HK40101281A - Combination therapies for the treatment of cancer - Google Patents

Description

Combination therapy for cancer

Related applications

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

Background Technology

Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a crucial role in signal transduction via the Toll/IL-1 receptor (TIR). Multiple IRAK enzymes are key components in signal transduction pathways mediated by the interleukin-1 receptor (IL-1R) and Toll-like receptors (TLRs) (Janssens, S et al., Mol. Cell. 11, 2003, 293–302). The mammalian IRAK family comprises four members: 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 interactions 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 triggered by activation of the IL-18 receptor (Kanakaraj et al., J. Exp. Med. 189(7): 1999, 1129-38) and those triggered by activation of the LPS receptor (Yang et al., J. Immunol. 163, 1999, 639-643). Of the four members of the mammalian IRAK family, IRAK4 is considered the “mother IRAK.” Under overexpression conditions, all IRAKs mediate activation of the nuclear factor-κB (NF-κB) and stress-induced mitogen-activated protein kinase (MAPK) signaling cascade amplification. However, only IRAK-1 and IRAK4 have been shown to possess active kinase activity. Although IRAK-1 kinase activity may be unnecessary for its function in IL-1-induced NF-κB activation (Kanakaraj et al., J. Exp. Med. 187(12), 1998, 2073–2079) and (Xiaoxia Li et al., Mol. Cell. Biol. 19(7), 1999, 4643–4652), IRAK4 signal transduction requires its kinase activity (Li S et al., Proc. Natl. Acad. Sci. USA 99(8), 2002, 5567–5572) and (Lye, E et al., J. Biol. Chem. 279(39); 2004, 40653–8). Given the central role of IRAK4 in Toll-like/IL-1R signaling and immune protection, IRAK4 inhibitors have been considered valuable therapeutic agents for inflammatory diseases, sepsis and autoimmune diseases (Wietek C et al., Mol. Interv. 2: 2002, 212–215).

Mice lacking IRAK4 survived and showed complete elimination of the production of inflammatory cytokines in response to IL-1, IL-18, or LPS (Suzuki et al., Nature, 416(6882), 2002, 750-756). Similarly, human patients lacking IRAK4 were severely immunocompromised and unresponsive to these cytokines (Medvedev et al., J. Exp. Med., 198(4), 2003, 521-531 and Picard et al., Science 299(5615), 2003, 2076-2079). Knock-in mice containing inactive IRAK4 were completely resistant to lipopolysaccharide and CpG-induced shock (Kim TW et al., JExp Med 204:2007, 1025-36) and (Kawagoe T et al., JExp Med 204(5):2007, 1013-1024) and showed that IRAK4 kinase activity is essential for cytokine production, MAPK activation and the induction of NF-κB-regulated genes in response to TLR ligands (Koziczak-Holbro M et al., J Biol Chem; 282(18):2007; 13552-13560). Inactivation of IRAK4 kinase (IRAK4 KI) in mice leads to resistance to EAE due to a reduction in inflammatory cells infiltrating the CNS and a decrease in antigen-specific CD4+ T cell-mediated IL-17 production (Kirk A et al., The Journal of Immunology, 183(1), 2009, 568-577).

Non-Hodgkin lymphoma (NHL) is the most common hematologic 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 theme is the overactivity of the NFκB signaling pathway. Specific molecular changes driving this pathway have been identified in subsets of NHL. For example, diffuse large B-cell lymphoma (hereinafter also referred to as “DLBCL”) is an aggressive lymphoma that can occur in or outside the lymphatic system, in the gastrointestinal tract, testes, thyroid gland, skin, breast, bone, or brain. DLBCL is a cancer of B cells, a type of white blood cell responsible for producing antibodies. It is the most common type of non-Hodgkin lymphoma in adults, occurring in 7–8 cases per 100,000 people annually. This cancer primarily occurs in older individuals, with a median age of diagnosis of approximately 70 years, but it can also occur in children and young adults in rare cases. DLBCL is an aggressive tumor, and the first symptom of the disease is usually the observation of a rapidly growing mass. The five-year survival rate is only 58%. DLBCL has subtypes named according to their cell origin and includes germinal center B-cell-like (GCB) and activated B-cell-like (ABC). They are distinguished by their poor prognosis and, in some cases, require specific treatments.

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

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

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

Summary of the Invention

In one aspect, this disclosure provides a method for treating a subject's cancer, the method comprising administering to the subject in combination an IRAK4 inhibitor or an IRAK4 degrader, a BCL-2 inhibitor, and a nucleoside analogue.

In another aspect, this disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject in combination an IRAK4 inhibitor or an IRAK4 degrader and a nucleoside analogue.

Simple Explanation of the Diagram

Figure 1A shows the efficacy of certain therapies 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 using CellTiter Glo assays (Promega, Madison, WI) according to the manufacturer's instructions. All values are expressed as mean ± SE. Cell viability data were analyzed using one-way ANOVA. A p-value less than 0.05 was considered significant. Statistical analysis was performed using GraphPadPrism 8.0 software. The combination of compound 1, azacitidine, and venetoclax showed synergistic efficacy.

Figure 1B shows the efficacy of certain therapies in the azacitidine-resistant OCI-AML2 cell line. Cells were treated continuously for 96 hours with clinically relevant drug concentrations. Relative cell viability was measured at 0 and 96 hours using a CellTiter Glo assay (Promega, Madison, WI) according to the manufacturer's instructions. All values are expressed as mean ± SE. Cell viability data were analyzed using one-way ANOVA. A p-value less than 0.05 was considered significant. Statistical analysis was performed using GraphPadPrism 8.0 software. The combination of compound 1, azacitidine, and venetoclax showed synergistic efficacy.

Detailed Implementation

IL-1R-associated kinase 4 (IRAK4) is a serine/threonine kinase and a key component of the myddosome complex. The myddosome is a crucial component of the innate immune system, transmitting intracellular signals from IL-1R and Toll-like receptors (TLRs) to induce NFκB activation. This pathway is also oncogenic in many malignancies. In over 90% of WM cases, a common activation missense mutation occurs in the adaptor protein myelodifferentiation primary response 88 (MYD88), where leucine is replaced by proline at position 265 (L265P), leading to uncontrolled proliferation. MYD88 consists of an N-terminal death domain, a median linker domain, and a C-terminal Toll/interleukin-1 receptor domain (Figure 2). Toll-like receptor (TLR) and interleukin-1 receptor family (IL-1R) signaling occur through MYD88. MYD88 is involved in the assembly and activation of IL-1R-associated kinase 4 (IRAK4), thereby stimulating the NF-κB-mediated anti-apoptotic signaling cascade. IL-1R-associated kinase 1 (IRAK1) is recruited by MYD88 through direct interaction with IRAK4 (the closest IRAK). IRAK1 activation ultimately leads to the formation of TRAF6-TAK1-IKK (tumor necrosis factor receptor-associated factor 6-transforming growth factor β-activated kinase 1-IkB kinase), activation of the NF-κB pathway, and promotion of cell survival.

Oncogenic signaling is transmitted via mydd bodies and requires IRAK4 for activation. TLRs are widely expressed on tumor cells, regulating growth and other tumor functions. MYD88 is a known oncogene that can be mutated in various malignancies and requires IRAK4. The long form of IRAK4 (IRAK4-L) is known to be oncogenic in AML and MDS, with over half of these cases overexpressing IRAK4-L. Compound 1 is the first clinical candidate targeting IRAK4 to be evaluated in cancer patients, and the evidence presented in this paper demonstrates that targeting IRAK4 produces anticancer activity in patients.

In one aspect, this disclosure provides a method for treating a subject's cancer, the method comprising administering to the subject in combination an IRAK4 inhibitor or an IRAK4 degrader, a BCL-2 inhibitor, and a nucleoside analogue.

In some preferred embodiments, the method includes administering a combination of an IRAK4 inhibitor, a BCL-2 inhibitor, and a nucleoside analog to a subject.

In another aspect, this disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject in combination an IRAK4 inhibitor or an IRAK4 degrader and a nucleoside analogue.

In some preferred embodiments, the method includes administering an IRAK4 inhibitor and a nucleoside analog to the subject in combination.

In some preferred embodiments, the IRAK4 inhibitor is present in other preferred embodiments.

In some preferred embodiments, the BCL-2 inhibitor is venetoc.

In some preferred embodiments, the nucleoside analog is azacitidine.

In certain particularly preferred embodiments, the IRAK4 inhibitor is

The BCL-2 inhibitor is venetoclax; and

The nucleoside analogue is azacitidine.

In other particularly preferred embodiments, the IRAK4 inhibitor is and

The nucleoside analogue is azacitidine.

This disclosed IRAK4 inhibitor

In some embodiments, the IRAK4 inhibitor has a structure represented by formula (I) or a pharmaceutically acceptable salt thereof:

Or its pharmaceutically acceptable salt;

in

_Z1 is an optional substituted heteroaryl group;

_Z2 is an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl group, or a direct bond;

_R1 is an alkyl, cyano, -NRa _{, Rb} , or optionally substituted group selected from cycloalkyl, aryl, or heterocyclic groups; wherein the substituent is independently alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO- _CH2 -O-alkyl, -OP(O)(O-alkyl) ₂ , or _-CH2 -OP(O)(O-alkyl) ₂ in each occurrence.

R ₂ is, in each instance, an independently selected substituted group chosen from alkyl or cycloalkyl groups; wherein the substituent is, in each instance, a halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl, or haloalkoxy group;

_R3 is independently hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NR _a R _b , hydroxy or hydroxyalkyl in each occurrence;

_Ra is hydrogen or alkyl;

_Rb is hydrogen, alkyl, acyl, hydroxyalkyl, _-SO₂ -alkyl, or optionally substituted cycloalkyl; and

'm' and 'n' are 1 or 2 independently.

In some embodiments, _Z1 is a 5- or 6-membered optional substituted heteroaryl group.

In some embodiments, _Z1 is an optional substituted heteroaryl group; wherein the optional substituent is an alkyl group.

In some embodiments, _Z1 is selected from tetrazolyl, thiophenyl, triazolyl, pyrroleyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, and pyrazolyl.

In some embodiments, _Z1 is selected from pyridinyl, oxazolyl, and furanyl; wherein the pyridinyl group is optionally substituted with an alkyl group; in particular, the alkyl group is methyl.

In some embodiments, _Z2 is selected from the following 5- or 6-membered heteroaryl groups: tetrazolyl, thiophenyl, triazolyl, pyrroleyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, or pyrazolyl.

In some embodiments, _Z2 is selected from the following 5- or 6-membered heterocyclic alkyl groups: aziridine, oxaziridine, imidazoalkyl, pyrrolidinyl, oxazolidinyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, or 1,4-dioxane.

In some embodiments, _Z2 is pyridyl, pyrazolyl, or pyrrolidinyl.

In some implementations, _Z2 is a direct bond.

In some implementations, the IRAK4 inhibitor has a structure represented by formula (IA):

Or its pharmaceutically acceptable salt.

In some implementations, the IRAK4 inhibitor has a structure represented by formula (IB):

Or its pharmaceutically acceptable salt.

In some implementations, the IRAK4 inhibitor has a structure represented by formula (IC):

Or its pharmaceutically acceptable salt.

In some implementations, is

In some implementations, _Z2 is pyridyl.

In some implementations, _Z2 is a pyrazolyl group.

In some embodiments, _Z2 is a pyrrolidinyl group.

In some embodiments, _R1 is an optionally substituted heterocyclic group; wherein the substituent is halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, -OCO-CH2- _O -alkyl, -OP(O)(O-alkyl) ₂ or _-CH2 -OP(O)(O-alkyl) ₂ .

In some embodiments, _R1 is optionally substituted aziridine, piperidinyl, morpholinyl, pyrrolidinyl or aziridine-heptyl; wherein the substituent is amino, halogen, hydroxyl, hydroxyalkyl, aminoalkyl, -OCO- _CH2 -O-alkyl, -OP(O)(O-alkyl) ₂ or _-CH2 -OP(O)(O-alkyl) ₂ .

In some embodiments, _R1 is an optionally substituted piperidinyl group; wherein the substituent is a hydroxyl group.

In some embodiments, _R1 is an optionally substituted phenyl group; wherein the substituent is a halogen.

In some embodiments, _R1 is a cycloalkyl group.

In some implementations, _R1 is cyclopropyl or cyclohexyl.

In some embodiments, _R1 is _-NRaRb ; _Ra is hydrogen; _Rb is an optionally substituted cycloalkyl group; wherein the substituent is a hydroxyl _group .

In some implementations, _R1 is a cyano group.

In some embodiments, _R2 is an optionally substituted alkyl group; wherein the substituent is an alkoxy group.

In some embodiments, _R2 is a cycloalkyl group.

In some embodiments, _R3 is hydrogen, halogen, alkyl, _alkoxy , _-NRaRb , hydroxyl, or hydroxyalkyl; _Ra is hydrogen or alkyl; and _Rb is hydrogen, alkyl, acyl, hydroxyalkyl, or _-SO2 -alkyl.

In some embodiments, _Z1 is an optionally substituted pyridyl group; _cycloZ2 is a pyridyl, pyrazolyl, pyrrolidinyl, or direct bond; _R1 is an optionally substituted group selected from cyclopropyl, piperidinyl, morpholinyl, or pyrrolidinyl; _R2 is an optionally substituted alkyl or cycloalkyl group; _R3 is hydrogen, halogen, alkyl, _alkoxy , _-NRaRb , hydroxyl, or hydroxyalkyl; _Ra is hydrogen or alkyl; and _Rb is hydrogen or hydroxyalkyl.

In some embodiments, _Z1 is oxazolyl; _Z2 is pyridinyl, pyrazolyl, or _pyrrolidinyl ; _R1 is cyano, _-NRaRb , or an optionally substituted group selected from cyclopropyl, cyclohexyl, phenyl, azacyclobutyl, piperidinyl, morpholinyl, or pyrrolidinyl; _R2 is an optionally substituted alkyl or cycloalkyl; _R3 is hydrogen, halogen, alkyl, alkoxy, _-NRaRb , hydroxy, _or hydroxyalkyl; _Ra is hydrogen or alkyl; _Rb is hydrogen, alkyl, acyl, hydroxyalkyl, _-SO2 -alkyl, or an optionally substituted cycloalkyl.

In some embodiments, _R3 is _-NRaRb ; _Ra is hydrogen or _alkyl ; _Rb is hydrogen, alkyl, acyl, hydroxyalkyl, _-SO2 -alkyl or optionally substituted cycloalkyl; wherein the optional substituent is hydroxyl;

In some implementations, 'n' is 1.

In some implementations, 'n' is 2.

In some implementations, 'm' is 1.

In some implementations, 'm' is 2.

In some implementations, the IRAK4 inhibitor is:

Or its pharmaceutically acceptable salts or stereoisomers.

In other embodiments, the IRAK4 inhibitor is represented by formula (II):

Or its pharmaceutically acceptable salt;

in,

_X1 and _X3 are independently CH or N; _X2 is _CR2 or N; the condition is that one or more of _X1 , _X2 or _X3 is N;

A is either O or S;

Y is _-CH2- or O;

Z is an aryl or heterocyclic group;

_R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxy, hydroxyalkyl or -NR _a R _b ;

_R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or -NR _a R _b ; wherein the substituent is alkyl, amino, halogroup or hydroxyl;

_R3 is either alkyl or hydroxyl in each occurrence;

_Ra and _Rb are independently hydrogen, alkyl, acyl, or heterocyclic groups;

'm' and 'n' are independently 0, 1, or 2; and

'p' is 0 or 1.

In some implementations, part of it is

In some implementations, Z is an aryl or a 5- or 6-membered heterocyclic group.

In some embodiments, Z is phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, azacyclobutane, oxacyclobutane, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxane, thiomorpholinyl dioxide, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophene, or dihydropyranyl; each of which is optionally substituted with an alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, or -NR _a R _b ; _Ra and R _b are independently hydrogen, alkyl, or acyl.

In some embodiments, Z is phenyl, oxazolyl, furanyl, thiophenyl, or pyridyl; each of which is optionally substituted by one or more _R1 .

In some implementations, is

In some implementations, the IRAK4 inhibitor has a structure represented by formula (OIA):

Or its pharmaceutically acceptable salt.

In some embodiments, the IRAK4 inhibitor has a structure represented by formula (IIB):

Or its pharmaceutically acceptable salt.

In some implementations, the IRAK4 inhibitor has a structure represented by formula (IIC):

Or its pharmaceutically acceptable salt.

In some implementations, Y is O or _CH2 .

In some embodiments, _R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl, or _-NRaRb ; _Ra and _Rb are independently hydrogen, alkyl _, or acyl.

In some embodiments, _R1 is pyridinyl, pyrazolyl, pyrrolidinyl, or piperidinyl; each of which is optionally substituted with an alkyl, alkoxy, _{halogen, hydroxy, hydroxyalkyl, or -NRaRb; Ra and Rb are independently hydrogen} or acyl.

In some implementations, _R2 is hydrogen.

In some embodiments, _R2 is an optional substituted cycloalkyl group.

In some implementations, _R2 is cyclopropyl.

In some embodiments, _R2 is an optionally substituted heterocyclic group; wherein the substituent is an alkyl, amino, halogen, or hydroxyl group.

In some embodiments, _R2 is piperidinyl, pyrrolidinyl, morpholinyl, piperazine, aziridine, pyrazolyl, furanyl, pyridinyl, aziridine-heptyl or aziridine-bicyclo[3.2.1]octyl; wherein the substituent is alkyl, amino, halogen or hydroxyl.

In some embodiments, _R2 is an optional aryl group; wherein the substituent is a halogen.

In some embodiments, _R2 is an optionally substituted phenyl group; wherein the substituent is fluorine.

In some embodiments, _R2 is _{-NRaRb ;} where _Ra and _Rb are independently hydrogen or heterocyclic groups.

In some embodiments, _R2 is _{-NRaRb ;} wherein _Ra and _Rb are independently hydrogen or pyrroloalkyl.

In some embodiments, A is O or S; Y is -CH _2- or O; R ₁ is a halogen, pyridyl, pyrazolyl, pyrrolidinyl, each optionally substituted with an alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl or -NR _a R _b ; R ₂ is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or -NR _a R _b ; wherein the substituent is alkyl, amino, halogen or hydroxyl; _Ra and R _b are independently hydrogen or alkyl.

In some embodiments, A is O or S; Y is -CH _2- or O; R ₁ is pyridyl, pyrazolyl, pyrrolidinyl; each of which is optionally substituted with alkyl, hydroxyl, hydroxyalkyl or -NR _a R _b ; _Ra and R _b are independently hydrogen; R ₂ is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or -NR _a R _b ; wherein the substituent is alkyl, amino, halogen or hydroxyl; _Ra and R _b are independently hydrogen, alkyl, acyl or heterocyclic.

In some implementations, 'n' is 0, 1, or 2.

In some implementations, 'p' is 0 or 1.

In some implementations, 'm' is 0 or 2.

In some implementations, the IRAK4 inhibitor is selected from:

Or its pharmaceutically acceptable salts or stereoisomers.

In some preferred embodiments, the IRAK4 inhibitor is (i.e., compound 1) or a pharmaceutically acceptable salt thereof.

In another embodiment, the IRAK4 inhibitor has a structure represented by formula (III):

Or its pharmaceutically acceptable salt;

in,

Z ₁ indicates that the substituted cycloalkyl group, the substituted aryl group, the substituted heterocyclic group, or the substituted group is absent;

Z ₂ represents an optional substituted cycloalkyl group, an optional substituted aryl group, or an optional substituted heterocyclic group;

R ₁ is hydrogen, optionally substituted alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl.

_R2 is, each time, an amino group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted arylalkyl group, or an optionally substituted heterocyclic alkyl group.

_R3 is, in each occurrence, a hydroxyl group, a halogen group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl group, or -NR _a R _b ;

_Ra and _Rb are, in each instance, independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl.

m is 0, 1, or 2 each time it appears; and

n is 0, 1, or 2 each time it appears.

In some embodiments, _Z1 is an optional substituted heterocyclic group.

In some embodiments, _Z1 represents a cycloalkyl, aryl, or heterocyclic group, which is optionally substituted by one or more substituents selected independently of hydroxyl, halogen, alkyl, cycloalkyl, or NR _a R _b each time it appears.

In some embodiments, _Z1 is an optionally substituted heteroaryl group; wherein the optional substituent is an alkyl or cycloalkyl group.

In some embodiments, _Z1 is tetrazolyl, thiophene, triazolyl, pyrrole, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazoleyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, benzoisooxazolyl, benzothiazolyl, benzofuranyl, benzothiophene, benzotriazinyl, phthalazinyl, thiathane, dibenzofuranyl, dibenzothiophene, benzimidazolyl, indoleyl, isoindole The following groups are included: 1, ...

In some embodiments, _Z1 is tetrazolyl, thiophenyl, triazolyl, pyrroleyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazoleyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, or pyrazolyl.

In some embodiments, _Z1 is pyridyl or oxazolyl; wherein the oxazolyl group is optionally substituted with an alkyl group; in particular, the alkyl group is methyl.

In some implementations, _Z1 is not present.

In some embodiments, _Z2 is a cycloalkyl, aryl, or heterocyclic group.

In some embodiments, _Z2 represents a cycloalkyl, aryl, or heterocyclic group, optionally substituted with one or more substituents selected from hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, _-NRaRb , or _cycloalkoxy .

In some implementations, _Z2 is a heterocyclic group.

In some embodiments, _Z2 is an azahexacyclobutane, oxacyclobutane, furanyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, 1,4-dioxane, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrazolyl, thiophene, triazolyl, pyrroloyl, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazoalkyl, imidazoyl, thiadiazoyl, thiazoyl, thiazoalkyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrroloalkyl, oxazolalkyl, pyrazolalkyl, benzoisooxazolyl, benzothiazoyl, benzofuranyl, benzothiaphenyl, benzotriazinyl, indolyl, isoindolyl, indolyl, quinolinyl, isoquinolinyl, pyrrolopyridinyl, or pyrazolopyrimidinyl.

In some embodiments, _Z2 is pyridyl, piperazine, pyrimidinyl, pyrrolidinyl, 1,2,3,4-tetrahydropyridyl, piperidinyl, pyrazolopyrimidinyl, or pyrrolopyridyl.

In some implementations, the IRAK4 inhibitor has a structure represented by formula (IIIA):

Or its pharmaceutically acceptable salt.

In some embodiments, the IRAK4 inhibitor has a structure represented by formula (IIIB):

Or its pharmaceutically acceptable salt.

In some implementations, the group is

In some implementations, _Z2 is pyridyl.

In some embodiments, _Z2 is a pyrrolidinyl group.

In some embodiments, _Z2 is piperidinyl, piperazine, tetrahydropyridinyl, pyrimidinyl, or pyrazolopyridinyl.

In some embodiments, _R1 is hydrogen, optionally substituted alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl.

In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein _R1 is an alkyl, cycloalkyl, aryl, heterocyclic, or aralkyl group, optionally substituted by one or more substituents selected independently of hydroxyl, halogen, alkyl, or hydroxyalkyl groups each time it appears.

In some embodiments, _R1 is a heterocyclic group; optionally substituted with a halogen, hydroxyl or hydroxyalkyl group.

In some embodiments, _R1 is optionally substituted with azahexacyclic butyl, piperidinyl, morpholinyl, pyrrolidinyl, or azaheptanyl.

In some embodiments, _R1 is a piperidinyl group optionally substituted with a hydroxyl group.

In some embodiments, R1 is a pyrroleyl group optionally substituted with a hydroxyl group.

In some embodiments, _R2 is, each time, an amino group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted arylalkyl group, or an optionally substituted heterocyclic alkyl group.

In some embodiments, _R2 is an alkyl, cycloalkyl, aryl, heterocyclic, arylalkyl, or heterocyclic alkyl group, optionally substituted by one or more substituents selected independently of alkyl, cycloalkyl, or heterocyclic groups each time it appears.

In some embodiments, _R2 is an optional substituted alkyl group, preferably methyl.

In some embodiments, _R2 is an optionally substituted cycloalkyl group, preferably cyclopropyl.

In some embodiments, _R3 is a hydroxyl group, a halogen group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl group, or -NR _a R _b each time it appears; wherein _Ra is hydrogen or an optionally substituted alkyl group; and R _b is hydrogen, an optionally substituted alkyl group, an optionally substituted acyl group, a hydroxyalkyl group, or -SO ₂ -alkyl group.

In some embodiments, _Z1 is an optionally substituted pyridyl group; _Z2 is a pyrrolidinyl group; _R1 is an optionally substituted group selected from piperidinyl or pyrrolidinyl; _R2 is an optionally substituted alkyl group; _R3 is a halogen, alkyl, -NR _a R _b , hydroxyl or hydroxyalkyl group; _Ra is hydrogen or alkyl; and _Rb is hydrogen or hydroxyalkyl.

In some embodiments, _Z1 is oxazolyl; _Z2 is pyridinyl, pyrimidinyl, or pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazine, or pyrrolopyridinyl; _R1 is an optionally substituted group selected from piperidinyl or pyrrolidinyl; _R2 is an optionally substituted alkyl or cyclopropyl; _R3 is a halogen, alkyl, alkoxy, _-NRaRb , hydroxyl, or hydroxyalkyl optionally substituted cyclopropyl; _Ra is hydrogen or alkyl; and _Rb is hydrogen, alkyl, acyl, hydroxyalkyl, _{-SO2 -} alkyl, or optionally substituted cycloalkyl.

In some implementations, 'm' is 0.

In some implementations, 'm' is 1.

In some implementations, 'm' is 2.

In some implementations, 'n' is 0.

In some implementations, 'n' is 1.

In some implementations, 'n' is 2.

In some implementations, the IRAK4 inhibitor is selected from:

Or its pharmaceutically acceptable salt.

In other implementations, the IRAK4 inhibitor is PF-06650833, BAY1830839, BAY1834845, R835, GS-5718, or ND-2158.

IRAK4 inhibitors (e.g., compound 1) can be administered in any amount or manner that elicits the desired response in a subject. For example, a subject may be given 100 mg to 400 mg of IRAK4 inhibitor twice daily, or a subject may be given 200 mg to 1000 mg of IRAK4 inhibitor once daily. In some embodiments, a subject may be given 100 mg to 400 mg of IRAK4 inhibitor twice daily. In some embodiments, a subject may be given 200 mg to 400 mg of IRAK4 inhibitor twice daily. In some preferred embodiments, a subject may be given 250 mg to 350 mg of IRAK4 inhibitor twice daily. In some implementations, subjects are given approximately 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg of an IRAK4 inhibitor twice daily. In some implementations, subjects are given approximately 50 mg, 75 mg, 100 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, or 400 mg of an IRAK4 inhibitor twice daily. In some implementations, subjects are given approximately 50 mg, 100 mg, 200 mg, or 300 mg of an IRAK4 inhibitor twice daily. In some embodiments, approximately 50 mg of IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 200 mg of IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 225 mg of IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 250 mg of IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 275 mg of IRAK4 inhibitor is administered to the subject twice daily. In a particularly preferred embodiment, approximately 300 mg of IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 325 mg of IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 350 mg of IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 375 mg of IRAK4 inhibitor is administered to the subject twice daily. In other embodiments, approximately 400 mg of IRAK4 inhibitor is administered to the subject twice daily.

In some implementations, a subject is given approximately 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg of an IRAK4 inhibitor once daily. In some implementations, a subject is given approximately 50 mg of an IRAK4 inhibitor once daily. In some implementations, a subject is given approximately 75 mg of an IRAK4 inhibitor once daily. In some implementations, a subject is given approximately 100 mg of an IRAK4 inhibitor once daily. In some implementations, a subject is given approximately 125 mg of an IRAK4 inhibitor once daily. In some implementations, a subject is given approximately 150 mg of an IRAK4 inhibitor once daily.

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

The IRAK4 degrading agent disclosed herein

In some embodiments, the method includes applying an IRAK4 degrading agent. In some embodiments, the IRAK4 degrading agent is KT-474, KYM-001, or IRAKMiD. In some embodiments, the IRAK4 degrading agent is the IRAK4 degrading agent disclosed in US 2019/0151295 A1, WO2019/133531 A1, WO 2020/113233 A1, and WO 2021/011868 A1, the contents of which are incorporated herein by reference in their entirety.

This disclosed BCL-2 inhibitor

The combinations disclosed herein can be used in combination with any BCL-2 inhibitor. In some preferred embodiments, the BCL-2 inhibitor is venetoclax. In some embodiments, 400 mg of venetoclax is administered daily. In some embodiments, venetoclax is administered orally.

The nucleoside analogues disclosed herein

The combinations disclosed herein can be used in combination with any nucleoside analogue. In some embodiments, the nucleoside analogue is a cytidine analogue. In some embodiments, the nucleoside analogue is azacitidine, decitabine, cytarabine, gemcitabine, 5'-deoxy-5-fluorouridine, fludarabine, cladribine, trisatatabine, or clofarabine. In some preferred embodiments, the nucleoside analogue is azacitidine. In some embodiments, azacitidine is administered at a dose of 75 mg/ ^m² daily. In some embodiments, azacitidine is administered at a dose of 100 mg/ ^m² daily. In some embodiments, azacitidine is administered subcutaneously. In other embodiments, azacitidine is administered at a dose of 300 mg daily. In some embodiments, azacitidine is administered orally.

This disclosure of cancer

In some implementations, cancer is a blood malignancy, such as leukemia or lymphoma, such as non-Hodgkin's lymphoma. In some implementations, hematologic malignancies are myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphoblastic leukemia (e.g., acute lymphoblastic leukemia), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., DLBCL or ABC-DLBLC), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt lymphoma, non-Burkkit high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, transformed high-grade B-cell lymphoma (HGBL), lymphoplasmacytic lymphoma (LPL), central nervous system lymphoma (CNSL), or MALT lymphoma. In some implementations, the hematologic malignancy is myeloid leukemia. In other embodiments, the hematologic malignancy is myeloid leukemia (e.g., acute myeloid leukemia). In some embodiments, the hematologic malignancy is acute myeloid leukemia (e.g., AML). In some embodiments, the AML is primary AML. In other embodiments, the AML is secondary AML. In some embodiments, the AML is resistant to treatment with an FMS-associated receptor tyrosine kinase 3 (FLT3) inhibitor. In some embodiments, the AML is associated with a mutation in the FLT3 kinase. In some embodiments, the mutation is an internal tandem repeat (ITD). In some embodiments, the mutation is a D835H, D835V, D835Y, K663Q, N841L, or F691L mutation. In some embodiments, the mutation is a D835Y mutation. In other embodiments, the hematologic malignancy is myelodysplastic syndrome (MDS). In some embodiments, the MDS is high-grade. In other embodiments, the MDS is low-grade. In some embodiments, the MDS is high-risk. In other embodiments, the hematologic malignancy is lymphoblastic leukemia (e.g., acute lymphoblastic leukemia). In other embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, CLL is high-risk CLL. In other embodiments, the hematologic malignancy is small lymphocytic lymphoma (SLL). In other embodiments, the hematologic malignancy is follicular lymphoma. In other embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In other embodiments, the hematologic malignancy is activated B-cell-like (ABC) DLBCL. In other embodiments, the hematologic malignancy is germinal center B-cell-like (GCB) DLBCL. In some embodiments, DLBCL is extranodal. In some embodiments, DLBCL is extranodal leg lymphoma, extranodal testicular lymphoma, or extranodal nonspecific (NOS) lymphoma. In other embodiments, the hematologic malignancy is mantle cell lymphoma. In yet another embodiment, the hematologic malignancy is Waldenström macroglobulinemia. In some embodiments, DLBCL or WM is characterized by an L265P mutation in MYD88. In other embodiments, the hematologic malignancy is multiple myeloma. In other embodiments, the hematologic malignancy is marginal zone lymphoma. In other embodiments, the hematologic malignancy is Burkitt lymphoma. In other embodiments, the hematologic malignancy is non-Burkitt high-grade B-cell lymphoma. In other embodiments, the hematologic malignancy is extranodal marginal zone B-cell lymphoma. In other embodiments, the hematologic malignancy is transformed high-grade B-cell lymphoma (HGBL). In other embodiments, the hematologic malignancy is lymphoplasmacytic lymphoma (LPL). In other embodiments, the hematologic malignancy is CNS lymphoma. In other embodiments, the CNS lymphoma is primary CNS lymphoma (PCNSL). In other embodiments, the hematologic malignancy is MALT lymphoma. In some embodiments, the above-mentioned hematologic malignancy is relapsed or refractory. In some embodiments, the above-mentioned hematologic malignancy is resistant to treatment with BTK inhibitors. In some embodiments, the aforementioned hematologic malignancies are resistant to treatment with BTK inhibitors as monotherapy. In some embodiments, the hematologic malignancies are resistant to treatment with ibrutinib, acalabrutinib, zanubrutinib, evatinib, ONO-4059, spetinib, or HM71224. In some preferred embodiments, the hematologic malignancies are resistant to treatment with ibrutinib.

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

The combinations disclosed herein can be used as first-line therapy or administered to patients who have not achieved a partial or complete response to one or more prior anticancer or anti-inflammatory therapies. In some embodiments, the subject has previously received at least one anticancer therapy. In some embodiments, the patient has previously received one anticancer therapy. In other embodiments, the patient has previously received two anticancer therapies. In other embodiments, the patient has previously received three anticancer therapies. In other embodiments, the patient has previously received four anticancer therapies. In other embodiments, the patient has previously received five anticancer therapies. In some embodiments, at least one anticancer therapy is selected from antiCD20 antibodies, nitrogen mustard, steroids, purine analogs, DNA topoisomerase inhibitors, DNA intercalating agents, microtubule inhibitors, BCL-2 inhibitors, proteasome inhibitors, Toll-like receptor inhibitors, kinase inhibitors, SRC kinase inhibitors, PI3K kinase inhibitors, BTK inhibitors, glutaminase inhibitors, PD-1 inhibitors, PD-L1 inhibitors, and methylating agents; or combinations thereof. In some embodiments, the anticancer therapy is selected from ibrutinib, rituximab, bendamustine, bortezomib, dexamethasone, chlorambucil, cladribine, cyclophosphamide, doxorubicin, vincristine, venetoclax, ifosfamide, prednisone, opzomib, ixazomib, acalatinib, zanubrutinib, IMO-08400, ederaris, ibritex, CB-839, fludarabine, and thalidomide; or combinations thereof. In some embodiments, the anticancer therapy is ibrutinib. In some embodiments, the anticancer therapy is ibrutinib and rituximab. In some embodiments, the anticancer therapy is bendamustine. In some embodiments, the anticancer therapy is bendamustine and rituximab. In some embodiments, the anticancer therapy is bortezomib. In some embodiments, the anticancer therapy is bortezomib and dexamethasone. In some embodiments, the anticancer therapy is bortezomib and rituximab. In some embodiments, the anticancer therapy is bortezomib, rituximab, and dexamethasone. In some embodiments, chlorambucil. In some embodiments, the anticancer therapy is cladribine. In some embodiments, the anticancer therapy is cladribine and rituximab. In some embodiments, the anticancer therapy is cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (i.e., CHOP-R). In some embodiments, the anticancer therapy is cyclophosphamide, prednisone, and rituximab (i.e., CPR). In some embodiments, the anticancer therapy is fludarabine. In some embodiments, the anticancer therapy is fludarabine and rituximab. In some embodiments, the anticancer therapy is fludarabine, cyclophosphamide, and rituximab. In some preferred embodiments, the anticancer therapy is rituximab. In some preferred embodiments, the anticancer therapy comprises rituximab. In some embodiments, the anticancer therapy is rituximab, cyclophosphamide, and dexamethasone (i.e., RCD). In some embodiments, the anticancer therapy is thalidomide. In some embodiments, the anticancer therapy is thalidomide and rituximab. In some embodiments, the anticancer therapy is venetoclax. In some embodiments, the anticancer therapy is cyclophosphamide, bortezomib, and dexamethasone (i.e., R-CyBorD). In some embodiments, the anticancer therapy is a hypomethylating agent. In some embodiments, the subject has previously received at least 6 cycles of a hypomethylating agent. In some embodiments, the anticancer therapy is any of the foregoing combinations, for example, the subject may first receive rituximab and then subsequently receive a combination of rituximab, cyclophosphamide, and dexamethasone (i.e., RCD).

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

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

Subjects may also have one or more pre-existing or developed gene mutations that make their cancer more or less resistant to therapy. In some embodiments, the subject has a mutation in RICTOR. In some embodiments, the subject has an N1065S mutation in RICTOR. In some preferred embodiments, the subject has a mutation in MYD88. In some, and even more preferred, embodiments, the subject has an L265P mutation in MYD88. In some embodiments, the subject has a mutation in TET2. In some embodiments, the subject does not have a mutation in CXCR4. In other embodiments, the subject has a mutation in CXCR4. In some embodiments, the subject shows early progression. In some embodiments, the subject has not previously received a BTK inhibitor.

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

Application method

IRAK4 inhibitors or IRAK4 degraders, BCL-2 inhibitors, and nucleoside analogs can be administered in various ways. For example, IRAK4 inhibitors or IRAK4 degraders, BCL-2 inhibitors, and nucleoside analogs can be administered simultaneously.

In other implementations, an IRAK4 inhibitor or IRAK4 degrader may be applied first, followed by a BCL-2 inhibitor, and finally a nucleoside analog.

In other embodiments, an IRAK4 inhibitor or IRAK4 degrader may be administered first, followed by a BCL-2 inhibitor, and then a nucleoside analogue. In other embodiments, an IRAK4 inhibitor or IRAK4 degrader may be administered secondarily, followed by a BCL-2 inhibitor, and then a nucleoside analogue. In other embodiments, an IRAK4 inhibitor or IRAK4 degrader may be administered secondarily, followed by a BCL-2 inhibitor, and then a nucleoside analogue. In other embodiments, an IRAK4 inhibitor or IRAK4 degrader may be administered last, followed by a BCL-2 inhibitor, and then a nucleoside analogue. In other embodiments, an IRAK4 inhibitor or IRAK4 degrader may be administered last, followed by a BCL-2 inhibitor, and then a nucleoside analogue. In some embodiments, the IRAK4 inhibitor or IRAK4 degrader, the BCL-2 inhibitor, and the nucleoside analogue are administered to each other within approximately 5 minutes to approximately 168 hours.

In some embodiments, the IRAK4 inhibitor, BCL-2 inhibitor, and nucleoside analogue are administered simultaneously. In other embodiments, the IRAK4 inhibitor may be administered first, followed by the BCL-2 inhibitor, and then the nucleoside analogue. In other embodiments, the IRAK4 inhibitor may be administered second, followed by the BCL-2 inhibitor, and then the nucleoside analogue. In other embodiments, the IRAK4 inhibitor may be administered second, followed by the BCL-2 inhibitor, and then the nucleoside analogue. In other embodiments, the IRAK4 inhibitor may be administered last, followed by the BCL-2 inhibitor, and then the nucleoside analogue. In other embodiments, the IRAK4 inhibitor may be administered last, followed by the BCL-2 inhibitor, and then the nucleoside analogue. In some embodiments, the IRAK4 inhibitor, BCL-2 inhibitor, and nucleoside analogue are administered to each other within approximately 5 minutes to approximately 168 hours.

In some embodiments, the IRAK4 inhibitor or IRAK4 degrader and the nucleoside analog are administered simultaneously. In other embodiments, the IRAK4 inhibitor and the nucleoside analog are administered to each other over approximately 5 minutes to approximately 168 hours.

In some embodiments, the IRAK4 inhibitor and the nucleoside analogue are administered simultaneously. In other embodiments, the IRAK4 inhibitor and the nucleoside analogue are administered to each other within approximately 5 minutes to approximately 168 hours.

Pharmaceutical Composition

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

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

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

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

The pharmaceutical composition (formulation) can be administered to a subject via any of a variety of routes of administration, including oral (e.g., as an lavage in an aqueous or non-aqueous solution or suspension, tablets, capsules (including spray capsules and gelatin capsules), pills, powders, granules, or pastes applied to the tongue); absorption through the oral mucosa (e.g., sublingual); subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment, or spray applied to the skin). The compound can also be formulated for inhalation. In some embodiments, the compound can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions applicable thereto can be found, for example, in U.S. Patent Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896 and the patents referenced therein.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In some embodiments, the intended salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In some embodiments, the intended salts of the present invention include, but are not limited to, L-arginine, benzylamine, benzathine, betaine, calcium hydroxide, choline, tannin, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, hepatoside, 1H-imidazolium, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In some embodiments, the intended salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In some embodiments, the intended salts of the present invention include, but are not limited to, 1-hydroxy-2-naphtholic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetaminobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, caprylic acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (caprylic acid), carbonic acid, cinnamic acid, citric acid, cyclohexylaminosulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, etc. Acids, galactobionic acid, gentic acid, d-glucoheptanoic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutamate, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, and undecanoic acid salts.

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

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

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

definition

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

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

Unless otherwise defined herein, chemical terms used herein are used in accordance with conventional usage in the art, for example, in “The McGraw-Hill Dictionary of Chemical Terms”, edited by Parker S., McGraw-Hill, San Francisco, C.A. (1985).

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

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

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

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

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

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

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

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

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

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

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

As used herein, the term "optionally substituted" means that one to six hydrogen groups in a given structure are substituted by a group including, but not limited to, the specified substituents: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO- _CH₂ -O-alkyl, -OP(O)(O-alkyl) _₂ , or _–CH₂ -OP(O)(O-alkyl) _₂ . Preferably, "optionally substituted" means that one to four hydrogen groups in a given structure are substituted by the aforementioned substituents. More preferably, one to three hydrogen groups are substituted by the aforementioned substituents. It should be understood that the substituents may be further substituted.

As used herein, the term "alkyl" refers to a saturated aliphatic group, including but not limited to _C1 - _C10 straight-chain alkyl or _C1 - _C10 branched alkyl. Preferably, "alkyl" refers to _C1 - _C6 straight-chain alkyl or _C1 - _C6 branched alkyl. Most preferably, "alkyl" refers to _C1 - _C4 straight-chain alkyl or _C1 -C4 branched alkyl. 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. "alkyl" may optionally be substituted.

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

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

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

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

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

The term "alkyl" refers to a saturated aliphatic group, including straight-chain alkyl, branched alkyl, cycloalkyl (alicyclic), alkyl-substituted cycloalkyl, and cycloalkyl-substituted alkyl. In a preferred embodiment, the straight-chain or branched alkyl group has 30 or fewer carbon atoms in its main chain (e.g., _C1-30 for straight chains and _C3-30 for branched chains), more preferably 20 or fewer.

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

When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "C_{_xy}" or "C <sub>_x -C_{_y}" is intended to include groups containing x to y carbon atoms in the chain. _C₀ alkyl indicates a hydrogen atom at the terminal position of the group, or a bond if it is internal. For example, C _₁-6 alkyl groups contain one to six carbon atoms in the chain.

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

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

As used herein, the term "amide" refers to a group.

^R9 and ^R10 each independently represent hydrogen or hydrocarbon groups, or ^R9 and ^R10 together with the N atom they are attached to form a heterocycle with 4 to 8 atoms in the ring structure.

The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines and their salts, for example, they can be represented as

Part of

^R9 , ^R10 , and ^R10 ' each independently represent a hydrogen or hydrocarbon group, or ^R9 and ^R10 together with the N atom they are attached to form a heterocycle with 4 to 8 atoms in the ring structure.

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

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

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

The term "carbamate" is recognized in the art and refers to a group...

^R9 and ^R10 independently represent hydrogen or hydrocarbon groups.

As used herein, the term "carbocycloalkyl" refers to an alkyl group that has been substituted with a carbocycloyl group.

The term "carbocyclic ring" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocyclic ring may be self-saturated, unsaturated, or aromatic. Carbocyclic rings include bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocyclic ring may be self-saturated, unsaturated, or aromatic. In exemplary embodiments, an aromatic ring (e.g., phenyl) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, where valence allows. Exemplary "carbocyclic rings" include cyclopentane, cyclohexane, bicyclic [2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclic [4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include naphthane, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. The “carbocyclic ring” may be substituted at any one or more positions capable of carrying a hydrogen atom.

As used herein, the term "carbocycloalkyl" refers to an alkyl group that has been substituted with a carbocycloyl group.

The term "carbonate" is recognized in the art and refers to the group -OCO _2- .

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

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

As used herein, the term "ester" refers to the group -C(O) ^OR9 , where ^R9 represents a hydrocarbon group.

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

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

As used herein, the terms “heteroaryl alkyl” and “heteroaryl alkyl” refer to alkyl groups substituted with heteroaryl groups.

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

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

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

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

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

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

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

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

The term “sulfate” is recognized in the art and refers to the group _–OSO3H or its pharmaceutically acceptable salt.

The term "sulfonamide" is recognized in the art and refers to sulfonamides made from the general formula

The group represented,

^R9 and ^R10 independently represent hydrogen or hydrocarbon groups.

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

The term "sulfonate" is recognized in the art and refers to the group _SO3H or its pharmaceutically acceptable salt.

The term "sulfone" is recognized in the art and refers to the group –S(O) _2- .

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

As used herein, the term "thioalkyl" refers to an alkyl group that has been substituted with a thiol group.

As used herein, the term "thioester" refers to the group -C(O) ^SR9 or –SC(O) ^R9.

R ⁹ represents a hydrocarbon group.

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

The term "urea" is recognized in the art and can be represented by a general formula.

^R9 and ^R10 independently represent hydrogen or hydrocarbon groups.

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

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

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

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

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

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

Furthermore, certain alkenyl-containing compounds may exist as Z (iso-isomers) or E (trans-isomers). In each case, this disclosure includes mixtures and individual isomers.

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

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

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

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

As used in this article, the term "partial response" refers to an objective response in at least one organ or tissue of the subject, with no evidence of progression elsewhere. For example, a partial response could refer to a disease state (e.g., a reduction in tumor volume) of 50% or more.

As used herein, the term "complete response" means the complete disappearance of measurable evidence of a subject's disease. For example, in some embodiments, a complete response may mean the complete and measurable disappearance of a subject's cancer. In other embodiments, a complete response may mean the complete and measurable disappearance of a subject's symptoms (e.g., the return of a subject's cytokine count to normal).

The term "compound 1" refers to

Example

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

Example 1: Exemplary treatment of cancer using a combination of IRAK-4 inhibitors, Bcl-2 inhibitors, and nucleoside analogs.

Materials and methods

CellTiter Glo cell viability assays were used to evaluate the antitumor effects of compound 1 in combination with the AML SOC drugs daunorubicin, Ara-C, decitabine, azacitidine, and venetoc in FLT3-WT AML cell lines THP-1, F-36P, OCl-AML2, and GDM-1. The GI ₅₀ (concentration at which 50% maximum cell proliferation inhibition) of each drug was determined in the AML cell lines. The GI ₅₀ (below peak plasma concentration) or peak plasma concentration (if GI ₅₀ is above peak plasma concentration) of each drug was used as the clinically relevant concentration for the combination assay.

result

We determined that the THP-1 and F-36P cell lines were resistant to clinically relevant concentrations of venetoclax, while the OCl-AML2 cell line was resistant to azacitidine treatment (Table 1). A synergistic effect of compound 1 in combination with Ara-C was observed in the THP-1 cell line. We found that compound 1 enhanced the antitumor activity of azacitidine in three of the four FLT3-WT AML cell lines, while we did not observe any additive or synergistic effect of compound 1 in combination with decitabine (Table 2). The combination of venetoclax and compound 1 inhibited cell growth more effectively in two of the four AML FLT3-WT cell lines than either agent alone. Furthermore, we found that compound 1 significantly enhanced the antitumor activity of azacitidine + venetoclax in all AML FLT3-WT cell lines (Table 2).

Table 1. GI50 (μM) of Compound 1 and Standard Care Medications for AML

Cells were treated within 72 hours. Relative cell viability was measured at 0 and 72 hours using CellTiterGlo assays (Promega, Madison, WI). GI ₅₀ was calculated using GraphPadPrism 8.0 software.

Table 2. Exemplary combination therapies

Cells were treated continuously for 96 hours at clinically relevant drug concentrations. Relative cell viability was measured at 0 and 96 hours by CellTiterGlo assay (Promega, Madison, WI) according to the manufacturer's instructions. All values are expressed as mean ± SE. Cell viability data were analyzed using one-way ANOVA. A p-value less than 0.05 was considered significant. Statistical analysis was performed using GraphPadPrism 8.0 software. + Growth inhibition less than 50%, p < 0.05; ++ 50-100% growth inhibition, p < 0.05; +++ Induction of cell death (cytotoxicity), p < 0.05; NS, not significant; ND, undefined. *Venetoc-resistant cell lines, **Azacitidine/decitabine-resistant cell lines. Clinically relevant concentrations (peak plasma concentrations): Compound 1–10 μM; Venetoc -1 μM; and Azacitidine -4 μM.

Overview

These exemplary results demonstrate that the combination of compound 1, azacitidine, and venetoclax exhibits synergistic activity in FLT3-WT leukemia cells, providing a theoretical basis for clinical testing of this combination in FLT3-WT AML patients.

Incorporate by reference

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

Equivalent implementation plan

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

Claims (207)

1. A method of treating a subject with cancer, the method comprising administering to the subject in combination an IRAK4 inhibitor or an IRAK4 degrader and a nucleoside analogue. 2. The method of claim 1, wherein the method comprises administering an IRAK4 inhibitor and a nucleoside analog to the subject in combination. 3. A method of treating a subject's cancer, the method comprising administering to the subject in combination an IRAK4 inhibitor or an IRAK4 degrader, a BCL-2 inhibitor, and a nucleoside analogue. 4. The method of claim 3, wherein the method comprises administering to the subject in combination an IRAK4 inhibitor, a BCL-2 inhibitor, and a nucleoside analogue. 5. The method according to any one of claims 1-4, wherein the IRAK4 inhibitor has a structure represented by formula (I): Or its pharmaceutically acceptable salt; in, _Z1 is an optional substituted heteroaryl group; _Z2 is an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl group, or a direct bond; _R1 is _an alkyl, cyano, _-NRaRb or an optionally substituted group selected from cycloalkyl, aryl or heterocyclic groups; wherein the substituent is independently alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl) ₂ or _-CH2 -OP(O)(O-alkyl) ₂ in _each occurrence; _R2 is, in each instance, an optional substituted group selected from alkyl or cycloalkyl; wherein the substituent is, in each instance, a halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl, or haloalkoxy. _R3 is independently hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NR _a R _b , hydroxy or hydroxyalkyl in each occurrence; _Ra is hydrogen or alkyl; _Rb is hydrogen, alkyl, acyl, hydroxyalkyl, _-SO₂ -alkyl, or optionally substituted cycloalkyl; and 'm' and 'n' are 1 or 2 independently. 6. The method of claim 5, wherein _Z1 is a 5-membered or 6-membered heteroaryl group. 7. The method of claim 5 or 6, wherein _Z1 is an optionally substituted heteroaryl group, wherein the optional substituent is an alkyl group. 8. The method according to any one of claims 5-7, wherein _Z1 is tetrazolyl, thiophenyl, triazolyl, pyrroleyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazoleyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, and pyrazolyl. 9. The method according to any one of claims 5-8, wherein _Z1 is selected from pyridinyl and oxazolyl. 10. The method of claim 5, wherein the compound is represented by formula (IA). Or its pharmaceutically acceptable salt. 11. The method of claim 5, wherein the compound is represented by formula (IB). Or its pharmaceutically acceptable salt. 12. The method of claim 5, wherein the compound is represented by formula (IC). Or its pharmaceutically acceptable salt. 13. The method according to any one of claims 5-12, wherein _Z2 is a 5- or 6-membered heterocyclic alkyl or a 5- or 6-membered heteroaryl. 14. The method according to any one of claims 5-13, wherein _Z2 is a heterocyclic alkyl group or a direct bond. 15. The method of any one of claims 5-13, wherein _Z2 is an azacyclobutane, oxacyclobutane, imidazoalkyl, pyrrolyl, oxazolyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxane, tetrazolyl, thiopheneyl, triazolyl, pyrrolyl, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperazinyl, imidazoyl, oxadiazolyl, thiazoyl, isothiazolyl, oxazolyl, furanyl, and pyrazolyl. 16. The method of any one of claims 5-13, wherein _Z2 is pyridyl, pyrazolyl, pyrrolidinyl, or a direct bond. 17. The method of any one of claims 5-14, wherein _Z2 is a direct bond. 18. The method of any one of claims 5-17, wherein m is 1 and n is 1 or 2. 19. The method of any one of claims 5-18, wherein m and n are each 1. 20. The method according to any one of claims 5-19, wherein _R1 is selected from cyano, cycloalkyl, halogen, _-NRaRb , _aryl and heterocyclic groups. 21. The method according to any one of claims 5-20, wherein _R1 is selected from cyano, cycloalkyl, aryl, and heterocyclic groups. 22. The method according to any one of claims 5-21, wherein _R1 is selected from cyclopropyl, cyclohexyl, piperidinyl, and morpholinyl. 23. The method of any one of claims 5-21, wherein _R1 is an optionally substituted heterocyclic group; wherein the substituent is a halogen, hydroxyl, hydroxyalkyl, or amino group. 24. The method of any one of claims 5-21, wherein _R1 is optionally substituted azahexacyclic butyl, piperidinyl, morpholinyl, pyrrolidinyl, or azaheptanyl. 25. The method of any one of claims 5-21, wherein _R1 is optionally substituted piperidinyl or morpholinyl. 26. The method of any one of claims 5-21, wherein _R1 is an optionally substituted phenyl group; wherein the substituent is a halogen. 27. The method of any one of claims 5-21, wherein _R1 is cyano or cycloalkyl. 28. The method of any one of claims 5-22, wherein _R1 is cyclopropyl or cyclohexyl. 29. The method of any one of claims 5-20, wherein _R1 is _-NRaRb ; _Ra is _hydrogen ; _Rb is an optionally substituted cycloalkyl group; and wherein the substituent is a hydroxyl group. 30. The method of any one of claims 5-29, wherein _R2 is an optionally substituted alkyl group and the substituent is an alkoxy group. 31. The method according to any one of claims 5-29, wherein _R2 is cyclopropyl or cyclopentyl. 32. The method according to any one of claims 5-31, wherein _R3 is hydrogen, halogen, alkyl, alkoxy, -NR _a R _b , hydroxyl or hydroxyalkyl. 33. The method according to any one of claims 5-32, wherein _R3 is selected from hydrogen, halogen, alkyl, alkoxy and hydroxyl. 34. The method according to any one of claims 5-32, wherein _R3 is selected from hydrogen, alkyl and _{-NRaRb .} 35. The method of any one of claims 5-32, wherein _R3 is H. 36. The method of claim 5, wherein the compound of formula (I) is selected from: Or its pharmaceutically acceptable salts or stereoisomers. 37. The method of claim 5, wherein the compound of formula (I) is selected from: N-(2-Cyclopentyl-6-morpholinyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridinecarboxamide; N-(6-(4-hydroxypiperidin-1-yl)-2,3-dimethyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; and N-(2-cyclopentyl-6-cyclopropyl-2H-indazole-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridinecarboxamide. 38. The method of claim 5, wherein the compound of formula (I) is selected from: N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)oxazol-4-carboxamide; N-(6-(4-(aminomethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; and (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(3-hydroxypyrrolidine-1-yl)pyridinecarboxamide. 39. The method of any one of claims 1-4, wherein the IRAK4 inhibitor has a structure represented by formula (II): Or its pharmaceutically acceptable salt; in _X1 and _X3 are independently CH or N; _X2 is _CR2 or N; the condition is that one or more of _X1 , _X2 or _X3 is N; A is O or S; Y is _-CH2- or O; Z is an aryl or heterocyclic group; _R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogroup, hydroxy, hydroxyalkyl or -NR _a R _b ; _R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or _-NRaRb ; wherein the substituent is alkyl, amino, halogroup or _hydroxyl . _R3 is either alkyl or hydroxyl in each occurrence; _Ra and _Rb are independently hydrogen, alkyl, acyl, or heterocyclic groups; 'm' and 'n' are independently 0, 1 or 2; 'p' is 0 or 1. 40. The method of claim 39, wherein A is O or S; Y is _-CH2- or O; Z is an aryl or heterocyclic group; _R1 is independently a halogroup or _{an optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogroup or -NRaRb; wherein Ra and Rb are independently hydrogen} , alkyl or heterocyclic groups; _R2 is hydrogen, cycloalkyl, heterocyclic, or _{-NRaRb ;} 'm' is 0; and 'n' is 1. 41. The method of claim 39, wherein A is O or S; Y is _-CH2- or O; Z is an aryl or heterocyclic group; _R1 is independently a halogroup or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl or -NR _a R _b ; wherein _Ra and R _b are independently hydrogen, alkyl or heterocyclic group; _R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group or _-NRaRb , wherein the substituent is selected from amino, halogen or hydroxyl _groups ; 'm' and 'n' are independently 0, 1, or 2; and 'p' is 0 or 1. 42. The method of claim 39, wherein the portion is 43. The method according to any one of claims 39-42, wherein Z is an aryl or a 5- or 6-membered heterocyclic group. 44. The method of any one of claims 39-43, wherein Z is an optionally substituted heterocyclic group selected from the following: phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrazinyl, pyridazinyl, azacyclic butyl, oxacyclic butyl, imidazolyl, pyrrolyl, Oxazolyl, thiazolyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxyl, thiomorpholinyl dioxide, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl and azabicyclo[3.2.1]octyl; each of which is optionally substituted with an alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl or -NR _a R _b ; and _Ra and R _b are independently hydrogen, alkyl or acyl. 45. The method of claim 39, wherein the compound has a structure represented by formula (IIA): Or its pharmaceutically acceptable salt. 46. The method of claim 45, wherein A is O or S; Y is _-CH2- or O; _R1 is independently a halogroup or _{an optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogroup or -NRaRb; wherein Ra and Rb are independently hydrogen} , alkyl or heterocyclic groups; _R2 is hydrogen, cycloalkyl, heterocyclic, or _{-NRaRb ;} 'm' is 0; and 'n' is 1. 47. The method of claim 45, wherein A is O or S; Y is _-CH2- or O; _R1 is independently a halogroup or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl or -NR _a R _b ; wherein _Ra and R _b are independently hydrogen, alkyl or heterocyclic group; _R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or _-NRaRb , wherein the substituent is selected from amino, halo, or hydroxyl _groups ; and 'm' and 'n' are independently 0, 1, or 2. 48. The method of claim 39, wherein the compound has a structure represented by formula (IIB): Or its pharmaceutically acceptable salt. 49. The method of claim 48, wherein A is O or S; Y is _-CH2- or O; _R1 is independently a halogroup or _{an optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogroup or -NRaRb; wherein Ra and Rb are independently hydrogen} , alkyl or heterocyclic groups; _R2 is hydrogen, cycloalkyl, heterocyclic, or _{-NRaRb ;} and 'n' is 1. 50. The method of claim 48, wherein A is O or S; Y is _-CH2- or O; _R1 is independently a halogroup or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl or -NR _a R _b ; wherein _Ra and R _b are independently hydrogen, alkyl or heterocyclic group; _R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or _-NRaRb , wherein the substituent is selected from amino, halo, or hydroxyl _groups ; and 'm' and 'n' are independently 0, 1, or 2. 51. The method of claim 39, wherein the compound has a structure represented by formula (IIC). Or its pharmaceutically acceptable salt. 52. The method of any one of claims 39-51, wherein _R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl, or _-NRaRb ; and _Ra and _Rb are independently hydrogen or acyl _groups . 53. The method of any one of claims 39-51, wherein _R1 is an optionally substituted heterocyclic group; wherein the substituent is an alkyl, aminoalkyl, halogroup or _-NRaRb ; and _Ra and _Rb are independently hydrogen or _acyl groups. 54. The method of any one of claims 39-51, wherein _R1 is _{an optionally substituted heterocyclic group; and the substituent is an alkyl, aminoalkyl, halogroup or -NRaRb; wherein Ra and Rb are independently hydrogen} , alkyl or heterocyclic groups. 55. The method of any one of claims 39-51, wherein _R1 is an optionally substituted heterocyclic group; and the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or _-NRaRb ; wherein _Ra and _Rb are independently _hydrogen , alkyl, or heterocyclic groups. 56. The method of any one of claims 52-55, wherein _R1 is pyridyl, pyrazolyl, pyrrolidinyl, or piperidinyl. 57. The method of claims 52-56, wherein _R1 is _an optionally substituted pyrazolyl group, wherein the substituent is an alkyl, hydroxyl, or _-NRaRb . 58. The method of any one of claims 39-51, wherein _R1 is a halogen group. 59. The method of any one of claims 39-58, wherein _R2 is hydrogen, cycloalkyl, heterocyclic _, or _-NRaRb . 60. The method of any one of claims 39-58, wherein _R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group or _-NRaRb , wherein the substituent is selected from amino, halogen or hydroxyl _groups . 61. The method of any one of claims 39-58, wherein _R2 is a optionally substituted heterocyclic group selected from the following: piperidinyl, pyrrolidinyl, morpholinyl, piperazine, aziridine, pyrazolyl, furanyl or azirbicyclo[3.2.1]octyl; wherein the substituent is hydroxyl, halogen, alkyl or amino. 62. The method of any one of claims 39-58, wherein _R2 is piperidinyl, pyrrolidinyl, morpholinyl, or piperazineyl. 63. The method of any one of claims 39-58, wherein _R2 is hydrogen. 64. The method of any one of claims 39-58, wherein _R2 is a cycloalkyl group. 65. The method of claim 64, wherein _R2 is cyclopropyl. 66. The method of any one of claims 39-65, wherein _R3 is an alkyl group. 67. The method of any one of claims 39-66, wherein m is 0 and p is 1. 68. The method of any one of claims 39-66, wherein m is 0 or 2, and p is 0 or 1. 69. The method of claim 39, wherein the compound of formula (II) is selected from: Or its pharmaceutically acceptable salts or stereoisomers. 70. The method of claim 39, wherein the compound of formula (II) is selected from... 6'-Amino-N-(2-morpholinyloxazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinyloxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridinecarboxamide hydrochloride; and (R)-N-(5-(3-hydroxypyrrolidone-1-yl)-2-morpholinyloxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide. 71. The method of claim 39, wherein the compound of formula (II) is selected from: N-(5-(3-fluoropiperidin-1-yl)-2-morpholinylthiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(azacycloheptane-1-yl)-2-morpholinylthiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinyloxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; and N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridinecarboxamide. 72. The method of claim 39, wherein the compound of formula (II) is a pharmaceutically acceptable salt thereof. 73. The method of claim 39, wherein the compound of formula (II) is a pharmaceutically acceptable salt thereof. 74. The method of claim 39, wherein the compound of formula (II) is a pharmaceutically acceptable salt thereof. 75. The method of claim 39, wherein the compound of formula (II) is a pharmaceutically acceptable salt thereof. 76. The method of claim 39, wherein the compound of formula (II) is a pharmaceutically acceptable salt thereof. 77. The method of any one of claims 1-4, wherein the IRAK4 inhibitor has a structure represented by formula (III): Or its pharmaceutically acceptable salt; in, Z ₁ is an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or none at all; _Z2 is an optional substituted cycloalkyl, aryl, or heterocyclic group; R ₁ is hydrogen, optionally substituted alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl. _R2 is hydrogen, halogen, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl in each instance. _R3 is, in each occurrence, a hydroxyl group, a halogen, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl group, or -NR _a R _b ; _Ra and _Rb are, in each instance, independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl. m is 0, 1, or 2 each time it appears; and n is 0, 1, or 2 each time it appears. 78. The method of claim 77, wherein _Z1 is an optionally substituted heterocyclic group. 79. The method of claim 77 or 78, wherein _Z1 is a heterocyclic group selected from: tetrazolyl, thiophene, triazolyl, pyrrole, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazole, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, benzoisooxazolyl, benzothiazolyl, benzofuranyl, benzothiophene, benzotriazinyl, phthalazinyl, thiathanth, dibenzofuranyl, dibenzothiophene, benzimidazole The following groups are listed: yl, indolyl, isoindolyl, indazole, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, purine, pteridinyl, 9H-carbazolyl, α-carbazolyl, inazinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridinyl, furanopyridinyl, purine, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotridiazolyl, carbazolyl, dibenzothiophene, acridinel, and pyrazolopyrimidinel. 80. The method of any one of claims 77-79, wherein the compound is represented by formula (IIIA). Or its pharmaceutically acceptable salt. 81. The method of any one of claims 77-79, wherein the compound is represented by formula (IIIIA). Or its pharmaceutically acceptable salt. 82. The method of any one of claims 77-81, wherein _Z2 is a heterocyclic group. 83. The method of any one of claims 77-82, wherein _Z2 is a heterocyclic group selected from: aza-butyl, oxa-butyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxyl, tetrazolyl, thiophene, triazolyl, pyrrolyl, pyridinyl, tetrahydropyridinyl, pyranyl, pyrazinyl, pyridinyl, pyrimidinyl, piperazinyl, imidazolyl, oxadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, indololinyl, indololinylmethyl, 2-aza-bicyclo[2.2.2]octyl, benzodihydropyranyl, xanthonyl, or pyrrolopyridinyl. 84. The method of any one of claims 77-82, wherein _Z2 is pyrrolidinyl, piperidinyl, piperazine, pyridinyl, pyrimidinyl, tetrahydropyridinyl, or pyrrolopyridinyl. 85. The method of any one of claims 77-82, wherein _Z2 is pyrrolidinyl or pyridinyl. 86. The method of any one of claims 77-85, wherein _R1 is an optionally substituted heterocyclic group. 87. The method of any one of claims 77-85, wherein _R1 is a heterocyclic group; optionally substituted with a halogen, hydroxyl or hydroxyalkyl group. 88. The method of any one of claims 77-85, wherein _R1 is optionally substituted aza-butyl, piperidinyl, morpholinyl, pyrrolidinyl, or aza-bicyclooctyl. 89. The method of any one of claims 77-85, wherein _R1 is piperidinyl. 90. The method of any one of claims 77-89, wherein _R2 is an optionally substituted alkyl group. 91. The method of any one of claims 77-90, wherein _R2 is an alkyl group optionally substituted with a heterocyclic group. 92. The method of any one of claims 77-89, wherein _R2 is hydrogen. 93. The method of any one of claims 77-89, wherein _R2 is cyclopropyl. 94. The method of any one of claims 77-93, wherein _R3 is a halogen, alkyl, haloalkyl, _-NRaRb , _cycloalkyl , hydroxy, or hydroxyalkyl. 95. The method according to any one of claims 77-93, wherein _R3 is methyl, hydroxyl or amino. 96. The method according to any one of claims 77-93, wherein _R3 is a hydroxyl or amino group. 97. The method of claim 77, wherein Z ₁ is an optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic group; _Z2 is an optional substituted cycloalkyl, aryl, or heterocyclic group; R ₁ is hydrogen, alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, arylalkyl, or heterocyclic alkyl. _R2 is an amino group, an alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an arylalkyl group, or a heterocyclic alkyl group. _R3 is a hydroxyl, alkyl, alkoxy, or -NR _{aR b} ; _Ra and _Rb are, in each instance, hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, arylalkyl, or heterocyclic alkyl. m is 1; and n is 1. 98. The method of claim 77, wherein _Z1 is a heterocyclic group; _Z2 is a heterocyclic group; _R1 is an optional substituted heterocyclic group; _R2 is an alkyl group; R ₃ is a hydroxyl, alkyl, or amino group; m is 1; and n is 1. 99. The method of claim 77, wherein the compound of formula (III) is selected from: Or its pharmaceutically acceptable salts or stereoisomers. 100. The method of claim 77, wherein the compound of formula (III) is selected from: (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)oxazol-4-carboxamide; 6-((S)-3-hydroxypyrrolidone-1-yl)-N-(5-((S)-3-hydroxypyrrolidone-1-yl)-1-methyl-1H-indazol-6-yl)pyridinecarboxamide; (S)-N-(1-ethyl-5-(3-hydroxypyrrolidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; and (S)-N-(5-(3-hydroxypyrrolidone-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyrimidin-4-yl)oxazol-4-carboxamide hydrochloride. 101. The method of claim 77, wherein the compound of formula (III) is selected from: (S)-2-(2-Cyclopropylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(1-Cyclopropyl-5-(3-hydroxypyrrolidone-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; and (S)-6-(3-aminopyrrolidone-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazole-6-yl)pyridinecarboxamide. 102. The method of any one of claims 1-101, wherein the method comprises administering 100-400 mg of the IRAK4 inhibitor to the subject twice daily. 103. The method of any one of claims 1-101, wherein the method comprises administering 200-400 mg of the IRAK4 inhibitor to the subject twice daily. 104. The method of any one of claims 1-101, wherein the method comprises administering 250-350 mg of the IRAK4 inhibitor to the subject twice daily. 105. The method of any one of claims 1-101, the method comprising administering to the subject twice daily about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the IRAK4 inhibitor. 106. The method of any one of claims 1-101, wherein the method comprises administering to the subject twice daily an IRAK4 inhibitor of about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg. 107. The method of any one of claims 1-101, wherein the method comprises administering to the subject twice daily about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the IRAK4 inhibitor. 108. The method of any one of claims 1-101, wherein the method comprises administering about 200 mg of the IRAK4 inhibitor to the subject twice daily. 109. The method of any one of claims 1-101, wherein the method comprises administering about 225 mg of the IRAK4 inhibitor to the subject twice daily. 110. The method of any one of claims 1-101, wherein the method comprises administering about 250 mg of the IRAK4 inhibitor to the subject twice daily. 111. The method of any one of claims 1-101, wherein the method comprises administering about 275 mg of the IRAK4 inhibitor to the subject twice daily. 112. The method of any one of claims 1-101, wherein the method comprises administering about 300 mg of the IRAK4 inhibitor to the subject twice daily. 113. The method of any one of claims 1-101, wherein the method comprises administering about 325 mg of the IRAK4 inhibitor to the subject twice daily. 114. The method of any one of claims 1-101, wherein the method comprises administering about 350 mg of the IRAK4 inhibitor to the subject twice daily. 115. The method of any one of claims 1-101, wherein the method comprises administering about 375 mg of the IRAK4 inhibitor to the subject twice daily. 116. The method of any one of claims 1 to 143, wherein the method comprises administering about 400 mg of the IRAK4 inhibitor to the subject twice daily. 117. The method of any one of claims 1-101, the method comprising administering to the subject once daily about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the IRAK4 inhibitor. 118. The method of any one of claims 1-101, wherein the method comprises administering about 50 mg of the IRAK4 inhibitor to the subject once daily. 119. The method of any one of claims 1-101, wherein the method comprises administering about 75 mg of the IRAK4 inhibitor to the subject once daily. 120. The method of any one of claims 1-101, the method comprising administering about 100 mg of the IRAK4 inhibitor to the subject once daily. 121. The method of any one of claims 1-101, the method comprising administering about 125 mg of the IRAK4 inhibitor to the subject once daily. 122. The method of any one of claims 1-101, wherein the method comprises administering about 150 mg of the IRAK4 inhibitor to the subject once daily. 123. The method of any one of claims 1-122, wherein the IRAK4 inhibitor is administered orally to the subject. 124. The method of claim 3, wherein the method comprises administering to the subject in combination an IRAK4 degrader, a BCL-2 inhibitor, and a nucleoside analogue. 125. The method of claim 124, wherein the IRAK4 degrading agent is KT-474, KYM-001, or IRAKMiD. 126. The method of any one of claims 1-125, wherein the nucleoside analog is a cytidine analog. 127. The method of any one of claims 1-126, wherein the nucleoside analogue is azacitidine, decitabine, cytarabine, gemcitabine, 5'-deoxy-5-fluorouridine, fludarabine, cladribine, trisatabine, or clofarabine. 128. The method of any one of claims 1-127, wherein the nucleoside analog is azacitidine. 129. The method of claim 128, wherein the azacitidine is administered at a dose of 75 mg/ ^m² per day. 130. The method of claim 128, wherein the azacitidine is administered at a dose of 100 mg/ ^m² per day. 131. The method of claim 128, wherein the azacitidine is administered at a dose of 300 mg per day. 132. The method of any one of claims 128-131, wherein the azacitidine is administered orally. 133. The method of any one of claims 128-131, wherein the azacitidine is administered subcutaneously. 134. The method of any one of claims 1-133, wherein the BCL-2 inhibitor is venetoc. 135. The method of claim 134, wherein the method comprises administering 400 mg of venetoc daily. 136. The method of claim 134 or 135, wherein the venetoc is administered orally. 137. The method according to any one of claims 1-123 and 126-136, wherein the IRAK4 inhibitor is venetoc, the BCL-2 inhibitor is venetoc, and the nucleoside analog is azacitidine. 138. The method of any one of claims 1-137, wherein the cancer is a hematologic malignancy. 139. The method of claim 138, wherein the hematologic malignancy is non-Hodgkin's lymphoma. 140. The method of claim 138, wherein the hematologic malignancy is leukemia or lymphoma. 141. The method of any one of claims 138-140, wherein the hematologic malignancy is myeloid leukemia, myeloid leukemia (e.g., acute myeloid leukemia), myelodysplastic syndrome, lymphoblastic leukemia (e.g., acute lymphoblastic leukemia), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., DLBCL or ABC-DLBLC), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), multiple myeloma, marginal zone lymphoma (MZL), Burkitt lymphoma, non-Burkkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, transformed high-grade B-cell lymphoma (HGBL), lymphoplasmacytic lymphoma (LPL), central nervous system lymphoma (CNSL), or MALT lymphoma. 142. The method of claim 138, wherein the hematologic malignancy is myeloid leukemia. 143. The method of claim 138, wherein the hematologic malignancy is myeloid leukemia (e.g., acute myeloid leukemia). 144. The method of claim 138, wherein the hematologic malignancy is acute myeloid leukemia (e.g., AML). 145. The method of claim 138, wherein the AML is primary AML. 146. The method of claim 138, wherein the AML is secondary AML. 147. The method of any one of claims 143-146, wherein the AML is resistant to treatment. 148. The method of any one of claims 143-147, wherein the AML is resistant to treatment with an FMS-associated receptor tyrosine kinase 3 (FLT-3) inhibitor. 149. The method of any one of claims 143-148, wherein the AML is associated with a mutation of the FLT3 kinase. 150. The compound used as claimed in claim 149, wherein the mutation is an internal tandem repeat (ITD). 151. The compound used as claimed in claim 149, wherein the mutation is a D835H, D835V, D835Y, K663Q, N841L or F691L mutation. 152. The compound used as described in claim 149, wherein the mutation is the D835Y mutation. 153. The method of claim 138, wherein the hematologic malignancy is myelodysplastic syndrome. 154. The method of claim 153, wherein the myelodysplastic syndrome is high-grade. 155. The method of claim 153, wherein the myelodysplastic syndrome is low-grade. 156. The method of claim 138, wherein the hematologic malignancy is lymphoblastic leukemia (e.g., acute lymphoblastic leukemia). 157. The method of claim 138, wherein the hematologic malignancy is chronic lymphocytic leukemia (CLL). 158. The method of claim 157, wherein the CLL is a high-risk CLL. 159. The method of claim 138, wherein the hematologic malignancy is small lymphocytic lymphoma (SLL). 160. The method of claim 138, wherein the hematologic malignancy is follicular lymphoma. 161. The method of claim 138, wherein the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). 162. The method of claim 138, wherein the hematologic malignancy is activated B-cell-like (ABC) DLBCL. 163. The method of claim 138, wherein the hematologic malignancy is germinal center B-cell-like (GCB) DLBCL. 164. The method of any one of claims 161-163, wherein the DLBCL is extrajunctival. 165. The method of any one of claims 161-164, wherein the DLBCL is extranodal leg lymphoma, extranodal testicular lymphoma, or extranodal nonspecific (NOS) lymphoma. 166. The method of any one of claims 161-165, wherein the DLBCL is an extranodal leg lymphoma or an extranodal testicular lymphoma. 167. The method of claim 138, wherein the hematologic malignancy is Waldenström macroglobulinemia. 168. The method of any one of claims 161-167, wherein the DLBCL or WM is characterized by the L265P mutation in MYD88. 169. The method of claim 138, wherein the hematologic malignancy is mantle cell lymphoma. 170. The method of claim 138, wherein the hematologic malignancy is multiple myeloma. 171. The method of claim 138, wherein the hematologic malignancy is marginal zone lymphoma. 172. The method of claim 138, wherein the hematologic malignancy is Burkitt lymphoma. 173. The method of claim 138, wherein the hematologic malignancy is a non-Burkett high-grade B-cell lymphoma. 174. The method of claim 138, wherein the hematologic malignancy is extranodal marginal zone B-cell lymphoma. 175. The method of claim 138, wherein the hematologic malignancy is transformed high-grade B-cell lymphoma (HGBL). 176. The method of claim 138, wherein the hematologic malignancy is lymphoplasmacytic lymphoma (LPL). 177. The method of claim 138, wherein the hematologic malignancy is a CNS lymphoma. 178. The method of claim 178, wherein the CNS lymphoma is primary CNS lymphoma (PCNSL). 179. The method of claim 138, wherein the hematologic malignancy is MALT lymphoma. 180. The method of any one of claims 138-180, wherein the hematologic malignancy is recurrent. 181. The method of any one of claims 138-181, wherein the hematologic malignancy is refractory. 182. The method of any one of claims 1-137, wherein the cancer is selected from brain cancer, kidney cancer, liver cancer, stomach cancer, penile cancer, vaginal cancer, ovarian cancer, stomach cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, epidermal cancer, prostate cancer, and head and neck cancer. 183. The method of claim 183, wherein the cancer is pancreatic cancer. 184. The method of claim 183, wherein the cancer is colon cancer. 185. The method of any one of claims 183-185, wherein the cancer is a solid tumor. 186. The method of any one of claims 183-186, wherein the cancer is recurrent. 187. The method of any one of claims 183-187, wherein the cancer is refractory. 188. The method of any one of claims 1-188, wherein the IRAK4 inhibitor or IRAK4 degrader, the BCL-2 inhibitor, and the nucleoside analog are administered simultaneously. 189. The method of claim 189, wherein the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog are administered simultaneously. 190. The method of any one of claims 1-188, wherein the IRAK4 inhibitor or IRAK4 degrader, the BCL-2 inhibitor, and the nucleoside analog are administered to each other within about 5 minutes to about 168 hours. 191. The method of claim 191, wherein the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog are administered to each other within about 5 minutes to about 168 hours. 192. The method of any one of claims 1-192, wherein the subject achieves a partial response after administration of the IRAK4 inhibitor or IRAK4 degrader, the BCL-2 inhibitor, and the nucleoside analog. 193. The method of claim 193, wherein the subject achieves a partial response after administration of the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog. 194. The method of any one of claims 1-192, wherein the subject achieves a good partial response after administration of the IRAK4 inhibitor or IRAK4 degrader, the BCL-2 inhibitor, and the nucleoside analog. 195. The method of claim 195, wherein the subject achieves a good partial response after administration of the IRAK4 inhibitor, the BCL-2 inhibitor, and the nucleoside analog. 196. The method of any one of claims 1-177, wherein the subject achieves a complete response after administration of the IRAK4 inhibitor or IRAK degrader, the BCL-2 inhibitor, and the nucleoside analog. 197. The method of claim 197, wherein the subject achieves a complete response after administration of the IRAK4 inhibitor or IRAK degrader, the BCL-2 inhibitor, and the nucleoside analog. 198. The method of any one of claims 1, 2, 5-133 and 138-188, wherein the IRAK4 inhibitor or IRAK4 degrader and the nucleoside analog are administered simultaneously. 199. The method of any one of claims 1, 2, 5-133 and 138-188, wherein the IRAK4 inhibitor and the nucleoside analog are administered simultaneously. 200. The method of any one of claims 1, 2, 5-133 and 138-188, wherein the IRAK4 inhibitor or IRAK4 degrader and the nucleoside analogue are administered to each other within about 5 minutes to about 168 hours. 201. The method of any one of claims 1, 2, 5-133 and 138-188, wherein the IRAK4 inhibitor and the nucleoside analog are administered to each other within about 5 minutes to about 168 hours. 202. The method of any one of claims 1, 2, 5-133, 138-188, and 199-202, wherein the subject achieves a partial response after administration of the IRAK4 inhibitor or IRAK4 degrader and the nucleoside analogue. 203. The method of any one of claims 1, 2, 5-133, 138-188, and 199-202, wherein the subject achieves a partial response after administration of the IRAK4 inhibitor and the nucleoside analogue. 204. The method of any one of claims 1, 2, 5-133, 138-188, and 199-202, wherein the subject achieves a good partial response after administration of the IRAK4 inhibitor or IRAK4 degrader and the nucleoside analogue. 205. The method of any one of claims 1, 2, 5-133, 138-188, and 199-202, wherein the subject achieves a good partial response after administration of the IRAK4 inhibitor and the nucleoside analogue. 206. The method of any one of claims 1, 2, 5-133, 138-188, and 199-202, wherein the subject achieves a complete response after administration of the IRAK4 inhibitor or IRAK4 degrader and the nucleoside analogue. 207. The method of any one of claims 1, 2, 5-133, 138-188, and 199-202, wherein the subject achieves a complete response after administration of the IRAK4 inhibitor and the nucleoside analogue.