In some implementations, the subject has a mutation in NRAS. In some implementations, the subject shows early progression. In some implementations, the subject has not previously received a BTK inhibitor.

[0087] In some embodiments, the subject achieves partial remission after administration of the compound. In some embodiments, the subject achieves good partial remission after administration of the compound. In other embodiments, the subject achieves complete remission after administration of the compound. In some embodiments, the subject achieves partial remission within 7 days of receiving the compound. In some embodiments, the subject achieves good partial remission within 7 days of receiving the compound. In some embodiments, the subject achieves complete remission within 7 days of receiving the compound. In some embodiments, the subject's tumor volume decreases by approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95%. In some embodiments, the subject's tumor volume decreases by 5%. In some embodiments, the subject's tumor volume decreases by 10%. In some embodiments, the subject's tumor volume decreases by 15%. In some embodiments, the subject's tumor volume decreases by 20%. In some embodiments, the subject's tumor volume decreases by 25%. In some embodiments, the subject's tumor volume decreases by 30%. In some embodiments, the subject's tumor volume decreased by 35%. In some embodiments, the subject's tumor volume decreased by 40%. In some embodiments, the subject's tumor volume decreased by 45%. In some embodiments, the subject's tumor volume decreased by 50%. In some embodiments, the subject's tumor volume decreased by 55%. In some embodiments, the subject's tumor volume decreased by 60%. In some embodiments, the subject's tumor volume decreased by 65%. In some embodiments, the subject's tumor volume decreased by 70%. In some embodiments, the subject's tumor volume decreased by 80%. In some embodiments, the subject's tumor volume decreased by 85%. In some embodiments, the subject's tumor volume decreased by 90%. In some embodiments, the subject's tumor volume decreased by 95%.

[0088] Pharmaceutical Composition The compositions and methods of the present invention can be used to treat individuals in need. In some embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal (such as a human), the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiologically buffered saline, or other solvents or mediators, such as glycols, glycerol, oils (such as olive oil), or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are used for human administration, particularly for invasive routes of administration (i.e., routes that avoid transport or diffusion across the epithelial barrier, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. For example, excipients may be selected to achieve delayed release of the agent or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of dosage units, such as tablets, capsules (including dispersible capsules and gelatin capsules), granules, lyophilized formulations for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in transdermal delivery systems, such as skin patches. The composition may also be present in solutions suitable for topical application, such as lotions, creams, or ointments.

[0089] Pharmaceutically acceptable carriers may contain physiologically acceptable agents that function, for example, to stabilize compounds (such as those of the present invention), increase their solubility, or enhance their absorption. Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose, or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable carriers (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix in which compounds of the present invention may be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and their preparation and administration are relatively simple.

[0090] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0091] The phrase “pharmaceutically acceptable carrier” as used herein refers to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be “acceptable”, meaning it is compatible with other components of the formulation and harmless to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; and (9) oils, such as peanut oil and cottonseed oil. (10) Safflower oil, sesame oil, olive oil, corn oil and soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Atherless water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic compatible substances used in pharmaceutical preparations.

[0092] Pharmaceutical compositions (formulations) can be administered to a subject via any of a variety of routes of administration, including, for example, oral (e.g., extracts in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including dispersible capsules and gelatin capsules), granules, powders, pellets, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingual); subcutaneous; transdermal (e.g., as patches for application to the skin); and topical (e.g., as creams, ointments, or sprays for application to the skin). Compounds can also be formulated for inhalation. In some embodiments, the compound can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for such routes 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 referenced therein.

[0093] The formulation can be conveniently present in a single dosage form and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Generally, this amount, in terms of 100%, will be in the range of about 1% to about 99%, preferably about 5% to about 70%, and most preferably about 10% to about 30% of the active ingredient.

[0094] Methods for preparing these formulations or compositions include the step of 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 tightly combining the compound of the present invention with a liquid carrier or a finely chopped solid carrier, or both, and then, if necessary, shaping the product.

[0095] Formulations of the present invention suitable for oral administration may be in the form of capsules (including dispersible capsules and gelatin capsules), sachets, pills, tablets, lozenges (using a flavoring matrix, typically sucrose and gum arabic or tragacanth), lyophilized forms, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as lozenges (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic) and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The compositions or compounds may also be administered as large pills, syrups, or pastes.

[0096] To prepare solid dosage forms (capsules (including dispersible capsules and gelatin capsules), tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, Examples of excipients include: (4) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) solution blockers such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) colorants. In the case of capsules (including dispersible capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules, using such excipients as lactose and high molecular weight polyethylene glycol.

[0097] Tablets can be prepared by compression or molding, optionally together with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium carboxymethyl starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0098] Other solid dosage forms of tablets and pharmaceutical compositions, such as sugar-coated pills, capsules (including dispersible capsules and gelatin capsules), pellets, and granules, may optionally be coated and shelled, such as enteric coating and other coating notches or preparations well known in the field of pharmaceutical formulation. They may also be formulated using, for example, varying proportions of hydroxypropyl methylcellulose (to provide the desired release profile), other polymer matrices, liposomes, and / or microspheres to provide a slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacterial trap filter, or by incorporation with a sterilizing agent in the form of a sterile solid composition that can be immediately dissolved in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain a light-blocking agent and may be compositions that release the active ingredient, optionally in a delayed manner, only or preferably in a portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. If suitable, the active ingredient may also be in the form of microcapsules having one or more of the excipients described above.

[0099] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents; cyclodextrins and their derivatives; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitol; and mixtures thereof.

[0100] In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0101] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

[0102] Dosage forms for topical or transdermal application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. Active compounds can be mixed under sterile conditions with pharmaceutically acceptable carriers and any necessary preservatives, buffers, or propellants.

[0103] In addition to active compounds, ointments, pastes, creams, and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0104] In addition to the active compound, powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Aerosols may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0105] Transdermal patches offer the added advantage of 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 flux of the compound across the skin. The rate of this flux can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0106] As used herein, the phrases “parenteral administration” and “for parenteral” refer to administration methods other than enteral and local administration, typically by injection, and including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds combined 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 injectable solutions or dispersions prior to use. These dosage forms may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0107] Examples of suitable aqueous and non-aqueous carriers for use in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). For example, by using coating materials (such as lecithin), the desired particle size can be maintained in the case of dispersions, and by using surfactants, appropriate flowability can be maintained.

[0108] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. By including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenolic sorbic acid, protection against microbial activity can be ensured. It may also be necessary to include isotonic agents, such as sugars and sodium chloride, in the composition. Furthermore, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0109] In some cases, to prolong the action of a drug, it is necessary to slow the absorption of subcutaneously or intramuscularly injected drugs. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oily medium.

[0110] Injectable reservoir formulations are prepared by forming a microencapsulated matrix of the target compound within a biodegradable polymer, such as poly(lactide-polyglycolic acid). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable reservoir formulations are also prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0111] For use in the methods of the present invention, the active compound may be administered either on its own 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.

[0112] Introduction methods can also be provided via rechargeable or biodegradable devices. In recent years, various sustained-release polymer devices for controlled delivery of drugs, including protein biopharmaceuticals, have been developed and tested in vivo. A variety of biocompatible polymers, including hydrogels, both biodegradable and non-degradable, can be used to form implants for the sustained release of compounds at specific target sites.

[0113] The actual dosage level of the active ingredient in a pharmaceutical composition can be altered to obtain an amount of active ingredient that is non-toxic to the patient and effectively achieves the desired therapeutic response for a specific patient, composition, and method of administration.

[0114] The chosen dose level will depend on a variety of factors, including the activity of the specific compound or combination of compounds or its esters, salts or amides used, the route of administration, the time of administration, the excretion rate of the specific compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound used, the age, sex, weight, condition, general health and medical history of the patient being treated, and similar factors well known in the medical field.

[0115] A physician or veterinarian with ordinary skill in the art can readily determine and prescribe a therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may begin with a dose of the pharmaceutical composition or compound at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. A “therapeutically effective amount” refers to the concentration of the compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary depending on the subject’s weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient’s condition, the condition being treated, the stability of the compound, and, if necessary, another type of therapeutic agent administered with the compound of the present invention. A larger total dose can be delivered by administering the agent multiple times. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al., (1996) Harrison's Principles of Internal Medicine, 13th edition, 1814-1882, which is incorporated herein by reference).

[0116] Generally speaking, the appropriate daily dose of the active compound used in the compositions and methods of the present invention will be the amount of the compound at which the lowest effective therapeutic effect is achieved. This effective dose will typically depend on the factors described above.

[0117] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six, or more sub-dose, which are administered at appropriate intervals throughout the day, optionally in unit dosage form. In some embodiments of the invention, the active compound may be administered two or three times daily. In a preferred embodiment, the active compound is administered once daily.

[0118] Patients receiving this treatment are any animals in need, including primates, especially humans; as well as other mammals such as horses, cattle, pigs, sheep, cats and dogs; poultry; and pets in general.

[0119] In some embodiments, the compounds of the present invention may be used alone or in combination with another type of therapeutic agent.

[0120] This disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In some embodiments, the intended salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In some embodiments, the intended salts of the present invention include, but are not limited to, L-arginine, benzylamine, benzathine, betaine, calcium hydroxide, choline, tannin, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, hydrabamine, 1H-imidazolium, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, aminobutanetriol, and zinc salts. In some embodiments, the intended salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In some embodiments, the intended salts of the present invention include, but are not limited to, 1-hydroxynaphthylcarboxylic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-ketoglutaric acid, 4-acetaminobenzoic 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, caproic acid, and caprylic acid. Acids, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosidic acid, gentian acid, d-glucoheponic acid, d-glucuronic acid, glutamic acid, glutamate, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 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, dihydroxynaphthalic acid, phosphoric acid, propionic acid, 1-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1-tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, and undecanoic acid salt.

[0121] Pharmaceutically acceptable acid addition salts can also exist in various solvate forms, such as solvates with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates can also be prepared. The source of this solvate can be the solvent of crystallization, inherent in the solvent of preparation or crystallization, or foreign to such solvent.

[0122] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition.

[0123] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as palmitic acid ascorbate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0124] definition Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. Generally speaking, the nomenclature and techniques described herein in conjunction with chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry are those well-known and commonly used in the art.

[0125] Unless otherwise stated, the methods and techniques disclosed herein are generally performed according to conventional methods known in the art and described in the various general and more specific references cited and discussed throughout the specification. See, for example, “Principles of Neural Science”, McGraw-Hill Medical, New York, NY (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th Edition”, WH Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th Edition”, WH Freeman & Co., NY (1999); and Gilbert et al., “Developmental Biology, 6th Edition”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0126] Unless otherwise defined herein, chemical terms used herein are used in accordance with the usual usage in the art, as exemplified in "The McGraw-Hill Dictionary of Chemical Terms", edited by Parker S., McGraw-Hill, San Francisco, CA (1985).

[0127] All references to the foregoing, as well as any other publications, patents, and published patent applications, are specifically incorporated herein by reference. In case of conflict, this specification (including its specific definitions) shall prevail.

[0128] The term "pharmaceutical" is used herein to refer to compounds (such as organic or inorganic compounds, mixtures of compounds), biological macromolecules (such as nucleic acids, antibodies, including portions thereof, as well as humanized, chimeric, and human antibodies and monoclonal antibodies, proteins or portions thereof, such as peptides, lipids, carbohydrates), or extracts made from biological materials (such as bacterial, plant, fungal, or animal (particularly mammalian) cells or tissues). Pharmaceuticals include, for example, pharmaceuticals with known structures and pharmaceuticals with unknown structures. The ability of such pharmaceuticals to inhibit AR or promote AR degradation makes them suitable as "therapeutic agents" in the methods and compositions of this disclosure.

[0129] The terms “patient,” “subject,” or “individual” are used interchangeably and refer to humans or non-human animals. These terms include mammals such as humans, primates, livestock (including cattle, pigs, etc.), companion animals (e.g., canines, felines, etc.), and rodents (e.g., mice and rats).

[0130] "Treatment" of a condition or patient refers to steps taken to achieve a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, the reduction or improvement of one or more symptoms or conditions, a reduction in the severity of the disease, stabilization of the disease state (i.e., no worsening), prevention of the spread of the disease, a delay or slowing of disease progression, an improvement or reduction of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also refer to prolonged survival compared to expected survival without treatment.

[0131] The term "prevention" is recognized in the art and is well-known in the art when used in connection with a symptom (such as local recurrence (e.g., pain)), a disease (such as cancer), a syndrome (such as heart failure), or any other medical condition, and includes administering a composition that, relative to a subject not receiving the composition, reduces the frequency of symptoms of the medical condition or delays its onset in the subject. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a patient population receiving prophylactic treatment relative to an untreated control group, and / or delaying the appearance of detectable cancerous growths in a treated group, for example, reaching a statistically and / or clinically significant amount, compared to an untreated control group.

[0132] A substance, compound, or agent may be administered to a subject using one of a variety of methods known to those skilled in the art. For example, the compound or agent may be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., via a skin catheter). The compound or agent may also be suitably introduced via a rechargeable or biodegradable polymer device or other device (e.g., a patch and a pump) or formulation that provides a prolonged, slow, or controlled release of the compound or agent. Administration may also be performed, for example, once, multiple times, and / or over one or more prolonged periods.

[0133] The appropriate method of administering a substance, compound, or agent to a subject will also depend on factors such as the subject's age and / or physical condition, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered to the subject orally (e.g., by ingestion). In some embodiments, the orally administered compound or agent is an extended-release or slow-release formulation, or is administered using a device for such slow or extended release.

[0134] As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent remains effective in the body (e.g., both agents are effective simultaneously in the patient, which may include the 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 the different therapeutic agents.

[0135] The "therapeutic effective amount" or "therapeutic dose" of a drug or agent is the amount of drug or agent that will have the expected therapeutic effect when administered to a subject. A complete therapeutic effect does not necessarily occur with the administration of a single dose and may only occur after a series of doses. Therefore, a therapeutic effective amount can be administered once or multiple times. The precise effective amount required by the subject will depend on factors such as the subject's body type, health, and age, as well as the nature and extent of the condition being treated (such as cancer or MDS). Technicians can readily determine the effective amount for a given situation through routine experiments.

[0136] As used herein, the terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both cases where the event or situation occurs and cases where it does not occur. For example, “optionally substituted alkyl” means that the alkyl group may be substituted as well as cases where the alkyl group is not substituted.

[0137] It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to obtain chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods described below. If the substituent itself is substituted by more than one group, it should be understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure is obtained.

[0138] As used herein, the term "optionally substituted" means that one to six hydrogen groups in a given structure are substituted by a specified substituent, which includes, but is not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2. Preferably, "optionally substituted" means that one to four hydrogen groups in a given structure are substituted by the aforementioned substituents. More preferably, one to three hydrogen groups are substituted by the substituents described above. It should be understood that the substituents may be further substituted.

[0139] As used herein, the term "alkyl" refers to a saturated aliphatic group, including but not limited to C1-C1 groups. 10 Straight-chain alkyl groups or C1-C 10Branched alkyl group. Preferably, the "alkyl" group refers to a C1-C6 straight-chain alkyl group or a C1-C6 branched alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight-chain alkyl group or a C1-C4 branched alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 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.

[0140] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbon C(O)-, preferably alkyl C(O)-.

[0141] The term "acylamino" is recognized in the art and refers to an amino group substituted with an acyl group, and can be represented, for example, by the formula alkyl group C(O)NH-.

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

[0143] The term "alkoxy" refers to an alkyl group with an oxygen atom attached to it. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc.

[0144] The term "alkoxyalkyl" refers to an alkyl group that has been substituted with an alkoxy group, and can be represented by the general formula alkyl-O-alkyl.

[0145] The term "alkyl" refers to a saturated aliphatic group, including straight-chain alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In a preferred embodiment, the straight-chain or branched alkyl group has 30 or fewer alkyl groups in its main chain (e.g., for a straight chain of C12-24 ... 1-30 For a branch of C 3-30 (and more preferably 20 or fewer carbon atoms).

[0146] Furthermore, the term "alkyl" as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter referring to alkyl moieties having substituents that replace hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0147] Term "C" x - y "or "C x -C y"When used in conjunction with chemical motifs such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it is intended to include groups containing x to y carbons in the chain. C0 alkyl indicates that the hydrogen at the terminal position of the group is a bond if it is internal." 1-6 Alkyl groups, for example, contain one to six carbon atoms in the chain.

[0148] As used herein, the term "alkylamino" refers to an amino group that is substituted by at least one alkyl group.

[0149] 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-.

[0150] As used herein, the term "amide" refers to a group. Where R 9 and R 10 Each independently represents a hydrogen or hydrocarbon group, or R 9 and R 10 Together with the N atoms to which they are attached, they form heterocycles with 4 to 8 atoms in the ring structure.

[0151] The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines and their salts, for example, portions that can be represented by the following formula: or , Where R 9 R 10 and R 10 Each can independently represent a hydrogen or hydrocarbon group, or R 9 and R 10 Together with the N atoms to which they are attached, they form heterocycles with 4 to 8 atoms in the ring structure.

[0152] As used herein, the term "aminoalkyl" refers to an alkyl group that has been substituted with an amino group.

[0153] As used herein, the term "aralkyl" refers to an alkyl group that has been substituted with an aryl group.

[0154] As used herein, the term "aryl" includes a substituted or unsubstituted monocyclic aromatic group, wherein each atom of the ring is a carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is aromatic, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0155] The term "carbamate" is recognized in the art and refers to a group... or , Where R 9 and R 10 Independently represents a hydrogen or hydrocarbon group.

[0156] As used herein, the term "carbocyclic alkyl" refers to an alkyl group that has been substituted with a carbocyclic group.

[0157] The term "carbocyclic ring" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocyclic ring can be selected from saturated rings, unsaturated rings, and aromatic rings. A carbocyclic ring includes a bicyclic molecule in which one, two, or three or more atoms are shared between two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocyclic ring can be selected from saturated rings, unsaturated rings, and aromatic rings. In an exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused 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, where valence allows. Exemplary "carbocyclic rings" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decahydronaphthalene, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. The “carbocyclic ring” can be substituted at any one or more positions that can carry hydrogen atoms.

[0158] As used herein, the term "carbocyclic alkyl" refers to an alkyl group that has been substituted with a carbocyclic group.

[0159] The term "carbonate" is recognized in the art and refers to the group -OCO2-.

[0160] As used herein, the term "carboxyl" refers to a group represented by the formula -CO2H.

[0161] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term "cycloalkyl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is a cycloalkyl group and the substituents (e.g., R...) are... 100The ring is attached to a cycloalkyl ring; for example, other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, etc.

[0162] As used herein, the term "ester" refers to the group -C(O)OR 9 , where R 9 It represents a hydrocarbon group.

[0163] As used herein, the term "ether" refers to a hydrocarbon group connected to another hydrocarbon group via oxygen. Therefore, the ether substituent of the hydrocarbon group can be hydrocarbon-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocyclic-O-heterocycles and aryl-O-heterocycles. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0164] As used herein, the terms “halogenated group” and “halogen” refer to halogens and include chlorine, fluorine, bromine and iodine.

[0165] As used herein, the term "hetaralkyl" refers to an alkyl group that has been substituted with a heteroaralkyl group.

[0166] The term "heteroaryl" includes substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is heteroaromatic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0167] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0168] As used herein, the term "heterocyclic alkyl" refers to an alkyl group that has been substituted with a heterocyclic group.

[0169] The terms "heterocyclic group," "heterocyclic," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclic group" and "heterocyclic" also include polycyclic ring systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is heterocyclic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc.

[0170] As used herein, the term "hydrocarbon group" refers to a group bonded by carbon atoms without =O or =S substituents and typically has at least one carbon-hydrogen bond and a predominant carbon backbone, but may optionally include heteroatoms. Therefore, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbon groups, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked by oxygen rather than carbon) are not hydrocarbon groups. Hydrocarbon groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, ynyl, and combinations thereof.

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

[0172] The term "lower" when used in conjunction with a chemical moiety (such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy) is intended to include groups in which the substituents have ten or fewer atoms, preferably six or fewer atoms. "Lower alkyl" refers, for example, to an alkyl group containing ten or fewer carbon atoms, preferably six or fewer carbon atoms. In some embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the expressions hydroxyalkyl and aralkyl (in which case, for example, when calculating the carbon atoms in the alkyl substituents, the atoms in the aryl group are not counted).

[0173] The terms "polycyclic," "polycyclic," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic) in which two or more atoms are shared by two adjacent rings; for example, the rings are "fused rings." Each ring in a polycyclic ring may be substituted or unsubstituted. In some embodiments, each ring of a polycyclic ring contains 3 to 10, preferably 5 to 7, atoms.

[0174] The term "sulfate" is recognized in the art and refers to the group -OSO3H or its pharmaceutically acceptable salt.

[0175] The term "sulfonamide" is recognized in the art and refers to a substance derived from the general formula... or The group represented, Where R 9 and R 10 Independently represents either hydrogen or hydrocarbon groups.

[0176] The term "sulfoxide" is recognized in the art and refers to the group -S(O)-.

[0177] The term "sulfonate" is recognized in the art and refers to the group SO3H or its pharmaceutically acceptable salt.

[0178] The term "sulfone" is recognized in the art and refers to the group -S(O)2-.

[0179] The term "substituted" refers to a portion having a substituent having hydrogen on one or more carbons of the main chain. It should be understood that "substituted" or "replaced by" includes the implicit condition that such substitution is consistent with the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For a suitable organic compound, permissible substituents may be one or more, and may be the same or different. For the purposes of this invention, heteroatoms (such as nitrogen) may have hydrogen substituents and / or any permissible substituent of the organic compound described herein that satisfies the valence of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (such as thioesters, thioacetates, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, hypophosphonates, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfinylamino groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that, where appropriate, the substituted portion of the hydrocarbon chain may itself be substituted.

[0180] As used herein, the term "thioalkyl" refers to an alkyl group that has been replaced by a thiol group.

[0181] As used herein, the term "thioester" refers to the group -C(O)SR. 9or -SC(O)R 9 , where R 9 It indicates a hydrocarbon group.

[0182] As used in this article, the term "thioether" is equivalent to ether, in which oxygen is replaced by sulfur.

[0183] The term "urea" is recognized in the art and can be represented by the following general formula: Where R 9 and R 10 Independently represents either hydrogen or hydrocarbon groups.

[0184] As used herein, the term “regulation” includes both inhibiting or suppressing functions or activities (such as cell proliferation) and enhancing functions or activities.

[0185] The phrase “pharmaceutically acceptable” is recognized in the art. In some embodiments, the term includes, to a reasonable extent of medical judgment, compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that, upon contact with human and animal tissues, do not cause excessive toxicity, irritation, allergic reactions or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0186] "Pharmaceutically acceptable salt" or "salt" as used in this article refers to an acid addition salt or base addition salt that is suitable for or compatible with the treatment of the patient.

[0187] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any basic compound represented by Formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Monoacid salts or diacid salts can be formed, and such salts can exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts of compounds of Formula I are more soluble in water and a variety of hydrophilic organic solvents and typically exhibit higher melting points compared to their free basic forms. The selection of suitable salts will be known to those skilled in the art. Other non-pharmaceutical acceptable salts, such as oxalates, can be used, for example, for the isolation of compounds of formula I for laboratory use, or for subsequent conversion into pharmaceutically acceptable acid addition salts.

[0188] As used herein, the term "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acid compound or any intermediate thereof represented by Formula I. Exemplary inorganic bases forming suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases forming suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and methylpyridine or ammonia. The selection of suitable salts is known to those skilled in the art.

[0189] Many compounds that can be used in the methods and compositions of this disclosure have at least one stereocenter in their structure. This stereocenter may be present in an R or S configuration, and the use of the R and S symbols is consistent with the rules described in Pure Appl. Chem. (1976), 45, 11-30. This disclosure covers all stereoisomers of compounds, salts, prodrugs, or mixtures thereof, such as enantiomers and diastereomers (including all possible mixtures of stereoisomers). See, for example, WO 01 / 062726.

[0190] Furthermore, certain compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each case, this disclosure includes mixtures and individual isomers.

[0191] Some compounds may also exist in tautomeric forms. Although not explicitly indicated in the formulas described herein, such forms are intended to be included within the scope of this disclosure.

[0192] A “prodrug” or “pharmaceutically acceptable prodrug” is a compound that, upon administration, is metabolized (e.g., hydrolyzed or oxidized) in a host to form a compound of this disclosure (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds having a biologically unstable or cleavable (protective) group on the functional moiety of an active compound. Prodrugs include compounds that can be oxidized, reduced, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation, or dephosphorylation to produce an active compound. Examples of prodrugs using esters or aminophosphates as biologically unstable or cleavable (protective) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce compounds of formula I. This disclosure includes prodrugs of the compounds described herein within its scope. Conventional methods for selecting and preparing suitable prodrugs are described, for example, in “Design of Prodrugs”, edited by H. Bundgaard, Elsevier, 1985.

[0193] As used herein, the phrase “pharmaceutically acceptable carrier” refers to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid filters, diluents, excipients, solvents, or encapsulating materials that can be used to formulate medicines for medical or therapeutic purposes.

[0194] 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 typically accompanied by poor absorption. The LogS value is the unit stripped logarithm (base 10) of solubility measured in moles per liter.

[0195] As used herein, the phrase “expression level” refers to the level and / or prevalence of an expressed 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., incidence) and / or level of the protein in one or more cells (preferably multiple cells) of the tissue or throughout the tissue sample.

[0196] As used in this article, the term "AZA" stands for azacitidine.

[0197] As used in this article, the term “VEN” stands for Venetok.

[0198] As used in this article, the term "BID" means twice-daily administration of the drug.

[0199] As used in this article, the term "QD" refers to daily administration of medication.

[0200] As used in this article, the term "CR" refers to complete remission.

[0201] As used in this article, the term "CRi" refers to CR with incomplete hematologic recovery.

[0202] As used in this article, the term "CRh" refers to a CR with partial hematologic recovery.

[0203] As used in this article, the term "mCR" refers to complete myelopathic remission.

[0204] As used in this article, the term "OS" refers to overall survival.

[0205] As used in this article, the term "PR" refers to partial relief.

[0206] As used in this article, the term "MTD" refers to the maximum tolerated dose.

[0207] As used in this article, the term "RP2D" refers to the recommended phase 2 dose.

[0208] As used in this article, the term “ANC” refers to the absolute neutrophil count.

[0209] The term "WBC" refers to the white blood cell count.

[0210] Example The invention will now be described in general terms, and will be more readily understood by referring to the following embodiments, which are for illustrative purposes only and are not intended to limit the invention.

[0211] Exemplary methods and compounds relating to the content of this disclosure can be found, for example, in U.S. Patents 10 / 160,753, 09 / 732,095, 10 / 758,518, and 11 / 419,875; U.S. Application 17 / 680,995; and pending PCT patent applications US21 / 59668, US2021 / 030192, WO22 / 031330, and US23 / 21812, the contents of which are incorporated herein by reference in their entirety.

[0212] Example 1: Examples of compound 1 in subjects with AML or MPS, with or without prior BCL-2 therapy. Sexual performance Exemplary early clinical results of the trial were reported on Figure 1A and Figure 1B middle.

[0213] Goals and End Points Phase 1 (monotherapy) / Phase 1b (combination therapy) primary objectives • Phase 1: Based on safety and tolerability, dose-limiting toxicities, and pharmacokinetic and pharmacodynamic results, determine the MTD and RP2D of compound 1 in patients with AML or intermediate-, high-, or very high-risk MDS (hrMDS). • Phase 1b: Based on safety and tolerability, dose-dependent toxicity, and pharmacokinetic and pharmacodynamic results, determine the MTD and RP2D of compound 1 in combination with AZA in treatment-naïve patients with AML or hrMDS, or in combination with VEN in relapsed / refractory patients, following first-line treatment. Phase 1 (monotherapy) / Phase 1b (combination therapy) primary endpoint • MTD (defined as the highest dose with a dose-limiting toxicity rate of < 33% in the first treatment cycle of at least 6 patients [time range: 28 days]) •RP2D (Determined in consultation between the sponsor and the CSC, taking into account all aspects of safety, tolerability, bioactivity, pharmacokinetics, and preliminary efficacy in the trial population [time range: 24 months]) • Safety as measured by adverse events, ECG, chemical and hematological laboratory values, vital signs, and physical examination. Secondary goals for Phase 1 (monotherapy) / Phase 1b (combination therapy) • Use non-compartmental analysis and appropriate pharmacokinetic models to characterize the pharmacokinetic parameters of compound 1. • Assess anticancer activity Secondary endpoints for Phase 1 (monotherapy) / Phase 1b (combination therapy) • Via C max C min T max AUC 0-24 AUC 0-inf and T 1 / 2 Pharmacokinetic parameters of compound 1 were measured (time range 24 months). • Clinical response in AML or hrMDS assessed as follows: ○AML: ■ The proportion of patients achieving CR + CRh ■ The proportion of patients who achieve CRi, CR, or CRH ○hrMDS: Overall remission rate of CR + PR + mCR ○ Transfusion independence Phase 1 (monotherapy) / Phase 1b (combination therapy) Exploratory goals • Assess the potential association between target-related biomarkers, selected gene mutations, gene expression profiles, cell of origin or other molecular taxonomic subtypes, and antileukemic activity. • Evaluate the pharmacodynamic effects of compound 1 on selected biomarkers in peripheral blood and bone marrow. • Further evaluate the anticancer activity of RP2D Phase 1 (monotherapy) / Phase 1b (combination therapy) exploratory endpoint • It can perform RNA expression profiling, DNA / RNA sequencing, protein profiling, IRAK4 / NF-κB pathway status, differentiation markers / apoptosis, etc. on peripheral blood and / or tumor samples to analyze changes induced by the investigational treatment and identify potential predictive biomarkers.

[0214] • Clinical response in AML or hrMDS assessed as follows: ○ Duration of Relief (DOR) ○Relief time ○Total OS 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 treatment, in combination with AZA in treatment-naïve adult patients with AML or hrMDS, or in combination with VEN in patients with relapsed / refractory AML or hrMDS.

[0215] The Phase 1 dose escalation (monotherapy) portion was performed in patients with AML and hrMDS.

[0216] The Phase 1b portion of the study (combination therapy) involves patients with AML or hrMDS receiving compound 1 in combination with azacitidine (AZA) or venetoclax (VEN). Patients currently receiving combination therapy who have benefited from treatment should continue the study at a dose of 300 mg BID or lower as per the protocol.

[0217] This study utilized the Clinical Safety Committee (CSC), whose task was to review all available safety information. The CSC was responsible for determining whether the dose level should be increased or whether a new dose level should be opened. The CSC also specified whether any or all patients enrolled in the new cohort would require a waiting period.

[0218] Phase 1 dose escalation (monotherapy) The starting dose level is 200 mg BID, which has been determined to be safe, achieve the relevant drug exposure level, and show indications of biological activity and clinical efficacy in study compound 1-101. Three patients with AML or MDS will be enrolled at the specified dose. If none of the first three patients experience 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 experiences dose-limiting toxicity, three more patients may be added to increase the dose level.

[0219] If two or three of the first six patients experience dose-limiting toxicities, the dose level will be considered above the MTD, and additional enrollment will be made at a lower dose level. Any adverse event leading to dose reduction or discontinuation is considered a dose-limiting toxicity unless the adverse event is significant and solely disease-related. Provisional dose levels are summarized in Table 1.

[0220] Table 1: Provisional dose levels of compound 1 for AML and MDS *If the MTD is not reached at dose level 2, higher dose levels can be tested. These levels will be determined by the CSC after reviewing all available data.

[0221] Phase 1b (Combination Therapy) Compound 1 + AZA The starting dose level for compound 1 will be 200 mg BID, continued for 21 days (days 1-21), with a 28-day cycle. Details of dose escalation are provided below. AZA 75 mg / m² 2 It will be administered intravenously (IV) or subcutaneously (SC) in 7 doses over a 28-day cycle (e.g., 7 consecutive doses starting from day 1 or divided doses with 5-2 rest days at the weekend), and administered according to local prescribing information (Table 2).

[0222] Notes : • According to the label, the toxicity is 50 mg / m³. 2 In cases where the dose is lower or even lower, the AZA dose is reduced.

[0223] • The expected dosage of compound 1 will be 200 mg, 300 mg, 400 mg BID; decreasing DL-1 and DL-2; 150 mg, 100 mg, administered over 21 days, with a cycle of 28 days.

[0224] Table 2: Dosage levels of compound 1 + azacitidine Compound 1 + VEN The starting dose level for Compound 1 will be 200 mg BID for 21 days (days 1-21), with a cycle of 28 days. Details of dose escalation are provided below. VEN will be administered orally at the same time daily (day 1) according to the product label, escalating to 400 mg over 3 days for 21 days, with a cycle of 28 days. The second and subsequent cycles will begin at the target dose level (Table 3).

[0225] Notes : • The expected dosage of compound 1 will be 200 mg, 300 mg, and 400 mg BID; decreasing DL-1 and DL-2: 150 mg and 100 mg, administered over 21 days, with a 28-day cycle. • For VENs with a labeled dosing regimen, the second and subsequent cycles begin at the target dose level.

[0226] Bone marrow assessment and continuous safety assessment 2 weeks after administration can shorten the cycle length to 14 days. ○ Adjust drug-drug interactions by reducing the starting dose and target dose levels according to the label, and reduce the dose according to the label.

[0227] Table 3: Dosage levels of compound 1 + venetoclax Incorporated by reference All publications and patents mentioned herein are incorporated herein by reference in their entirety, as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In the event of any conflict, this application (including any definitions herein) shall prevail.

[0228] equivalent While specific embodiments of the subject invention have been discussed, the foregoing description is illustrative rather than restrictive. Many variations of the invention will become apparent to those skilled in the art upon reading this description and the following claims. The full scope of the invention should be determined by reference to the full scope of the claims and their equivalents, the description, and such variations.

Claims

1. Use of an IRAK4 inhibitor or IRAK4 degrader in the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject who has previously received one or more immune checkpoint inhibitors for the treatment of said cancer.

2. The use according to claim 1, wherein the subject has previously received a programmed cell death protein 1 (PD-1) inhibitor.

3. The use according to claim 2, wherein the PD-1 inhibitor is nivolumab.

4. The use according to claim 1, wherein the subject has previously received a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor.

5. The use according to claim 4, wherein the CTLA-4 inhibitor is ipilimumab.

6. The use according to claim 1, wherein the subject has previously received a PD-1 inhibitor and a CTLA-4 inhibitor.

7. The use according to claim 6, wherein the PD-1 inhibitor is nivolumab and the CTLA-4 inhibitor is ipilimumab.

8. The use according to claim 1, wherein the subject has previously received a CD47 inhibitor.

9. The use according to claim 8, wherein the CD47 inhibitor is molotovicillin.

10. The use according to claim 1, wherein the subject has previously received at least one of a PD-1 inhibitor, a CTLA-4 inhibitor, a CD47 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a 4-1BB inhibitor, a CD27 inhibitor, a CD40 inhibitor, a CD80 inhibitor, or an OX-40 inhibitor; or a combination thereof.

11. The use according to claim 1, wherein the subject has previously received morolizumab, ipilimumab, nivolumab, atezolizumab, avelumab, camrelizumab, cimiprizumab, dacizumab, dotalimumab, durvalumab, galiximab, rucamumab, pembrolizumab, julalimumab, rivaril, celumab, sintilimab, spartazumab, torelizumab, tislelizumab, torelizumab, torelizumab, trimelimumab, urrelizumab, utorumab, varilimumab, MGD013, SHR- 1701, IMC-001, MCLA-145, CA-170, INCAGN02385, IMP701, MK-4280, ADG106, ISF35, CDX-1140, SEA-CD40, TTI-621, TJC4, TTI-622, ALX148, TG-1801, MEDI6469, BMS-986178 or PF-04518600; or at least one combination thereof.

12. The use according to claim 1, wherein the drug is used in combination with a BCL-2 inhibitor.

13. The use according to claim 12, wherein the BCL-2 inhibitor is venetoc.

14. The use according to claim 1, wherein the drug is used in combination with a BTK inhibitor.

15. The use according to claim 14, wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, sipebrutinib, or HM7 1224.

16. The use according to claim 1, wherein the cancer is a hematologic malignancy.

17. The use according to claim 16, wherein the hematologic malignancy is non-Hodgkin's lymphoma.

18. The use according to claim 16, wherein the hematologic malignancy is leukemia or lymphoma.

19. The use according to claim 16, wherein the hematologic malignancy is myeloid leukemia, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), ABC-DLBLC, mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt's lymphoma, non-Burkkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, transformed high-grade B-cell lymphoma (HGBL), lymphoplasmacytic lymphoma (LPL), central nervous system lymphoma (CNSL), primary CNS lymphoma (PCNSL), or MALT lymphoma.

20. The use according to claim 1, wherein the cancer is selected from brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, gastric cancer, breast cancer, bladder cancer, colon cancer, pancreatic cancer, lung cancer, cervical cancer, epidermal cancer, prostate cancer, and head and neck cancer.

21. The use according to claim 1, wherein the cancer is a solid tumor.

22. The use according to claim 1, wherein the cancer is recurrent or refractory.

23. The use according to any one of claims 1 to 22, wherein the medicament comprises an IRAK4 inhibitor, and the IRAK4 inhibitor has a structure represented by formula I: Or its pharmaceutically acceptable salt; in X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2 or X3 is N; A is O or S; Y is -CH2- or O; Z is an aryl or heterocyclic group; R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogroup, hydroxy, hydroxyalkyl, or -NR group. a R b ; R2 is hydrogen, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or -NR. a R b The substituents thereon are alkyl, amino, halogroups or hydroxyl groups; R3 is either an alkyl or hydroxyl group each time it appears; R a and R b It can be independently hydrogen, alkyl, acyl, or heterocyclic; 'm' and 'n' are independently 0, 1, or 2; and 'p' is 0 or 1.

24. The use according to claim 23, wherein the IRAK4 inhibitor has a structure represented by formula (IA): Or its pharmaceutically acceptable salt.

25. The use according to claim 23, wherein the IRAK4 inhibitor has a structure represented by formula (IB): Or its pharmaceutically acceptable salt.

26. The use according to claim 24, wherein A is O or S; Y is -CH2- or O; R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl, or -NR group. a R b ;where R a and R b It can be independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogenated, or hydroxyl groups; and 'm' and 'n' are independently 0, 1, or 2.

27. The use according to claim 23, wherein the IRAK4 inhibitor has a structure represented by formula (IC): Or its pharmaceutically acceptable salt.

28. The use according to claim 23, wherein the IRAK4 inhibitor is selected from: 。 29. The use according to claim 23, wherein the IRAK4 inhibitor is 。 30. The use according to claim 23, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

31. The use according to claim 23, wherein the IRAK4 inhibitor is .

32. The use according to claim 23, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

33. The use according to claim 23, wherein the IRAK4 inhibitor is .

34. The use according to claim 23, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

35. The use according to claim 23, wherein the IRAK4 inhibitor is .

36. The use according to claim 23, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

37. The use according to claim 23, wherein the IRAK4 inhibitor is .

38. The use according to claim 23, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

39. The use according to claim 23, wherein the IRAK4 inhibitor is .

40. The use according to claim 23, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

41. The use according to claim 23, wherein the IRAK4 inhibitor is .

42. The use according to claim 23, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

43. The use according to claim 23, wherein the IRAK4 inhibitor is .

44. The use according to claim 23, wherein the IRAK4 inhibitor is Pharmaceutically acceptable salts.

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