Combination Therapies for the Treatment of Cancer

Abstract

The present disclosure relates to methods of treating certain diseases and disorders (eg, cancer) using a combination of an IRAK4 inhibitor, a BCL-2 inhibitor, and a nucleoside analog.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 172,593, filed April 8, 2021, the contents of which are incorporated by reference in their entirety herein. [Background technology]

[0002] Interleukin-1 (IL-1) Receptor-Associated Kinase 4 (IRAK4) is a serine / threonine kinase enzyme that plays an essential role in signal transduction by the Toll / IL-1 receptor (TIR). The various IRAK enzymes are key components in the signal transduction pathways mediated by the interleukin-1 receptor (IL-1R) and Toll-like receptors (TLR) (Janssens, S, et al. Mol. Cell. 11, 2003, 293-302). There are four members of the mammalian IRAK family: IRAK-1, IRAK-2, IRAK-M, and IRAK4. These proteins are characterized by a typical N-terminal death domain and a centrally located kinase domain that mediates interaction with MyD88 family adaptor proteins. IRAK proteins and MyD88 have been shown to play a role in transducing signals other than those derived from the IL-1R receptor, including those induced by activation of the IL-18 receptor (Kanakaraj, et al. J. Exp. Med. 189(7):1999, 1129-38) and LPS receptor (Yang, et al., J. Immunol. 163, 1999, 639-643). Of the four members of the mammalian IRAK family, IRAK4 is considered to be the "master IRAK". Under overexpression conditions, all IRAKs can mediate activation of 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 have active kinase activity.IRAK-1 kinase activity is dispensable for function in IL-1-induced NF-kB activation (Kanakaraj et al., J. Exp. Med. 187(12), 1998, 2073-2079) and (Xiaoxia Li, et al, Mol. Cell. Biol. 19(7), 1999, 4643-4652), whereas IRAK4 requires kinase activity for signal transduction (Li S, et al. Proc. Natl. Acad. Sci. USA 99(8), 2002, 5567-5572) and (Lye, E et al, J. Biol. Chem. 279(39); 2004, 40653-8). Given the central role of IRAK4 in Toll-like / IL-1R signaling and immunological defense, IRAK4 inhibitors have been implicated as valuable therapeutic agents in inflammatory diseases, sepsis and autoimmune disorders (Wietek C, et al, Mol. Interv. 2:2002, 212-215).

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

[0004] Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy in adults, with an estimated 78,000 new cases and 20,000 deaths in the United States in 2020. The molecular pathology driving NHL is diverse, but a common thread is the activity of the NF-κB signaling pathway. Specific molecular alterations that have been identified that drive this pathway are a subset of NHL. For example, diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that can arise in lymph nodes or outside the lymphatic system, in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. DLBCL is a cancer of B cells, a type of white blood cell responsible for antibody production. It is the most common type of non-Hodgkin lymphoma among adults, with an annual incidence of 7-8 cases per 100,000 people per year. This cancer occurs primarily in older adults, with a median age of diagnosis of approximately 70 years, although rare cases can occur in children and young adults. DLBCL is an aggressive tumor, and the first sign of the disease is typically the observation of a rapid growth of a mass. The 5-year survival rate is only 58%. DLBCL is named according to its cell of origin and has subtypes, including germinal center B-cell-like (GCB) and activated B-cell-like (ABC). They differ in having a worse prognosis and in some cases require specialized approaches to treatment.

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

[0006] Other types of non-Hodgkin lymphomas 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 lymphomas can be caused by a variety of factors, including infectious agents (Epstein-Barr virus, Hepatitis C virus, and human T-cell leukemia virus), radiation and chemotherapy treatments, and autoimmune diseases. As a group, non-Hodgkin lymphomas affect 2.1% of the U.S. population during their lifetime. The percentage of people who survive more than 5 years after diagnosis is 71%.

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

[0008] In one aspect, the disclosure provides a method of treating cancer in a subject, the method comprising co-administering to the subject an IRAK4 inhibitor or IRAK4 degrader, a BCL-2 inhibitor, and a nucleoside analog.

[0009] In another aspect, the disclosure provides a method of treating cancer in a subject, the method comprising co-administering to the subject an IRAK4 inhibitor or an IRAK4 degrader and a nucleoside analog. [Brief description of the drawings]

[0010] [Figure 1A] Figure 1 shows the efficacy of certain treatments in venetoclax-resistant THP-1 cell lines. Cells were treated continuously for 96 hours with clinically relevant drug concentrations. Relative cell viability was measured at 0 and 96 hours by CellTiter Glo assay (Promega, Madison, WI) according to the manufacturer's instructions. All values ​​are presented as mean ± SE. One-way ANOVA was used to analyze cell viability assay data. p values ​​less than 0.05 were considered significant. Statistical analysis was performed using GraphPad Prism 8.0 software. Synergistic efficacy was observed with the combination of compound 1, azacitidine, and venetoclax. [Figure 1B] Figure 1 shows the efficacy of certain treatments in azacitidine-resistant OCI-AML2 cell lines. Cells were treated continuously for 96 hours with clinically relevant drug concentrations. Relative cell viability was measured at 0 and 96 hours by CellTiter Glo assay (Promega, Madison, WI) according to the manufacturer's instructions. All values ​​are presented as mean ± SE. One-way ANOVA was used to analyze cell viability assay data. p values ​​less than 0.05 were considered significant. Statistical analysis was performed using GraphPad Prism 8.0 software. Synergistic efficacy was observed with the combination of compound 1, azacitidine, and venetoclax. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] IL-1R-associated kinase 4 (IRAK4) is a serine / threonine kinase that is a key component of the myddosome complex. The myddosome, a key component of the innate immune system, transduces intracellular signals originating from IL-1R and Toll-like receptors (TLRs) to activate NFκB. This pathway is also oncogenic in several malignancies. More than 90% of WM cases harbor a common activating missense mutation (leucine to proline substitution at position 265 (L265P)) in an adaptor protein (myeloid differentiation primary response 88 (MYD88)) that results in loss of growth control. MYD88 is composed of an N-terminal death domain, a central linker domain, and a C-terminal Toll / interleukin-1 receptor domain (Figure 2). Signaling of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families occurs via MYD88. MYD88 is involved in the assembly and activation of IL-1R-associated kinase 4 (IRAK4), which stimulates the NF-κB-mediated anti-apoptotic signaling cascade. IL-1R-associated kinase 1 (IRAK1) is recruited by MYD88 through direct interaction with IRAK4 (the most proximal IRAK). Ultimately, activation of IRAK1 results in the formation of TRAF6-TAK1-IKK (tumor necrosis factor receptor-associated factor 6-transforming growth factor beta-activated kinase 1-IkB kinase), which activates the NF-κB pathway and promotes cell survival.

[0012] Oncogenic signaling is transmitted by the mydosome, and IRAK4 is required for mydosome activation. TLRs are widely expressed on tumor cells and control proliferation and other tumor functions. MYD88 is a known oncogene that is mutated in several malignancies and requires IRAK4. The long form of IRAK4 (IRAK4-L) is known to be oncogenic in itself in AML and MDS, where IRAK4-L is overexpressed in more than half of cases. Compound 1 is the first IRAK4-targeted clinical candidate to be evaluated in cancer patients, and evidence is disclosed herein that targeting IRAK4 results in anti-cancer activity in patients.

[0013] In one aspect, the disclosure provides a method of treating cancer in a subject, the method comprising co-administering to the subject an IRAK4 inhibitor or IRAK4 degrader, a BCL-2 inhibitor, and a nucleoside analog.

[0014] In certain preferred embodiments, the methods involve co-administering an IRAK4 inhibitor, a BCL-2 inhibitor, and a nucleoside analog to a subject.

[0015] In another aspect, the disclosure provides a method of treating cancer in a subject, the method comprising co-administering to the subject an IRAK4 inhibitor or an IRAK4 degrader and a nucleoside analog.

[0016] In certain preferred embodiments, the methods involve co-administering an IRAK4 inhibitor and a nucleoside analog to the subject.

[0017] In certain preferred embodiments, the IRAK4 inhibitor is [ka] In another preferred embodiment, the IRAK4 inhibitor is [ka] In yet another preferred embodiment, the IRAK4 inhibitor is [ka] In yet another preferred embodiment, the IRAK4 inhibitor is [ka] In yet another preferred embodiment, the IRAK4 inhibitor is [ka] It is.

[0018] In certain preferred embodiments, the BCL-2 inhibitor is venetoclax.

[0019] In certain preferred embodiments, the nucleoside analog is azacytidine.

[0020] In certain particularly preferred embodiments, the IRAK4 inhibitor is [ka] and The BCL-2 inhibitor is venetoclax; The nucleoside analog is azacytidine.

[0021] In other particularly preferred embodiments, the IRAK4 inhibitor is [ka] and The nucleoside analog is azacytidine.

[0022] IRAK4 Inhibitors of the Present Disclosure In certain embodiments, the IRAK4 inhibitor has formula (I): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, Z1 is an optionally substituted heteroaryl; Z2 is an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, or a direct bond; R1 is alkyl, cyano, or -NR a R b or an optionally substituted group selected from cycloalkyl, aryl, or heterocyclyl, wherein the substituents are, independently for each occurrence, alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl); R2, independently at each occurrence, is an optionally substituted group selected from alkyl or cycloalkyl, wherein the substituents, independently at each occurrence, are halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl, or haloalkoxy; R3, independently for each occurrence, is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NR a R b , hydroxyl, or hydroxyalkyl; R a is hydrogen or alkyl, R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl; "m" and "n" are independently 1 or 2.

[0023] In certain embodiments, Z 1 is a 5- or 6-membered optionally substituted heteroaryl.

[0024] In certain embodiments, Z1 is an optionally substituted heteroaryl, wherein the optional substituent is alkyl.

[0025] In certain embodiments, Z1 is selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, and pyrazolyl.

[0026] In certain embodiments, Z 1 is selected from pyridyl, oxazolyl, and furanyl, wherein the pyridyl group is optionally substituted with alkyl, and in particular, the alkyl is methyl.

[0027] In certain embodiments, Z2 is a 5- or 6-membered heteroaryl selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, or pyrazolyl.

[0028] In certain embodiments, Z2 is a 5- or 6-membered heterocycloalkyl selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, or 1,4-dioxanyl.

[0029] In certain embodiments, Z2 is pyridyl, pyrazolyl, or pyrrolidinyl.

[0030] In certain embodiments, Z2 is a direct bond.

[0031] In certain embodiments, the IRAK4 inhibitor has formula (IA): [ka] or a pharma- ceutically acceptable salt thereof.

[0032] In certain embodiments, the IRAK4 inhibitor has formula (IB): [ka] or a pharma- ceutically acceptable salt thereof.

[0033] In certain embodiments, the IRAK4 inhibitor has the formula (IC): [ka] or a pharma- ceutically acceptable salt thereof.

[0034] In certain embodiments, [ka] teeth, [ka] It is.

[0035] In certain embodiments, Z2 is pyridyl.

[0036] In certain embodiments, Z2 is pyrazolyl.

[0037] In certain embodiments, Z2 is pyrrolidinyl.

[0038] In certain embodiments, R1 is an optionally substituted heterocyclyl, where the substituents are halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl).

[0039] In certain embodiments, R1 is an optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl, or azepanyl, where the substituents are amino, halogen, hydroxyl, hydroxyalkyl, aminoalkyl, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl).

[0040] In certain embodiments, R1 is an optionally substituted piperidinyl, wherein the substituent is hydroxyl.

[0041] In certain embodiments, R1 is an optionally substituted phenyl, and the substituent is a halogen.

[0042] In certain embodiments, R1 is cycloalkyl.

[0043] In certain embodiments, R1 is cyclopropyl or cyclohexyl.

[0044] In certain embodiments, R is -NR a R b and R a is hydrogen and R b is an optionally substituted cycloalkyl, the substituent being hydroxyl.

[0045] In certain embodiments, R1 is cyano.

[0046] In certain embodiments, R2 is an optionally substituted alkyl, and the substituent is alkoxy.

[0047] In certain embodiments, R2 is cycloalkyl.

[0048] In certain embodiments, R3 is hydrogen, halogen, alkyl, alkoxy, -NR a R b, hydroxyl, or hydroxyalkyl; R a is hydrogen or alkyl; R b is hydrogen, alkyl, acyl, hydroxyalkyl, or -SO2-alkyl.

[0049] In certain embodiments, Z1 is an optionally substituted pyridyl, the Z2 ring is pyridyl, pyrazolyl, pyrrolidinyl, or a direct bond, R1 is an optionally substituted group selected from cyclopropyl, piperidinyl, morpholinyl, or pyrrolidinyl, R2 is an optionally substituted alkyl or cycloalkyl, and R3 is hydrogen, halogen, alkyl, alkoxy, -NR a R b , hydroxyl, or hydroxyalkyl; R a is hydrogen or alkyl; R b is hydrogen or hydroxyalkyl.

[0050] In certain embodiments, Z1 is oxazolyl, Z2 is pyridyl, pyrazolyl, or pyrrolidinyl, and R1 is cyano or -NR a R b or an optionally substituted group selected from cyclopropyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, morpholinyl, or pyrrolidinyl, R2 being an optionally substituted alkyl or cycloalkyl, and R3 being hydrogen, halogen, alkyl, alkoxy, -NR a R b , hydroxyl, or hydroxyalkyl; R a is hydrogen or alkyl; R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl.

[0051] In certain embodiments, R3 is -NR a R b and R a is hydrogen or alkyl; R bis hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl, the optional substituent being hydroxyl.

[0052] In certain embodiments, "n" is 1.

[0053] In certain embodiments, "n" is 2.

[0054] In certain embodiments, "m" is 1.

[0055] In certain embodiments, "m" is 2.

[0056] In certain embodiments, the IRAK4 inhibitor is [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0057] In other embodiments, the IRAK4 inhibitor has formula (II): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, X1 and X3 are independently CH or N, and X2 is CR2 or N, provided that only one of X1, X2, or X3 is N; A is O or S; Y is -CH2- or O; Z is aryl or heterocyclyl; R1 is, independently for each occurrence, halo or optionally substituted heterocyclyl, where the substituents are alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR a R b and R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR a R b and the substituents are alkyl, amino, halo, or hydroxyl; R3, for each occurrence, is alkyl or hydroxyl; R a and R b are independently hydrogen, alkyl, acyl, or heterocyclyl; "m" and "n" are independently 0, 1, or 2; "p" is 0 or 1.

[0058] In certain embodiments, [ka] The part that says, [ka] It is.

[0059] In certain embodiments, Z is aryl or 5- or 6-membered heterocyclyl.

[0060] In certain embodiments, Z is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, or dihydropyranyl, each of which is alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or -NR a R b Optionally replaced by R a and R b is independently hydrogen, alkyl, or acyl.

[0061] In certain embodiments, Z is phenyl, oxazolyl, furanyl, thienyl, or pyridyl, each of which is optionally substituted by one or more R 1 .

[0062] In certain embodiments, [ka] teeth, [ka] It is.

[0063] In certain embodiments, the IRAK4 inhibitor has the formula (OIA): [ka] or a pharma- ceutically acceptable salt thereof.

[0064] In certain embodiments, the IRAK4 inhibitor has formula (IIB): [ka] or a pharma- ceutically acceptable salt thereof.

[0065] In certain embodiments, the IRAK4 inhibitor has formula (IIC): [ka] or a pharma- ceutically acceptable salt thereof.

[0066] In certain embodiments, Y is O or CH2.

[0067] In certain embodiments, R is an optionally substituted heterocyclyl, the substituents being alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR a R b and R a and R b is independently hydrogen, alkyl, or acyl.

[0068] In certain embodiments, R is pyridyl, pyrazolyl, pyrrolidinyl, or piperidinyl, each of which is alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or -NR a R b Optionally replaced by R a and R b is independently hydrogen or acyl.

[0069] In certain embodiments, R2 is hydrogen.

[0070] In certain embodiments, R2 is an optionally substituted cycloalkyl.

[0071] In certain embodiments, R2 is cyclopropyl.

[0072] In certain embodiments, R2 is an optionally substituted heterocyclyl, where the substituent is alkyl, amino, halo, or hydroxyl.

[0073] In certain embodiments, R2 is piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanyl, pyridyl, azepanyl, or azabicyclo[3.2.1]octanyl, and the substituent is alkyl, amino, halo, or hydroxyl.

[0074] In certain embodiments, R2 is an optionally substituted aryl, wherein the substituent is halo.

[0075] In certain embodiments, R2 is an optionally substituted phenyl, where the substituent is fluoro.

[0076] In certain embodiments, R2 is -NR a R b and R a and R b is independently hydrogen or heterocyclyl.

[0077] In certain embodiments, R2 is -NR a R b and R a and R b is independently hydrogen or pyrrolidinyl.

[0078] In certain embodiments, A is O or S, Y is -CH2- or O, and R1 is halo, pyridyl, pyrazolyl, pyrrolidinyl, each of which is alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or -NR a R b and R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR a R b and the substituents are alkyl, amino, halo, or hydroxyl; R a and R b is independently hydrogen or alkyl.

[0079] In certain embodiments, A is O or S, Y is -CH2- or O, and R1 is pyridyl, pyrazolyl, pyrrolidinyl, each of which is alkyl, hydroxyl, hydroxyalkyl, or -NR a R b Optionally replaced by R a and R b is independently hydrogen, and R2 is hydrogen, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or -NR a R b and the substituents are alkyl, amino, halo, or hydroxyl; R a and R b is independently hydrogen, alkyl, acyl, or heterocyclyl.

[0080] In certain embodiments, "n" is 0, 1, or 2.

[0081] In certain embodiments, "p" is 0 or 1.

[0082] In certain embodiments, "m" is 0 or 2.

[0083] In certain embodiments, the IRAK4 inhibitor is [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0084] In certain preferred embodiments, the IRAK4 inhibitor is [ka] (i.e., Compound 1) or a pharma- ceutically acceptable salt thereof.

[0085] In another embodiment, the IRAK4 inhibitor has formula (III): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, Z1 represents optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or absent; Z2 represents an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heterocyclyl; R1 is hydrogen, optionally substituted alkyl, amino, halo, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; R2, for each occurrence, is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; R3, for each occurrence, is hydroxy, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, or -NR a R b and R a and R b is independently for each occurrence hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; m, for each occurrence, is 0, 1, or 2; n is 0, 1, or 2 for each occurrence.

[0086] In certain embodiments, Z1 is optionally substituted heterocyclyl.

[0087] In certain embodiments, Z1 is hydroxy, halo, alkyl, cycloalkyl, or NR a R b represents a cycloalkyl, aryl, or heterocyclyl optionally substituted with one or more substituents independently selected for each occurrence from:

[0088] In certain embodiments, Z1 is an optionally substituted heteroaryl, wherein the optional substituents are alkyl or cycloalkyl.

[0089] In certain embodiments, Z1 is tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, benzo ... Doryl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carboline, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotridiazolyl, carbazolyl, dibenzothienyl, acridinyl, and pyrazolopyrimidyl, each of which is optionally substituted.

[0090] In certain embodiments, Z1 is tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, or pyrazolyl.

[0091] In certain embodiments, Z 1 is pyridyl or oxazolyl, wherein the oxazolyl group is optionally substituted with alkyl, and particularly, the alkyl is methyl.

[0092] In certain embodiments, Z1 is absent.

[0093] In certain embodiments, Z2 is cycloalkyl, aryl, or heterocyclyl.

[0094] In certain embodiments, Z2 is hydroxy, halo, alkyl, alkoxyl, cycloalkyl, -NR a R b or cycloalkoxy.

[0095] In certain embodiments, Z2 is heterocyclyl.

[0096] In certain embodiments, Z2 is azetidinyl, oxetanyl, furanyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,4-dioxanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolidinyl, imidazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, oxazolidinyl, pyrazolidinyl, benzoisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, pyrrolopyridyl, or pyrazolopyrimidyl.

[0097] In certain embodiments, Z2 is pyridyl, piperazinyl, pyrimidyl, pyrrolidinyl, 1,2,3,4-tetrahydropyridyl, piperidinyl, pyrazolopyrimidyl, or pyrrolopyridyl.

[0098] In certain embodiments, the IRAK4 inhibitor has formula (IIIA): [ka] or a pharma- ceutically acceptable salt thereof.

[0099] In certain embodiments, the IRAK4 inhibitor has formula (IIIB): [ka] or a pharma- ceutically acceptable salt thereof.

[0100] In certain embodiments, [ka] The base is, [ka] It is.

[0101] In certain embodiments, Z2 is pyridyl.

[0102] In certain embodiments, Z2 is pyrrolidinyl.

[0103] In certain embodiments, Z2 is piperidinyl, piperazinyl, tetrahydropyridyl, pyrimidyl, or pyrazolopyridyl.

[0104] In certain embodiments, R1 is hydrogen, optionally substituted alkyl, amino, halo, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl.

[0105] In certain embodiments, the methods of the present invention include a compound of formula (III) or a pharma- ceutically acceptable salt, wherein R1 is alkyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, optionally substituted with one or more substituents independently selected for each occurrence from hydroxy, halo, alkyl, or hydroxyalkyl.

[0106] In certain embodiments, R1 is heterocyclyl optionally substituted with halogen, hydroxyl, or hydroxyalkyl.

[0107] In certain embodiments, R1 is optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl, or azepanyl.

[0108] In certain embodiments, R1 is piperidinyl optionally substituted with hydroxyl.

[0109] In certain embodiments, R1 is pyrrolidinyl optionally substituted with hydroxyl.

[0110] In certain embodiments, R2, for each occurrence, is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl.

[0111] In certain embodiments, R2 is alkyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heterocyclylalkyl, optionally substituted with one or more substituents independently selected for each occurrence from alkyl, cycloalkyl, or heterocyclyl.

[0112] In certain embodiments, R2 is optionally substituted alkyl, preferably methyl.

[0113] In certain embodiments, R2 is optionally substituted cycloalkyl, preferably cyclopropyl.

[0114] In certain embodiments, R, for each occurrence, is hydroxy, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, or -NR a R b and R a is hydrogen or optionally substituted alkyl, R b is hydrogen, optionally substituted alkyl, optionally substituted acyl, hydroxyalkyl, or -SO2-alkyl.

[0115] In certain embodiments, Z1 is an optionally substituted pyridyl, Z2 is pyrrolidinyl, R1 is an optionally substituted group selected from piperidinyl or pyrrolidinyl, R2 is an optionally substituted alkyl, and R3 is halogen, alkyl, -NR a R b , hydroxyl, or hydroxyalkyl; R a is hydrogen or alkyl; R b is hydrogen or hydroxyalkyl.

[0116] In certain embodiments, Z1 is oxazolyl, Z2 is pyridyl, pyrimidyl or pyrrolidinyl, piperidinyl, tetrahydropyridyl, piperazinyl, pyrrolopyridyl, R1 is an optionally substituted group selected from piperidinyl or pyrrolidinyl, R2 is an optionally substituted alkyl or cyclopropyl, and R3 is halogen, alkyl, alkoxy, -NR a R b , hydroxyl, hydroxyalkyl, optionally substituted cyclopropyl; R a is hydrogen or alkyl; R bis hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl.

[0117] In certain embodiments, "m" is 0.

[0118] In certain embodiments, "m" is 1.

[0119] In certain embodiments, "m" is 2.

[0120] In certain embodiments, "n" is 0.

[0121] In certain embodiments, "n" is 1.

[0122] In certain embodiments, "n" is 2.

[0123] In certain embodiments, the IRAK4 inhibitor is [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] or a pharma- ceutically acceptable salt thereof.

[0124] In other embodiments, the IRAK4 inhibitor is PF-06650833, BAY1830839, BAY1834845, R835, GS-5718, or ND-2158.

[0125] The IRAK4 inhibitor (e.g., compound 1) may be administered in any amount or manner that induces a desired response in a subject. For example, 100-400 mg of the IRAK4 inhibitor may be administered twice daily to a subject, or 200-1000 mg of the IRAK4 inhibitor may be administered once daily to a subject. In certain embodiments, 100-400 mg of the IRAK4 inhibitor is administered twice daily to a subject. In certain embodiments, 200-400 mg of the IRAK4 inhibitor is administered twice daily to a subject. In certain preferred embodiments, 250-350 mg of the IRAK4 inhibitor is administered twice daily to a subject. In certain embodiments, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of an IRAK4 inhibitor is administered twice daily to a subject. In certain embodiments, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of an IRAK4 inhibitor is administered twice daily to a subject. In certain embodiments, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of an IRAK4 inhibitor is administered to the subject twice daily. In certain embodiments, about 50 mg of an IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, about 200 mg of an IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, about 225 mg of an IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, about 250 mg of an IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, about 275 mg of an IRAK4 inhibitor is administered to the subject twice daily. In particularly preferred embodiments, about 300 mg of an IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, about 325 mg of an IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, about 350 mg of an IRAK4 inhibitor is administered to the subject twice daily. In another embodiment, about 375 mg of an IRAK4 inhibitor is administered twice daily to a subject.In another embodiment, about 400 mg of an IRAK4 inhibitor is administered twice daily to a subject.

[0126] In certain embodiments, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of IRAK4 inhibitor is administered to the subject once a day. In certain embodiments, about 50 mg of IRAK4 inhibitor is administered to the subject once a day. In certain embodiments, about 75 mg of IRAK4 inhibitor is administered to the subject once a day. In certain embodiments, about 100 mg of IRAK4 inhibitor is administered to the subject once a day. In certain embodiments, about 125 mg of IRAK4 inhibitor is administered to the subject once a day. In certain embodiments, about 150 mg of an IRAK4 inhibitor is administered to a subject once daily.

[0127] In certain preferred embodiments, the IRAK4 inhibitor is orally administered to the subject. In certain embodiments, about 50 mg of the IRAK4 inhibitor is orally administered to the subject twice a day. In other embodiments, about 200 mg of the IRAK4 inhibitor is orally administered to the subject twice a day. In other embodiments, about 250 mg of the IRAK4 inhibitor is orally administered to the subject twice a day. In particularly preferred embodiments, about 300 mg of the IRAK4 inhibitor is orally administered to the subject twice a day. In other embodiments, about 325 mg of the IRAK4 inhibitor is orally administered to the subject twice a day. In other embodiments, about 350 mg of the IRAK4 inhibitor is orally administered to the subject twice a day. In other embodiments, about 375 mg of the IRAK4 inhibitor is orally administered to the subject twice a day. In other embodiments, about 400 mg of the IRAK4 inhibitor is orally administered to the subject twice a day. In other embodiments, about 50 mg of the IRAK4 inhibitor is administered to the subject once a day. In yet another embodiment, about 75 mg of an IRAK4 inhibitor is administered to a subject once per day. In yet another embodiment, about 100 mg of an IRAK4 inhibitor is administered to a subject once per day. In yet another embodiment, about 125 mg of an IRAK4 inhibitor is administered to a subject once per day. In yet another embodiment, about 150 mg of an IRAK4 inhibitor is administered to a subject once per day.

[0128] IRAK4 degrading agents of the present disclosure In certain embodiments, the method includes administering an IRAK4 degrading agent. In certain embodiments, the IRAK4 degrading agent is KT-474, KYM-001, or IRAKMiD. In certain embodiments, the IRAK4 degrading agent is an IRAK4 degrading agent disclosed in US2019 / 0151295A1, WO2019 / 133531A1, WO2020 / 113233A1, and WO2021 / 011868A1, the contents of each of which are incorporated herein by reference in their entirety.

[0129] BCL-2 Inhibitors of the Present Disclosure The combination disclosed herein can be used in conjunction with any BCL-2 inhibitor.In certain preferred embodiments, the BCL-2 inhibitor is venetoclax.In certain embodiments, 400mg of venetoclax is administered daily.In certain embodiments, venetoclax is administered orally.

[0130] Nucleoside Analogs of the Present Disclosure The combinations disclosed herein may be utilized in conjunction with any nucleoside analog. In certain embodiments, the nucleoside analog is an analog of cytidine. In certain embodiments, the nucleoside analog is azacitidine, decitabine, cytarabine, gemcitabine, 5'-deoxy-5-fluorouridine, fludarabine, cladribine, troxacitabine, or clofarabine. In certain preferred embodiments, the nucleoside analog is azacitidine. In certain embodiments, azacitidine is administered at a dose of 75 mg / m 2 In certain embodiments, azacitidine is administered at a dose of 100 mg / m 2 In certain embodiments, azacitidine is administered subcutaneously. In other embodiments, azacitidine is administered daily at a dose of 300 mg. In certain embodiments, azacitidine is administered orally.

[0131] Cancer of the present disclosure In certain embodiments, the cancer is a hematological malignancy, e.g., leukemia or lymphoma, e.g., non-Hodgkin's lymphoma. In certain embodiments, the hematological malignancy is selected from the group consisting of myelogenous leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphoblastic leukemia (e.g., acute lymphoblastic leukemia), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., DLBCL or ABC-DLBLC), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma, and / or peripheral leukemia. lymphoma (MZL), Burkitt's lymphoma, non-Burkitt's high grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, transformed high grade B-cell lymphoma (HGBL), lymphoplasmacytic lymphoma (LPL), central nervous system lymphoma (CNSL), or MALT lymphoma. In certain embodiments, the hematological malignancy is myeloid leukemia. In other embodiments, the hematological malignancy is myeloid leukemia (e.g., acute myeloid leukemia). In certain embodiments, the hematological malignancy is acute myeloid leukemia (e.g., AML). In certain embodiments, the AML is primary AML. In other embodiments, the AML is secondary AML. In certain embodiments, the AML is resistant to treatment with an fms-related receptor tyrosine kinase 3 (FLT3) inhibitor. In certain embodiments, the AML is associated with a mutation in FLT3 kinase. In certain embodiments, the mutation is an internal tandem duplication (ITD).In certain embodiments, the mutation is a D835H mutation, a D835V mutation, a D835Y mutation, a K663Q mutation, a N841L mutation, or a F691L mutation. In certain embodiments, the mutation is a D835Y mutation. In still other embodiments, the hematological malignancy is myelodysplastic syndrome (MDS). In certain embodiments, the MDS is high-grade. In other embodiments, the MDS is low-grade. In certain embodiments, the MDS is high-risk. In still other embodiments, the hematological malignancy is lymphoblastic leukemia (e.g., acute lymphoblastic leukemia). In still other embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL). In certain embodiments, the CLL is high-risk CLL. In still other embodiments, the hematological malignancy is small lymphocytic lymphoma (SLL). In still other embodiments, the hematological malignancy is follicular lymphoma. In yet other embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL). In yet other embodiments, the hematological malignancy is activated B-cell-like (ABC) DLBCL. In yet other embodiments, the hematological malignancy is germinal center B-cell-like (GCB) DLBCL. In certain embodiments, the DLBCL is extranodal. In certain embodiments, the DLBCL is extranodal leg lymphoma, extranodal testicular lymphoma, or extranodal not otherwise specified (NOS) lymphoma. In still other embodiments, the hematological malignancy is mantle cell lymphoma. In further embodiments, the hematological malignancy is Waldenstrom's macroglobulinemia. In certain embodiments, the DLBCL or WM is characterized by a L265P mutation in MYD88. In still other embodiments, the hematological malignancy is multiple myeloma. In still other embodiments, the hematological malignancy is marginal zone lymphoma. In yet other embodiments, the hematological malignancy is Burkitt's lymphoma. In yet other embodiments, the hematological malignancy is non-Burkitt's high-grade B-cell lymphoma. In yet other embodiments, the hematological malignancy is extranodal marginal zone B-cell lymphoma. In yet other embodiments, the hematological malignancy is transformed high-grade B-cell lymphoma (HGBL). In yet other embodiments, the hematological malignancy is lymphoplasmacytic lymphoma (LPL).In yet another embodiment, the hematological malignancy is a CNS lymphoma. In yet another embodiment, the CNS lymphoma is a primary CNS lymphoma (PCNSL). In yet another embodiment, the hematological malignancy is a MALT lymphoma. In certain embodiments, the hematological malignancy may be relapsed or refractory. In certain embodiments, the hematological malignancy is resistant to treatment with a BTK inhibitor. In certain embodiments, the hematological malignancy is resistant to treatment with a BTK inhibitor as monotherapy. In certain embodiments, the hematological malignancy is resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ONO-4059, spebrutinib, or HM7 1224. In certain preferred embodiments, the hematological malignancy is resistant to treatment with ibrutinib.

[0132] In certain embodiments, the cancer is selected from brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, gastric cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, epidermoid cancer, prostate cancer, and head and neck cancer. In certain preferred embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is colon cancer. In certain embodiments, the cancer is a solid tumor. In various such embodiments, the cancer may be recurrent or refractory.

[0133] The combinations disclosed herein may be used as first-line therapy or may be administered to patients who have failed to achieve either a partial or complete response using one or more previous anti-cancer or anti-inflammatory therapies. In certain embodiments, the subject has previously received at least one anti-cancer therapy. In certain embodiments, the patient has previously received one anti-cancer therapy. In other embodiments, the patient has previously received two anti-cancer therapies. In yet other embodiments, the patient has previously received three anti-cancer therapies. In yet other embodiments, the patient has previously received four anti-cancer therapies. In yet other embodiments, the patient has previously received five anti-cancer therapies. In certain embodiments, the at least one anti-cancer therapy is selected from an anti-CD20 antibody, a nitrogen mustard, a steroid, a purine analog, a DNA topoisomerase inhibitor, a DNA intercalator, 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 PD-1 inhibitor, a PD-L1 inhibitor, and a methylating agent, or a combination thereof. In certain embodiments, the anti-cancer therapy is selected from ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, oprozomib, ixazomib, acalabrutinib, zanubrutinib, IMO-08400, idelalisib, umbrellasib, CB-839, fludarabine, and thalidomide, or combinations thereof. In certain embodiments, the anti-cancer therapy is ibrutinib. In certain embodiments, the anti-cancer therapy is ibrutinib and rituximab. In certain embodiments, the anti-cancer therapy is bendamustine. In certain embodiments, the anti-cancer therapy is bendamustine and rituximab. In certain embodiments, the anti-cancer therapy is bortezomib. In certain embodiments, the anti-cancer therapy is bortezomib and dexamethasone. In certain embodiments, the anti-cancer therapy is bortezomib and rituximab. In certain embodiments, the anti-cancer therapy is bortezomib, rituximab, and dexamethasone.In certain embodiments, the anti-cancer therapy is chlorambucil. In certain embodiments, the anti-cancer therapy is cladribine. In certain embodiments, the anti-cancer therapy is cladribine and rituximab. In certain embodiments, the anti-cancer therapy is cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R). In certain embodiments, the anti-cancer therapy is cyclophosphamide, prednisone, and rituximab (i.e., CPR). In certain embodiments, the anti-cancer therapy is fludarabine. In certain embodiments, the anti-cancer therapy is fludarabine and rituximab. In certain embodiments, the anti-cancer therapy is fludarabine, cyclophosphamide, and rituximab. In certain preferred embodiments, the anti-cancer therapy is rituximab. In certain preferred embodiments, the anti-cancer therapy includes rituximab. In certain embodiments, the anti-cancer therapy is rituximab, cyclophosphamide, and dexamethasone (i.e., RCD). In certain embodiments, the anti-cancer therapy is thalidomide. In certain embodiments, the anti-cancer therapy is thalidomide and rituximab. In certain embodiments, the anti-cancer therapy is venetoclax. In certain embodiments, the anti-cancer therapy is cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD). In certain embodiments, the anti-cancer therapy is a hypomethylating agent. In certain embodiments, the subject has previously received at least six cycles of a hypomethylating agent. In certain embodiments, the anti-cancer therapy is a combination of any of the above, for example, the subject may first receive rituximab, then at a later date receive a combination of rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).

[0134] The subject may also have undergone or be prepared for other non-chemotherapeutic treatments, such as surgery, radiation, or bone marrow transplant. In certain embodiments, the subject has previously undergone etoposide chemo-mobilization therapy. In certain embodiments, the subject has previously undergone bone marrow transplant. In certain embodiments, the subject has previously undergone stem cell transplant. In certain embodiments, the subject has previously undergone autologous cell transplant. In certain embodiments, the subject has previously undergone allogeneic stem cell transplant. In certain embodiments, the subject has previously undergone hematopoietic cell transplant. In certain embodiments, the subject has previously undergone carmustine, etoposide, cytarabine, and melphalan (i.e., BEAM conditioning). In certain embodiments, the subject has previously undergone reinduction therapy.

[0135] The subject may also have previously demonstrated a favorable outcome to a previous therapy only to require additional treatment at a later date. In certain embodiments, the subject has previously achieved a partial response. In certain embodiments, the subject has previously achieved a good partial response. In certain embodiments, the subject has previously achieved a complete response. In certain embodiments, the cancer is recurrent. In certain embodiments, the cancer is refractory.

[0136] The subject may also have one or more pre-existing or developed genetic mutations that render the subject's cancer more or less resistant to therapy. In certain embodiments, the subject has a mutation in RICTOR. In certain embodiments, the subject has a N1065S mutation in RICTOR. In certain preferred embodiments, the subject has a mutation in MYD88. In certain even more preferred embodiments, the subject has a L265P mutation in MYD88. In certain embodiments, the subject has a mutation in TET2. In certain embodiments, the subject does not have a mutation in CXCR4. In other embodiments, the subject has a mutation in CXCR4. In certain embodiments, the subject shows early progression. In certain embodiments, the subject has not previously received a BTK inhibitor.

[0137] In certain embodiments, after administration of the combination, the subject achieves a partial response. In certain embodiments, after administration of the combination, the subject achieves a good partial response. In other embodiments, after administration of the combination, the subject achieves a complete response. In certain embodiments, the subject achieves a partial response within 7 days of receiving the combination. In certain embodiments, the subject achieves a good partial response within 7 days of receiving the combination. In certain embodiments, the subject achieves a complete response within 7 days of receiving the combination. In certain embodiments, the subject's tumor volume is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In certain embodiments, the subject's tumor volume is reduced by 5%. In certain embodiments, the subject's tumor volume is reduced by 10%. In certain embodiments, the subject's tumor volume is reduced by 15%. In certain embodiments, the subject's tumor volume is reduced by 20%. In certain embodiments, the subject's tumor volume is reduced by 25%. In certain embodiments, the subject's tumor volume is reduced by 30%. In certain embodiments, the subject's tumor volume is reduced by 35%. In certain embodiments, the subject's tumor volume is reduced by 40%. In certain embodiments, the subject's tumor volume is reduced by 45%. In certain embodiments, the subject's tumor volume is reduced by 50%. In certain embodiments, the subject's tumor volume is reduced by 55%. In certain embodiments, the subject's tumor volume is reduced by 60%. In certain embodiments, the subject's tumor volume is reduced by 65%. In certain embodiments, the subject's tumor volume is reduced by 70%. In certain embodiments, the subject's tumor volume is reduced by 80%. In certain embodiments, the subject's tumor volume is reduced by 85%. In certain embodiments, the subject's tumor volume is reduced by 90%. In certain embodiments, the subject's tumor volume is reduced by 95%.

[0138] Method of administration The IRAK4 inhibitor or IRAK4 degrading agent, the BCL-2 inhibitor, and the nucleoside analog can be administered in several ways. For example, the IRAK4 inhibitor or IRAK4 degrading agent, the BCL-2 inhibitor, and the nucleoside analog can be administered simultaneously.

[0139] In other embodiments, the IRAK4 inhibitor or IRAK4 degrader may be administered first, the BCL-2 inhibitor second, and the nucleoside analog third.

[0140] In yet another embodiment, the IRAK4 inhibitor or IRAK4 degrading agent may be administered first, the BCL-2 inhibitor may be administered third, and the nucleoside analog may be administered second. In yet another embodiment, the IRAK4 inhibitor or IRAK4 degrading agent may be administered second, the BCL-2 inhibitor may be administered first, and the nucleoside analog may be administered third. In yet another embodiment, the IRAK4 inhibitor or IRAK4 degrading agent may be administered second, the BCL-2 inhibitor may be administered third, and the nucleoside analog may be administered first. In yet another embodiment, the IRAK4 inhibitor or IRAK4 degrading agent may be administered third, the BCL-2 inhibitor may be administered first, and the nucleoside analog may be administered second. In yet another embodiment, the IRAK4 inhibitor or IRAK4 degrading agent may be administered third, the BCL-2 inhibitor may be administered second, and the nucleoside analog may be administered first. In certain embodiments, the IRAK4 inhibitor or IRAK4 degrader, the BCL-2 inhibitor, and the nucleoside analog are administered within about 5 minutes to about 168 hours of each other.

[0141] In certain embodiments, the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog are administered simultaneously. In yet other embodiments, the IRAK4 inhibitor may be administered first, the BCL-2 inhibitor may be administered third, and the nucleoside analog may be administered second. In yet other embodiments, the IRAK4 inhibitor may be administered second, the BCL-2 inhibitor may be administered first, and the nucleoside analog may be administered third. In yet other embodiments, the IRAK4 inhibitor may be administered second, the BCL-2 inhibitor may be administered third, and the nucleoside analog may be administered first. In yet other embodiments, the IRAK4 inhibitor may be administered third, the BCL-2 inhibitor may be administered first, and the nucleoside analog may be administered second. In yet other embodiments, the IRAK4 inhibitor may be administered third, the BCL-2 inhibitor may be administered second, and the nucleoside analog may be administered first. In certain embodiments, the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog are administered within about 5 minutes to about 168 hours of each other.

[0142] In certain embodiments, the IRAK4 inhibitor or IRAK4 degrader and the nucleoside analog are administered simultaneously, hi other embodiments, the IRAK4 inhibitor and the nucleoside analog are administered within about 5 minutes to about 168 hours of each other.

[0143] In certain embodiments, the IRAK4 inhibitor and the nucleoside analog are administered simultaneously, hi other embodiments, the IRAK4 inhibitor and the nucleoside analog are administered within about 5 minutes to about 168 hours of each other.

[0144] Pharmaceutical Compositions The compositions and methods of the present disclosure can be utilized to treat individuals in need of treatment. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition, for example, comprising the 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 vehicles, such as glycols, glycerol, oils, such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized powders for reconstitution, powders, liquids, syrups, suppositories, injections, etc. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0145] Pharmaceutically acceptable carriers can include, for example, physiologically acceptable agents that act to stabilize, increase the solubility, or increase the absorption of a compound, such as the compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharma-ceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, in which, for example, the compound of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and are relatively easy to manufacture and administer.

[0146] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problems and complications, commensurate with a reasonable benefit / risk ratio.

[0147] The phrase "pharmacologically acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharma-ceutically 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil. and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffers, and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0148] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, orally (e.g., as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue, as aqueous or non-aqueous solutions or suspensions), absorption through the oral mucosa (e.g., sublingually), subcutaneously, transdermally (e.g., as a patch applied to the skin), and topically (e.g., as a cream, ointment, or spray applied to the skin). The compounds can also be prepared for inhalation. In certain embodiments, the compounds can be simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

[0149] The formulations can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0150] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, optionally shaping the product.

[0151] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (with flavored bases, usually sucrose and acacia or tragacanth), lyophilized powders, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as electuaries or syrups, or as pastilles (with inert bases, such as gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0152] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharma- ceutically 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 carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) sorbitol, ... Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarders, such as paraffin, (6) absorption enhancers, such as quaternary ammonium compounds, (7) wetting agents, such as cetyl alcohol and glycerol monostearate, (8) absorbents, such as kaolin and bentonite clay, (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, (10) complexing agents, such as modified and unmodified cyclodextrins, and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like.

[0153] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0154] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, can be prepared with coatings and shells, such as optionally scored or enteric coatings and other coatings known in the pharmaceutical formulation art. They can also be prepared to provide sustained or controlled release of the active ingredient therein, for example, using oxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres in various ratios to provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be compositions that release the active ingredient only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0155] Liquid dosage forms useful for oral administration include pharma- ceutically acceptable emulsions, lyophilized agents for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor oil, sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0156] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0157] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxylate, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0158] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0159] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal, vegetable and physical fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0160] Powders and sprays can contain, in addition to the active compounds, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0161] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be made by dissolving or dispersing active compound in suitable medium.Absorption enhancers can also be used to increase the flux of compound across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing compound in a polymer matrix or gel.

[0162] The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracystic, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into a sterile injectable solution or dispersion immediately prior to use and may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient or with suspending or thickening agents.

[0163] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0164] These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents in the compositions, such as sugars, sodium chloride, and the like. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0165] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injections in order to maintain the effect of the drug.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0166] Injectable depot forms are prepared by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0167] For use in the methods of the invention, the active compound may be provided per se or, for example, as a pharmaceutical composition containing 0.1-99.5% (more preferably 0.5-90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0168] The method of introduction can also be provided by refillable or biodegradable devices. For the controlled delivery of drugs, including proteinaceous biopharmaceuticals, various slow-release polymeric devices have been developed and tested in vivo in recent years. Various biocompatible polymers, including hydrogels, including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0169] The actual dosage level of the active ingredient in the pharmaceutical composition can be varied to provide an active ingredient effective to achieve a therapeutic response for a particular patient, composition, and mode of administration, without causing toxicity to the patient.

[0170] The selected dosage level will depend on a variety of factors, including factors well known in the medical art, such as, for example, the activity of the particular compound or combination of compounds, or esters, salts or amides thereof, being used, the route of administration, the time of administration, the rate of excretion of the particular compound being used, the duration of treatment, other drugs, compounds and / or substances being used in combination with the particular compound being used, the age, sex, weight, condition, general health and previous medical history of the patient being treated.

[0171] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dose of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of the compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered together with the compound of the present invention. Multiple administrations of the drug can deliver a large total dose. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0172] In general, a suitable daily amount of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective amount will generally depend upon the factors described above.

[0173] If necessary, the effective daily amount of the active compound may be administered as 1, 2, 3, 4, 5, 6 or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the invention, the active compound may be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day.

[0174] The patient to receive this treatment may be any animal in need of treatment, including primates, particularly humans; as well as other mammals, such as horses, cows, pigs, sheep, cats, and dogs; poultry; and common pets.

[0175] In certain embodiments, the compounds of the invention can be used alone or can be co-administered with another type of therapeutic agent.

[0176] The present disclosure includes the use of pharma- ceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, contemplated salts of the present invention include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptan ... Acids that may be used include, but are not limited to, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hipprinic acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenate.

[0177] Pharmaceutically acceptable acid addition salts may also exist as various solvates, with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent to the preparation or crystallization solvent, or exogenous to such solvent.

[0178] Wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0179] Examples of pharma- ceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0180] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. In general, the nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0181] The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and described in various general and more specific references cited and discussed throughout this specification, unless otherwise indicated. 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 ed.", WH Freeman & Co., New York (2000), Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", WH Freeman & Co., NY (1999), and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0182] As used herein, chemical terms, unless otherwise defined, are used according to conventional usage in the art, as exemplified by "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).

[0183] All of the above, and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including specific definitions, will control.

[0184] The term "agent" is used herein to refer to a compound (organic or inorganic compound, mixture of compounds, etc.), a biological macromolecule (nucleic acid, antibody, part thereof, as well as humanized, chimeric and human antibodies and monoclonal antibodies, protein or part thereof, e.g., peptide, lipid, carbohydrate), or an extract made from biological material such as a cell or tissue of bacteria, plant, fungus, or animal (especially mammalian). Agents include, for example, agents with known structure and agents with unknown structure. The ability of such agents to inhibit AR or promote AR degradation may qualify them as "therapeutic agents" in the methods and compositions of the present disclosure.

[0185] "Patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include mammals such as humans, primates, farm animals (including cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice, rats).

[0186] "Treating" a condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of disease, stable (i.e., not worsening) disease, prevention of disease spread, delay or slowing of disease progression, amelioration or palliation of disease symptoms, and remission (partial or complete). "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

[0187] The term "preventing" is art-recognized and, when used in reference to a condition such as local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is well understood in the art and includes administration of a composition that reduces the frequency or delays the onset of symptoms of the medical condition in a subject compared to subjects who do not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population relative to an untreated control population by a statistically and / or clinically significant amount.

[0188] "Administering" or "administration" of a substance, compound or agent to a subject can be performed using one of a variety of methods known in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ophthalmically, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through the skin tract). The compound or agent can also be suitably introduced by refillable or biodegradable polymeric or other devices, e.g., patches and pumps, or formulations that provide sustained, sustained, or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0189] The appropriate method of administering a substance, compound or agent to a subject also depends, for example, on the age and / or physical condition of the subject, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In certain embodiments, the compound or agent is administered to the subject orally, for example, by ingestion. In certain embodiments, the orally administered compound or agent is in a sustained or time-release formulation or is administered using a device for such sustained or time-release.

[0190] As used herein, the phrase "co-administration" refers to any form of administration of two or more different therapeutic agents, such that a second agent is administered while a previously administered therapeutic agent is still effective in the body (e.g., the two agents are effective on a patient at the same time, and a synergistic effect of the two agents may be involved). For example, the different therapeutic compounds may be administered simultaneously or sequentially, in the same formulation or in separate formulations. Thus, an individual undergoing such treatment may benefit from the combined effect of the different therapeutic agents.

[0191] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is a drug or agent that has an intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur in one administration, but may occur only after a series of administrations. Thus, a therapeutically effective amount can be administered in one or more administrations. The exact effective amount required by a subject depends, for example, on the subject's size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. Those skilled in the art can easily determine the effective amount for a given situation by routine experimentation.

[0192] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" refers to cases where the alkyl can be substituted as well as cases where the alkyl is not substituted.

[0193] It will be understood that one skilled in the art can select substituents and substitution patterns for the compounds of the present invention to provide chemically stable compounds that can be easily synthesized from readily available starting materials by techniques known in the art and those described below. It will be understood that when a substituent is itself substituted with multiple groups, such multiple groups can be present on the same carbon or on different carbons, so long as a stable structure results.

[0194] The term "optionally substituted" as used herein refers to one to six hydrogen radicals in a given structure being replaced with the radical of a specified substituent, including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl). Preferably, "optionally substituted" refers to one to four hydrogen radicals in a given structure being replaced with the aforementioned substituents. More preferably, one to three hydrogen radicals are replaced by the aforementioned substituents. It will be understood that the substituents may be further substituted.

[0195] As used herein, the term "alkyl" refers to saturated aliphatic groups, including, but not limited to, C-C 10 Straight chain alkyl group or C1-C 10 Branched alkyl groups are included. Preferably, the "alkyl" group refers to a C1-C6 straight chain alkyl group or a C1-C6 branched chain alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight chain alkyl group or a C1-C4 branched chain alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl, and the like. The "alkyl" group may be optionally substituted.

[0196] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0197] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0198] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0199] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0200] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0201] The term "alkyl" refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight-chain or branched-chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., C for straight chain). 1-30 , C for branched chains 3-30 ), more preferably having 20 or fewer carbon atoms.

[0202] Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups, such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0203] "C x-y " or "C x -Cy The term " when used in conjunction with a chemical moiety (such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy) is intended to include groups containing x to y carbons in the chain. C0 alkyl indicates a hydrogen when the group is in a terminal position and a bond when the group is internal. 1-6 An alkyl group contains, for example, 1 to 6 carbon atoms in the chain.

[0204] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0205] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0206] As used herein, the term "amide" [ka] This refers to the base, In the formula, R 9 and R 10 each independently represents a hydrogen or a hydrocarbyl group, or R taken together with the N atom to which it is attached 9 and R 10 completes a heterocycle having 4 to 8 atoms in the ring structure.

[0207] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, as well as salts thereof (e.g., [ka] (a part that can be represented by In the formula, R 9 , R 10 , and R 10 Each ' represents independently hydrogen or a hydrocarbyl group, and R taken together with the N atom to which it is attached 9 and R10 , completing a heterocycle having 4 to 8 atoms in the ring structure.

[0208] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0209] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0210] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is aromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0211] The term "carbamate" is art-recognized and [ka] This refers to the base, In the formula, R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.

[0212] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0213] The term "carbocycle" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an example embodiment, an aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, as valences permit. Examples of "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. Examples of fused carbocyclic rings include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocyclic ring" may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0214] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0215] The term "carbonate" is art-recognized and refers to the group -OCO2-.

[0216] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0217] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4-8 membered rings, more preferably 4-6 membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is a cycloalkyl, and the cycloalkyl ring may contain substituents (e.g., R 100 ) is added. For example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.

[0218] As used herein, the term "ester" refers to an ester of -C(O)OR 9 R 9 represents a hydrocarbyl group.

[0219] The term "ether" as used herein refers to a hydrocarbyl group linked to another hydrocarbyl group via oxygen. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers can include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0220] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0221] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0222] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, where the ring structure of such rings contains at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where at least one of the rings is heteroaromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0223] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0224] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0225] The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3-10 membered rings, more preferably 3-7 membered rings, whose ring structures contain at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is heterocyclic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0226] The term "hydrocarbyl" as used herein refers to a group bonded through a carbon atom that does not have =O or =S substituents, typically has at least one carbon-hydrogen bond and a primary carbon backbone, but may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for the purposes of this application, while substituents such as acetyl (having =O substituents on the linking carbon) and ethoxy (linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0227] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0228] The term "lower" when used in conjunction with chemical moieties (such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy) is meant to include groups in which the number of atoms present in the substituent is 10 or fewer, preferably 6 or fewer. "Lower alkyl" refers, for example, to alkyl groups containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, regardless of whether they are used alone or in combination with other substituents (such as when used in the descriptions hydroxyalkyl and aralkyl, where, for example, the atoms in the aryl group are not counted when counting the number of carbon atoms in the alkyl substituent).

[0229] The terms "polycyclyl", "polycycle", and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., such rings are "fused rings". Each ring of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms in the ring, preferably 5 to 7 atoms.

[0230] The term "sulfate" is art-recognized and refers to the group -OSO3H or a pharma- ceutically acceptable salt thereof.

[0231] The term "sulfonamide" is art-recognized and [ka] It refers to a group represented by the general formula: In the formula, R 9 and R 10independently represent hydrogen or hydrocarbyl.

[0232] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0233] The term "sulfonate" is art-recognized and refers to the group SO3H or a pharma- ceutically acceptable salt thereof.

[0234] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0235] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent, and that the substitution provides a stable compound (e.g., one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms (such as nitrogen) can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. Substituents may include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. Those skilled in the art will understand that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0236] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0237] As used herein, the term "thioester" refers to a -C(O)SR 9 Or -SC(O)R 9 This refers to the base, In the formula, R 9 represents hydrocarbyl.

[0238] The term "thioether" as used herein is the equivalent of an ether, where the oxygen is replaced by a sulfur.

[0239] The term "urea" is art-recognized and [ka] It can be represented by the general formula: In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0240] As used herein, the term "modulate" includes the inhibition or suppression of a function or activity (such as cell proliferation), as well as the enhancement of a function or activity.

[0241] The phrase "pharmacologically acceptable" is art-recognized. In certain embodiments, this term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problems and complications, commensurate with a reasonable benefit / risk ratio.

[0242] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a patient.

[0243] The term "pharmaceutically acceptable acid addition salts" as used herein refers to any non-toxic organic or inorganic salt of any base compound represented by formula 1. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Either mono- or di-acid salts can be formed, and such salts can exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of compounds of formula 1 are more soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points compared to their free base forms. The selection of an appropriate salt is known to those skilled in the art. Other non-pharmaceutical acceptable salts, such as oxalates, may be used, for example, in the isolation of compounds of formula 1 for laboratory use or for subsequent conversion to a pharmaceutical acceptable acid addition salt.

[0244] As used herein, the term "pharmaceutically acceptable basic addition salt" refers to any non-toxic organic or inorganic base addition salt of any acid compound represented by formula 1 or any of its intermediates. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline or ammonia. The selection of suitable salts is known to those skilled in the art.

[0245] Many of the compounds useful in the methods and compositions of the present disclosure have at least one asymmetric center in their structure. This asymmetric center can exist in the R or S configuration, and the R and S designations are used according to the rules set forth in Pure Appl.Chem.(1976),45,11-30. The present disclosure contemplates all stereoisomeric forms, including enantiomeric and diastereomeric forms of the compounds, salts, prodrugs, or mixtures thereof, including all possible mixtures of stereoisomers. See, for example, WO01 / 062726.

[0246] Furthermore, certain compounds containing alkenyl groups can exist as Z (Zusammen) or E (Entgegen) isomers, and in each case the present disclosure includes both mixtures and the separate individual isomers.

[0247] Some compounds may also exist in tautomeric forms. Such forms, although not explicitly shown in the formulae depicted herein, are intended to be included within the scope of the present disclosure.

[0248] "Prodrug" or "Pharmaceutically acceptable prodrug" refers to a compound that is metabolized (e.g., hydrolyzed or oxidized) in the host after administration to form a compound of the present disclosure (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group on the functional group of the active compound. Prodrugs include compounds that can undergo oxidation, reduction, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, reverse hydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation, or dephosphorylation to generate the active compound. Examples of prodrugs that use esters or phosphoramidates as biologically labile or cleavable (protecting) 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 the present disclosure are metabolized to generate a compound of formula I. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0249] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharma- ceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that is useful in formulating a drug for medicinal or therapeutic use.

[0250] 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 properties. Low solubility often leads to poor absorption. The LogS value is the unit stripped logarithm (base 10) of the solubility measured in mol / liter.

[0251] As used herein, the term "partial response" refers to a subject that has achieved a desired response in at least one organ or tissue, with no evidence of progression elsewhere.For example, partial response may refer to a greater than 50% reduction in disease state (e.g., tumor volume).

[0252] The term "complete response" as used herein means that the measurable evidence of disease in a subject completely disappears.For example, in certain embodiments, complete response can refer to the measurable complete disappearance of the cancer of a subject.In other embodiments, complete response can refer to the measurable complete disappearance of the symptoms of a subject (e.g., the cytokine measurement of a subject can return to normal).

[0253] The term "Compound 1" refers to [ka] Refers to... EXAMPLES

[0254] The invention will now be generally described, but will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting of the invention.

[0255] Example 1: Exemplary treatment of cancer using a combination of an IRAK-4 inhibitor, a Bcl-2 inhibitor, and a nucleoside analog Materials and Methods The antitumor efficacy of compound 1 was evaluated in combination with AML SOC drugs (daunorubicin, Ara-C, decitabine, azacitidine, and venetoclax) in FLT3-WT AML cell lines (THP-1, F-36P, OCl-AML2, and GDM-1) by performing a CellTiter Glo cell viability assay. The GI of each drug in AML cell lines was 50 The concentration at which 50% of the maximum cell growth inhibition was achieved was determined. 50 (less than peak plasma concentration) or peak plasma concentration (higher GI than peak plasma concentration)50 Either the 100mg or 150mg DMSO (if DMSO is high) was used as a clinically relevant concentration for combination experiments.

[0256] result The THP-1 and F-36P cell lines were found to be resistant to clinically relevant concentrations of venetoclax, while the OCl-AML2 cell line was found to be resistant to treatment with azacitidine (Table 1). A synergistic effect was observed by combining compound 1 with Ara-C in the THP-1 cell line. Compound 1 was found to enhance the antitumor effect of azacitidine in three of the four FLT3-WT AML cell lines, but no additive or synergistic effect was observed when compound 1 was combined with decitabine (Table 2). The combination of venetoclax and compound 1 efficiently suppressed cell proliferation in two of the four AML FLT3-WT cell lines compared with either of these two drugs alone. Furthermore, compound 1 was found to significantly enhance the antitumor effect of azacitidine + venetoclax in all AML FLT3-WT cell lines (Table 2). [Table 4] Cells were treated for 72 hours. Relative cell viability was measured by CellTiter Glo assay (Promega, Madison, WI) at 0 and 72 hours. GI 50 was calculated using GraphPad Prism 8.0 software. [Table 5]

[0257] Cells were treated continuously for 96 h with clinically relevant drug concentrations. At 0 and 96 h, relative cell viability was measured by CellTiter Glo assay (Promega, Madison, WI) according to the manufacturer's instructions. All values ​​are presented as mean ± SE. One-way ANOVA was used to analyze cell viability assay data. p values ​​< 0.05 were considered significant. Statistical analysis was performed using GraphPad Prism 8.0 software. + < 50% proliferation inhibition, p < 0.05; ++ 50-100% proliferation inhibition, p < 0.05; +++ induction of cell death (cytotoxic effect), p < 0.05; NS, not significant; ND, not determined. * Venetoclax-resistant cell lines, ** Azacitidine / decitabine resistant cell lines. Clinically relevant concentrations (peak plasma concentrations): compound 1-10 μM, venetoclax-1 μM, and azacitidine-4 μM.

[0258] summary These illustrative results demonstrate that the combination of Compound 1, azacitidine, and venetoclax exhibits synergistic activity in FLT3-WT leukemia cells and provide the rationale for clinically testing this combination in FLT3-WT AML patients.

[0259] Incorporation by Reference All publications and patents mentioned in this specification are herein incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including definitions herein, will control.

[0260] Equivalent Although specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the present disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. A pharmaceutical composition comprising an IRAK4 inhibitor for use in the treatment of cancer, the composition is for co-administration with a pyrimidinyl nucleoside analog and a BCL-2 inhibitor; The IRAK4 inhibitor has the formula (II): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein X １ and X ３ is independently CH or N; X ２ But, CR ２ or N, with the proviso that X １ , X ２ , or X ３ is N, A is O or S; Y is -CH ２ - or O, Z is aryl or heterocyclyl; R １ is, independently at each occurrence, halo or optionally substituted heterocyclyl, said substituents being alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR ａ R ｂ and R ２ is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR ａ R ｂ wherein the substituents are alkyl, amino, halo, or hydroxyl; R ３ is, for each occurrence, alkyl or hydroxyl; R ａ and R ｂ is independently hydrogen, alkyl, acyl, or heterocyclyl; "m" and "n" are independently 0, 1, or 2; "p" is 0 or 1; Pharmaceutical compositions.

2. A is O or S; Y is -CH ２ - or O, Z is aryl or heterocyclyl; R １ is, independently at each occurrence, halo or optionally substituted heterocyclyl, said substituents being alkyl, aminoalkyl, halo, or -NR ａ R ｂ and R ａ and R ｂ is independently hydrogen, alkyl, or heterocyclyl; R ２ is hydrogen, cycloalkyl, heterocyclyl, or -NR ａ R ｂ and "m" is 0, 2. The pharmaceutical composition for use according to claim 1, wherein "n" is 1.

3. A is O or S; Y is -CH ２ - or O, Z is aryl or heterocyclyl; R １ is, independently at each occurrence, halo or optionally substituted heterocyclyl, said substituents being alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ and R ａ and R ｂ is independently hydrogen, alkyl, or heterocyclyl; R ２ is hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR ａ R ｂ wherein the substituents are selected from amino, halo, or hydroxyl; "m" and "n" are independently 0, 1, or 2; 2. The pharmaceutical composition for use according to claim 1, wherein "p" is 0 or 1. 【Request 4】 【Chemical 2】 The part that says, 【Chemistry 3】 2. The pharmaceutical composition for use according to claim 1,

5. Z is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, and optionally substituted heterocyclyl selected from alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or -NR ａ R ｂ Optionally replaced by R ａ and R ｂ The pharmaceutical composition for use according to claim 1 , wherein is independently hydrogen, alkyl, or acyl.

6. The compound has formula (IIA): 【Chemistry 4】 2. The pharmaceutical composition for use according to claim 1, wherein the compound has a structure represented by:

7. A is O or S; Y is -CH ２ - or O, R １ is, independently at each occurrence, halo or optionally substituted heterocyclyl, said substituents being alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ and R ａ and R ｂ is independently hydrogen, alkyl, or heterocyclyl; R ２ is hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR ａ R ｂ wherein the substituents are selected from amino, halo, or hydroxyl; 7. The pharmaceutical composition for use according to claim 6, wherein "m" and "n" are independently 0, 1, or 2.

8. The compound has formula (IIB): 【Chemistry 5】 2. The pharmaceutical composition for use according to claim 1, wherein the compound has a structure represented by:

9. A is O or S; Y is -CH ２ - or O, R １ is, independently at each occurrence, halo or optionally substituted heterocyclyl, said substituents being alkyl, alkoxy, aminoalkyl, halo, hydroxyl, or -NR ａ R ｂ and R ａ and R ｂ is independently hydrogen, alkyl, or heterocyclyl; R ２ is hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR ａ R ｂ wherein the substituents are selected from amino, halo, or hydroxyl; 9. The pharmaceutical composition for use according to claim 8, wherein "m" and "n" are independently 0, 1, or 2.

10. The compound has the formula (IIC) 【Chemistry 6】 2. The pharmaceutical composition for use according to claim 1, wherein the compound has a structure represented by:

11. R １ is an optionally substituted heterocyclyl, said substituents being alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR ａ R ｂ and R ａ and R ｂ The pharmaceutical composition for use according to claim 1 , wherein is independently hydrogen or acyl.

12. R １ 12. The pharmaceutical composition for use according to claim 11, wherein is pyridyl, pyrazolyl, pyrrolidinyl, or piperidinyl.

13. R １ is an optionally substituted pyrazolyl, said substituents being alkyl, hydroxyl, or -NR ａ R ｂ 12. The pharmaceutical composition for use according to claim 11,

14. R １ The pharmaceutical composition for use according to claim 1 , wherein is halo.

15. R ２ is hydrogen, cycloalkyl, optionally substituted heterocyclyl, or -NR ａ R ｂ 2. The pharmaceutical composition for use according to claim 1, wherein said substituents are selected from amino, halo, or hydroxyl.

16. R ２ 2. The pharmaceutical composition for use of claim 1, wherein is an optionally substituted heterocyclyl selected from piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanyl, or azabicyclo[3.2.1]octanyl, said substituents being hydroxyl, halo, alkyl, or amino.

17. R ２ 2. The pharmaceutical composition for use according to claim 1, wherein is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl.

18. R ２ The pharmaceutical composition for use according to claim 1, wherein is hydrogen.

19. R ２ The pharmaceutical composition for use according to claim 1, wherein is cycloalkyl.

20. R ２ 20. The pharmaceutical composition for use according to claim 19, wherein is cyclopropyl.

21. R ３ The pharmaceutical composition for use according to claim 1, wherein is alkyl.

22. 2. The method of claim 1, wherein m is 0 and p is 1.

23. The compound of formula (II) 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 or a pharma- ceutically acceptable salt thereof.

24. 24. The pharmaceutical composition for use according to any one of claims 1 to 23, wherein the nucleoside analogue is azacytidine, decitabine, cytarabine, gemcitabine, 5'-deoxy-5-fluorouridine, fludarabine, cladribine, troxacitabine, or clofarabine.

25. The pharmaceutical composition for use according to any one of claims 1 to 23, wherein the cancer is a hematological malignancy.

26. 26. The pharmaceutical composition for use of claim 25, wherein the hematological malignancy is non-Hodgkin's lymphoma.

27. 26. The pharmaceutical composition for use of claim 25, wherein the hematological malignancy is leukemia or lymphoma.

28. The hematological malignancies include myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphoblastic leukemia (e.g., acute lymphoblastic leukemia), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., DLBCL or ABC-DLBLC), mantle cell lymphoma (MCL), Waldenstrom lymphoma (WCL), or leukemia (LE).

26. The pharmaceutical composition for use of claim 25, wherein the tumor is selected from the group consisting of Myeloma, Mondrian's macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt's lymphoma, non-Burkitt's 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.

29. 26. The pharmaceutical composition for use of claim 25, wherein the hematological malignancy is recurrent.

30. The pharmaceutical composition for use according to any one of claims 1 to 23, wherein the BCL-2 inhibitor is venetoclax.

31. A pharmaceutical composition for use according to any one of claims 1 to 23, wherein the BCL-2 inhibitor is venetoclax and the pyrimidinyl nucleoside analog is azacytidine.

32. A pharmaceutical composition for use according to any one of claims 1 to 23, wherein the BCL-2 inhibitor is venetoclax and the pyrimidinyl nucleoside analog is decitabine.

33. A pharmaceutical composition for use according to any one of claims 1 to 23, wherein the BCL-2 inhibitor is venetoclax and the pyrimidinyl nucleoside analog is cytarabine.

34. The IRAK4 inhibitor, 【Chemistry 7】 24. The pharmaceutical composition for use according to any one of claims 1 to 23, which is a medicament for treating or preventing osteoarthritis of the spinach, comprising the steps of:

35. The IRAK4 inhibitor, 【Chemistry 8】 24. The pharmaceutical composition for use according to any one of claims 1 to 23, which is a medicament for treating or preventing osteoarthritis of the spinach, comprising the steps of:

36. The IRAK4 inhibitor, 【Chemistry 9】 24. The pharmaceutical composition for use according to any one of claims 1 to 23, which is a medicament for treating or preventing osteoarthritis of the spinach, comprising the steps of:

37. The IRAK4 inhibitor, 【Chemistry 10】 24. The pharmaceutical composition for use according to any one of claims 1 to 23, which is a medicament for treating or preventing osteoarthritis of the spinach, comprising the steps of:

38. The IRAK4 inhibitor, 【Chemistry 11】 24. The pharmaceutical composition for use according to any one of claims 1 to 23, which is a medicament for treating or preventing osteoarthritis of the spinach, comprising the steps of:

39. The IRAK4 inhibitor, 【Chemistry 12】 24. The pharmaceutical composition for use according to any one of claims 1 to 23, which is a medicament for treating or preventing osteoarthritis of the spinach, comprising the steps of:

40. The IRAK4 inhibitor, 【Chemistry 13】 24. The pharmaceutical composition for use according to any one of claims 1 to 23, which is a medicament for treating or preventing osteoarthritis of the spinach, comprising the steps of:

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