Polycyclic IRAK and FLT3 inhibitor compounds and uses thereof

Abstract

Some embodiments of the present disclosure include compounds (e.g., compounds of Formula (I)) and compositions (e.g., pharmaceutical compositions) of the present invention that inhibit IRAK and / or FLT3 and can be used, for example, to treat certain diseases. Some embodiments include administration and methods of using compounds of the present invention (e.g., in compositions or pharmaceutical compositions) to treat (e.g., diseases such as hematopoietic cancer, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), etc.). Additional embodiments provide disease treatments using a combination of an IRAK and / or FLT3 inhibitor compound of the present invention and another therapy, such as a cancer therapy.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE This disclosure relates generally to compounds and compositions that are kinase inhibitors and their use in the treatment of diseases and disorders, including cancer.

[0002] Government Rights This invention was made in the fulfillment of a Cooperative Research and Development Agreement with the National Institutes of Health, an agency of the Department of Health and Human Services. The United States Government has certain rights in this invention.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 352,439, filed June 15, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0004] Myelodysplastic syndromes (MDS) are aggressive, potentially fatal blood disorders that arise from defective hematopoietic stem / progenitor cells, predispose to acute myeloid leukemia (AML) (Corey et al., 2007; Nimer, 2008), and often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). The majority of patients with MDS die from bone marrow failure, immune dysfunction, and / or progression to overt leukemia.

[0005] MDS is a heterogeneous disease with few treatment options due to the lack of effective medications that can provide durable responses. Current treatment options for MDS are limited and include allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapy (Ebert, 2010). While hemopoietic stem cell (HSC) transplantation can be used as a curative treatment for MDS, this option is unavailable to many elderly patients, who instead receive supportive care and blood transfusions to ameliorate disease complications. Unfortunately, MDS clones can persist in the bone marrow even after HSC transplantation, and the disease invariably progresses (Tehranchi et al., 2010). For progressive or high-risk MDS, patients may also receive immunosuppressive therapy, epigenetic modifiers, and / or chemotherapy (Greenberg, 2010). Despite recent advances, most MDS patients experience treatment-related toxicity or relapse (Sekeres, 2010a). Overall, the efficacy of these treatments varies, and generally, life expectancy is only slightly improved compared to symptomatic treatment. The complexity and heterogeneity of MDS and the lack of human xenograft models present challenging obstacles for the identification and evaluation of novel molecular targets for this disease.

[0006] Approximately 30% of MDS patients also develop aggressive AML due to the acquisition of additional mutations in defective hematopoietic stem / progenitor cells (HSPCs) (Greenberg et al., 1997). AML is a cancer of the myeloid lineage of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, but its incidence is expected to increase with the aging population. Although several risk factors and chromosomal abnormalities have been identified, the specific cause is unclear. As an acute leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated. The prognosis for AML resulting from MDS is poorer than that of other types of AML.

[0007] Although several compounds are known to treat hematological disorders and cancers (e.g., MDS, AML), such treatments are inadequate. While several known compounds, such as quizartinib, gilteritinib, and crenolanib, can be used to treat AML, some of these treatments do not result in complete or partial remission. In some cases, for example, treatment can result in adaptive resistance, or the selection of mutations resistant to inhibitors, particularly when repeated administration can result in desensitization of tumor cell growth, as with quizartinib (Melgar et al., 2019).

[0008] In the treatment of MDS and / or AML, there is a need to develop therapies that can inhibit adaptive resistance mechanisms to improve survival in the context of AML and MDS. There is also an unmet need in AML for drugs that increase overall survival, reduce hospital stays and readmission rates, overcome acquired resistance to other therapies, and increase the success rate of hematopoietic stem cell transplantation. Additionally, there is a need for drugs for treating MDS that can slow the rate of transformation to AML and reduce transfusion dependency.

[0009] Thus, there is a need to develop therapies and methods that effectively treat MDS and / or AML and / or other conditions or disorders characterized by dysregulated (e.g., hyperactive) IRAK (e.g., IRAK1 and / or 4). Additionally, in doing so, it is important to determine whether a patient is likely to respond to a particular treatment or method of treatment. Certain embodiments of the present disclosure can address one or more of these problems. Summary of the Invention

[0010] In one aspect, the present disclosure provides a compound of formula (I) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof, wherein R 1 is selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; and amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is selected from halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl. optionally substituted by one or more of xo, methanoyl (—COH), carboxy (—COH), nitro (—NO), —NH, —NHCH, —N(CH), cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH, —CONHCH, —CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; 2is selected from H, halogen, hydroxy, oxo, -CN, amino, -O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, heteroaryl, or fused-ring heteroaryl; and amino, -O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is selected from halogen, hydroxy, oxo, methanoyl (-CO H), carboxy (—COH), nitro (—NO), —NH, —NHCH, —N(CH), cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SOH), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH, —CONHCH, —CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C-C alkyl substituted with cycloalkyl; 3 , R 4 , and R 5are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; and methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl. optionally substituted by one or more of xo, methanoyl (—COH), carboxy (—COH), nitro (—NO), —NH, —NHCH, —N(CH), cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH, —CONHCH, —CON(CH), C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; 6 teeth, [ka] and R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; and R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl are optionally substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5; and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0011] In one embodiment, the compound of formula (I) is a compound of formula (IIr) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, wherein R 20r is C1-C6 alkoxy optionally substituted with one or more substituents selected from —OH and halogen; R 21r and R 23r are each independently a halogen, and R 22r is H and R 24ra , R 24rb , R 25ra , R 25rb , R 26ra , and R 26rb are each independently selected from H and halogen; R 24ra , R 24rb , R 25ra , R 25rb , R 26ra , and R 26rb In one embodiment, one or more of (i) to (iii): (i) R 20r but, [ka] (ii) R 21r and R 23r are each F, and (iii) R 25ra , R 25rb , R 26ra , R 24ra , and R 26rb are H and R 24rb is F. In one embodiment, the compound is: [ka]

[0012] In one embodiment, the compound of formula (I) is a compound of formula (IIs) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, wherein R 20s is selected from C1-C6 alkyl, C1-C6 alkoxy, and —OH, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more substituents selected from —OH and halogen; R 21s is C1-C6 alkyl, C3-C6 cycloalkyl, C5-C 12 spiro-fused cycloalkyl, and C-C heterocyclyl, wherein each C-C alkyl is optionally substituted with one or more substituents selected from —OH and halogen, and wherein the C-C cycloalkyl is optionally substituted with one or more substituents selected from C-C alkyl and halogen; and R 22s , R 23s , and R 24s are each independently H, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more halogens; and R 25sa , R 25sb , R 26sa , R 26sb , R 27sa , and R 27sb are each independently selected from H and halogen; R 25sa , R 25sb , R 26sa , R 26sb , R 27sa , and R 27sb In one embodiment, the compound of formula (I) is a compound of formula (IIs), wherein one or more of R 20s is -OCH3 and R 21s is unsubstituted C3 cycloalkyl or [ka] If (i) R 22s , R 23s , and R 24sAt least one of the following is selected from the group consisting of CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), or (ii) R 22s is a halogen, and R 23s is H and R 24s is H, or (iii) R 22s is H and R 23s is H and R 24s is a halogen; R 20s is -OCH3 and R 21s but, [ka] If R 22s , R 23s , and R 24s At least one of the following is not H and is R 20s is -OCH3, R 21s but, [ka] In one embodiment, (i) to (x): (i) R 20s is -OCH3, (ii) R 21s is unsubstituted C3-C6 cycloalkyl, [ka] (iii) R 22s , R 23s , and R 24s are each H; (iv) R 23s is H and R 22s and R 24s are each F, (v) R 22s is F and R 23s and R 24s are each H, (vi) R 24s is F and R 22s and R 23s are each H, (vii) R 23s is H and R22s and R 24s are each independently selected from —CH, —OCH, CN, C cycloalkyl, phenyl, and —O-phenyl; (viii) R 22s is selected from -CH, -OCH, CN, Ccycloalkyl, phenyl, and -O-phenyl; R 23s and R 24s are each H, (ix) R 24s is selected from -CH, -OCH, CN, Ccycloalkyl, phenyl, and -O-phenyl; R 22s and R 23s are each H, (x)R 25sa , R 26sa , R 26sb , R 27sa , and R 27sb are H and R 25sb is F. In one embodiment, the compound is [ka] [ka] is selected from.

[0013] In one embodiment, the compound of formula (I) is a compound of formula (IIt) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein: [ka] teeth, [ka] Selected from R 20t is C1-C6 alkoxy optionally substituted with one or more substituents selected from —OH and halogen; R 21t and R 23t are each independently a halogen, and R22t is H and R 24ta , R 24tb , R 25ta , R 25tb , R 26ta , R 26tb , R 27ta , R 27tb , R 28ta , R 28tb , R 29ta , and R 29tb are each independently selected from H and halogen. In one embodiment, (i)-(iv): (i) R 20t but, [ka] (ii) R 21t and R 23t are each F, (iii) [ka] but, [ka] and R 25ta , R 25tb , R 27ta , R 27tb , R 28ta , R 28tb , R 29ta , and R 29tb each of which is H; (iv) [ka] but, [ka] and R 25ta , R 25tb , R 27ta , R 27tb , R 28ta , R 28tb , and R 29ta is H and R 29tb is F. In one embodiment, the compound is [ka] is selected from.

[0014] In one embodiment, the compound of formula (I) is a compound of formula (IIu) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein: [ka] teeth, [ka] Selected from R 20u is selected from C1-C6 alkyl, C1-C6 alkoxy, and —OH, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; R 21u is C1-C6 alkyl, C3-C6 cycloalkyl, C5-C 12 spiro-fused cycloalkyl, and C-C heterocyclyl, wherein each C-C alkyl is optionally substituted with one or more substituents selected from —OH and halogen, and wherein the C-C cycloalkyl is optionally substituted with one or more substituents selected from C-C alkyl and halogen; and R 22u , R 23u , and R 24u are each independently H, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more halogens; and R 25ua , R 25ub , R 26ua , R 26ub , R 27ua , R 27ub , R 28ua , R 28ub , R29ua , and R 29ub are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, the compound of Formula (II) is a compound of Formula (IIu), wherein R 20u is -OCH3 and R 21u is unsubstituted C3 cycloalkyl or [ka] If (i) R 22u , R 23u , and R 24u At least one of the groups may be CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), or (ii) R 22u is a halogen, and R 23u is H and R 24u is H, or (iii) R 22u is H and R 23u is H and R 24u is a halogen; R 20u is -OCH3 and R 21u but, [ka] If R 22u , R 23u , and R 24u At least one of the following is not H and is R 20s is -OCH3, R 21s but, [ka] In one embodiment, (i) to (ix): (i) R 20u is -OCH3, (ii) R 21u is unsubstituted C3-C6 cycloalkyl, [ka] (iii) R 22u , R 23u , and R 24u are each H; (iv) R 23u is H and R 22u and R 24u are each F, (v) R 22u is F and R 23u and R 24u are each H, (vi) R 24u is F and R 22u and R 23u are each H, (vii) R 23u is H and R 22u and R 24u are each independently selected from —CH, —OCH, CN, C cycloalkyl, phenyl, and —O-phenyl; (viii) R 22u is selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl; R 23u and R 24u are each H, (ix) R 24u is selected from -CH, -OCH, CN, Ccycloalkyl, phenyl, and -O-phenyl; R 22u and R 23u are H, (x) [ka] but, [ka] and R 25ua , R 25ub , R 27ua , R 27ub , R 28ua , R 28ub , R 29ua , and R 29ub each of which is H, and (xi) [ka] but, [ka] and R 25ua , R 25ub , R 27ua , R 27ub , R 28ua , R 29ua , and R 29ub is H and R 28ub is F. In one embodiment, the compound is [ka] [ka] [ka] [ka] is selected from.

[0015] In one embodiment, a compound of Formula (I), including a compound of any one of Formulae (IIr)-(IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, is an inhibitor of at least one of IRAK1, IRAK4, and FLT3. In one embodiment, the compound is an inhibitor of IRAK1 and IRAK4. In one embodiment, the compound is an inhibitor of IRAK1, IRAK4, and FLT3.

[0016] In another aspect, the present disclosure provides a composition comprising a compound of formula (I), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, comprising a compound of any one of formulas (IIr) to (IIu), wherein the composition further comprises a formulation component, adjuvant, or carrier, and the composition is selected from the group consisting of chemotherapeutic agents, BCL2 inhibitors, immunomodulatory agents, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (anti-metabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, Plk inhibitors, MEK inhibitors, CDK inhibitors, CDK9 inhibitors, and the like. inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, smoothened receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura In one embodiment, the composition is used in combination with one or more of a BCL2 inhibitor, a BTK inhibitor, a gluocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof; the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them; the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitor BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one of them; or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.

[0017] In yet another aspect, the present disclosure provides a method for treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II), including any one of the compounds of Formulae (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, or a composition as described above, including a compound of Formula (II), including any one of the compounds of Formulae (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof. In one embodiment, the method comprises administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (II) and a formulation ingredient, adjuvant, or carrier. In one embodiment, the disease or disorder responds to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition. In one embodiment, the disease or disorder comprises a hematopoietic cancer. In one embodiment, the disease or disorder is (i) myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, marginal zone lymphoma, glioblastoma multiforme, myelofibrosis, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, or (ii) at least one cancer selected from bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer; or (ii) at least one inflammatory or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, Crohn's disease, and colitis.In one embodiment, the method includes the use of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetobolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody-drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK2 inhibitor ... / ERK inhibitors including MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura The method further comprises administering to the subject one or more additional therapies selected from an EGFR inhibitor, an Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT 1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a menin-KMT2A / MLL inhibitor, and a multikinase inhibitor. In one embodiment, the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them, the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitor BAY1251152 and atubeciclib, or a pharmaceutically acceptable salt of any one of them, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is BCL2 inhibitor-resistant acute myeloid leukemia (AML) and / or FLT3 inhibitor-resistant AML. In one embodiment, a compound of formula (I) comprising any one of compounds of formula (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, or the above-mentioned composition comprising a compound of formula (I) comprising any one of compounds of formula (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, and one or more additional therapies are administered together in one administration or one composition. In one embodiment, a compound of Formula (I) comprising any one of compounds of Formula (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, or the above-mentioned composition comprising a compound of Formula (I) comprising any one of compounds of Formula (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, and one or more additional therapies are administered separately in two or more doses or two or more compositions. In one embodiment, a disease or disorder is alleviated by inhibiting at least one of IRAK1, IRAK4, and FLT3 in a subject. In one embodiment, a disease or disorder is alleviated by inhibiting IRAK1 and IRAK4 in a subject. In one embodiment, a disease or disorder is alleviated by inhibiting IRAK1, IRAK4, and FLT3 in a subject.

[0018] In yet another aspect, the present disclosure provides a method of increasing survivability in a subject diagnosed with or suspected of having acute myeloid leukemia (AML), the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), including any one of the compounds of Formulae (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, or a composition as described above, comprising a compound of Formula (I), including any one of the compounds of Formulae (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof. In one embodiment, the subject's survivability is increased compared to a subject treated with a therapeutically effective amount of standard of care for AML. In one embodiment, the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is human. In one embodiment, the subject's survival is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with a therapeutically effective amount of standard of care for AML. In one embodiment, the method comprises administering to a subject a therapeutically effective amount of a compound of formula (I), including a compound of any one of formulas (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, or a composition comprising a compound of formula (I), including a compound of formula (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, about every 6 hours, 12 hours, 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week.In one embodiment, the method includes the use of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetobolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody-drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK2 inhibitor ... / ERK inhibitors including MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura The method further comprises administering to the subject one or more additional therapies selected from an EGFR inhibitor, an Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT 1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a menin-KMT2A / MLL inhibitor, and a multikinase inhibitor. In one embodiment, the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them, the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitor BAY1251152 and atubeciclib, or a pharmaceutically acceptable salt of any one of them, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the AML is BCL2 inhibitor-resistant and / or FLT3 inhibitor-resistant. In one embodiment, a compound of formula (I) comprising any one of compounds of formula (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, or the above-mentioned composition comprising a compound of formula (I) comprising any one of compounds of formula (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, and one or more additional therapies are administered together in one administration or one composition. In one embodiment, a compound of Formula (I) comprising any one of the compounds of Formula (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, or a composition as described above comprising a compound of Formula (I) comprising any one of the compounds of Formula (IIr) to (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, and one or more additional therapies are administered separately in two or more doses or two or more compositions. In one embodiment, survivability is increased by inhibiting at least one of IRAK1, IRAK4, and FLT3 in a subject. In one embodiment, survivability is increased by inhibiting IRAK1 and IRAK4 in a subject. In one embodiment, survivability is increased by inhibiting IRAK1, IRAK4, and FLT3 in a subject. [Brief explanation of the drawings]

[0019] [Figure 1] 1 shows the individual single-agent time course activity of Compound 106 and gilteritinib at dose levels 6, 7, and 8 in the Caspase-Glo® apoptosis assay in MOLM14 FLT3-ITD(D835Y) AML cells over 24 hours.

[0020] [Figure 2] 1 shows the individual single-agent time course activity of Compound 106 and emavusertib (CA-4948) at dose levels 6, 7, and 8 in the Caspase-Glo® apoptosis assay in MOLM14 FLT3-ITD(D835Y) AML cells over 24 hours.

[0021] [Figure 3] Figure 1 shows the individual single-agent time course activity of Compound 106, gilteritinib, emabsertib, and venetoclax over 24 hours, and the combined activity of these compounds with venetoclax at dose level 8, in the Caspase-Glo® apoptosis assay in MOLM14 FLT3-ITD(D835Y) AML cells.

[0022] [Figure 4] 1 shows the individual single-agent activity of compound 106, gilteritinib, emabsertib, and venetoclax at dose level 7, and the combined activity of these compounds at dose level 7 with venetoclax at dose level 7 in the Caspase-Glo® apoptosis assay in MOLM14 FLT3-ITD(D835Y) AML cells.

[0023] [Figure 5] 1 shows the individual single-agent activity of compound 106, gilteritinib, emabsertib, and venetoclax at dose level 6, and the combined activity of these compounds at dose level 6 with venetoclax at dose level 6 in the Caspase-Glo® apoptosis assay in MOLM14 FLT3-ITD(D835Y) AML cells.

[0024] [Figure 6] Figure 1 shows the combined activity of Compound 106 at dose level 7 with venetoclax at dose level 7. The addition of 4.12 nM 5-azacytodine provides little or no additional benefit in the Caspase-Glo® apoptosis assay in MOLM14 FLT3-ITD(D835Y) AML cells.

[0025] [Figure 7] 1 provides the structures of gilteritinib and emabsertib (CA-4948).

[0026] [Figure 8] 1 is a summary table of groups and treatments for Example 17.

[0027] [Figure 9A] Figure 9A demonstrates that mice treated with Compound 106 have improved survival compared to mice treated with gilteritinib or emabsertib (CA-4948). Figure 9A shows 90-day survival data for mice engrafted with MOLM14 FLT3-ITD(D835Y) AML cells and orally treated with MF once daily at 30 mg / kg of gilteritinib, emabsertib (CA-4948), and Compound 106 versus vehicle control. Enhanced survival is seen with Compound 106 compared to either gilteritinib or emabsertib. [Figure 9B] Figure 9B: A chart demonstrating that mice treated with compound 106 have improved survival rates compared to mice treated with gilteritinib or emabsertib (CA-4948). Figure 9B: A chart demonstrating that the increased efficacy of compound 106 is not due to higher plasma levels relative to gilteritinib or emabsertib. Both Cmax and area under the curve (AUC) are provided. The chart also demonstrates that at the doses studied, compound 106 has a larger window for hERG IC50 than emabsertib (CA-4948).

[0028] [Figure 10] FIG. 9B is a chart showing that compound 106 is superior to gilteritinib or emabsertib (CA-4948) in reducing leukemia burden corrected for survival in mice over the duration of the 90-day study shown in FIG. 9A.

[0029] [Figure 11-1] Figure 1 shows the outcome of representative compound combinations with venetoclax in a Cell Titer Glo assay in MOLM 14 (D835Y) cells at 48 hours. Panel A shows the relative excess HSA values of compound 106 compared to representative FLT3 inhibitors. A negative excess HSA score indicates that the drug combination is better than either drug alone, with greater synergy observed with more negative excess HSA scores. [Figure 11-2] Panel B shows the relative concentrations (nM) of Compound 106, CG-806, gilteritinib hemifumerate, or emabsertib (CA-4948), respectively, to sufficiently enhance (less than 10%) the cellular titer Glo response of 125 nM venetoclax at 48 hours. Lower concentrations indicate a greater ability to synergize with venetoclax. Panels C and D show the concentration ranges in which combinations of venetoclax with either Compound 106 (Panel C) or gilteritinib hemifumerate (Panel D) were studied in a 10x10 combination matrix. The numbers in each cell represent the % response (left) or Delta Bliss score (right) at each given concentration combination. The numbers within the circles represent the resulting response where the indicated concentration of each agent reduces the activity of 125 nM venetoclax by less than 10%.

[0030] [Figure 12-1]Figure 1 shows the outcome of representative compound combinations with azacytidine in a Cell Titer Glo assay in MOLM 14 (D835Y) cells at 48 hours. Panel A shows the relative excess HSA values of compound 106 compared to representative FLT3 inhibitors. A negative excess HSA score indicates that the drug combination is better than either drug alone, with greater synergy observed with more negative excess HSA scores. [Figure 12-2] Panel B shows the relative concentrations (nM) of Compound 106, CG-806, gilteritinib hemifumerate, or emabsertib (CA-4948), respectively, required to sufficiently enhance (less than 10%) the cellular titer Glo response of 1250 nM azacitidine at 48 hours. Lower concentrations indicate greater ability to synergize with azacitidine. Panels C and D show the concentration ranges in which azacitidine was studied in combination with either Compound 106 (Panel C) or gilteritinib hemifumerate (Panel D) in a 10x10 combination matrix. The number in each cell represents the % response (left) or Delta Bliss score (right) at each given concentration combination. The numbers enclosed within the circles represent the resulting response where the indicated concentration of each agent reduces the activity of 1250 nM azacitidine by less than 10%.

[0031] [Figure 13-1] Figure 1 shows the outcome of representative compound combinations with venetoclax in a Cell Titer Glo assay in THP1 cells at 48 hours. Panel A shows the relative excess HSA values of compound 106 compared to representative FLT3 inhibitors. A negative excess HSA score indicates that the drug combination is better than either drug alone, with greater synergy observed with more negative excess HSA scores. [Figure 13-2]Panel B shows the relative concentrations (nM) of CG-806, Compound 106, gilteritinib hemifumerate, or emabsertib (CA-4948), respectively, to enhance (less than 30%) the cellular titer Glo response of 2500 nM venetoclax at 48 hours. Lower concentrations indicate a greater ability to synergize with venetoclax. Panels C and D show the concentration ranges in which combinations of venetoclax with either Compound 106 (Panel C) or emabsertib (CA-4948) (Panel D) were studied in a 10x10 combination matrix. The numbers in each cell represent the % response (left) or Delta Bliss score (right) at each given concentration combination. The numbers within the circles represent the resulting response where the indicated concentration of each agent reduces the activity of 2500 nM venetoclax by less than 30%.

[0032] [Figure 14-1] Figure 1 shows the results of representative compound combinations with azacitidine in a Cell Titer Glo assay in THP1 cells at 48 hours. Panel A shows the relative excess HSA values of compound 106 compared to representative FLT3 inhibitors. A negative excess HSA score indicates that the drug combination is better than either drug alone, with greater synergy observed with more negative excess HSA scores. [Figure 14-2]Panel B shows the relative concentrations (nM) of Compound 106, CG-806, gilteritinib hemifumerate, or emabsertib (CA-4948), respectively, required to sufficiently enhance (less than 50%) the cellular titer Glo response of 2500 nM azacitidine at 48 hours. Lower concentrations indicate greater ability to synergize with azacitidine. Panels C and D show the concentration ranges in which azacitidine was studied in combination with either Compound 106 (Panel C) or emabsertib (CA-4948) (Panel D) in a 10x10 combination matrix. The number in each cell represents the % response (left) or Delta Bliss score (right) at each given concentration combination. The numbers enclosed within the circles represent the resulting response where the indicated concentration of each agent reduces the activity of 2500 nM azacitidine to less than 50%. DETAILED DESCRIPTION OF THE INVENTION

[0033] The following applications are incorporated herein by reference in their entirety for all purposes: International Patent Application No. PCT / US2017 / 059091 (International Publication No. WO 2018 / 081738), filed October 30, 2017; TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed April 4, 2019; U.S. Patent Application No. 16 / 339,692 (U.S. Publication No. 2021 / 0292843); TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed May 22, 2014; International Patent Application No. PCT / US2014 / 039156 (International Publication No. WO 2014 / 190163); Combination Therapy for MDS; U.S. Patent No. 9,168,257, issued October 27, 2015; Combination Therapy for MDS, U.S. Patent No. 9,504,706 issued November 29, 2016; Combination Therapy for MDS, U.S. Patent No. 9,855,273 issued January 2, 2018; Combination Therapy for MDS, International Patent Application No. PCT / US2017 / 047088 filed August 16, 2017 (International Publication No. WO 2018 / 038988); Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, U.S. Patent No. 11,254,667 issued February 22, 2022, subtitled imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors, U.S. Patent Application No. 17 / 568,023 filed January 4, 2022 (U.S. Publication No. 2022 / 0213094), subtitled Imidazo[l,2-a]-pyridines as IRAK 1 / 4 and FLT3 Inhibitors, U.S. Patent Application No. 16 / 804,518 filed February 28, 2020 (U.S. Publication No. 2020 / 0199123), subtitled Imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors, U.S. Patent Application No. 17 / 587,070, filed January 28, 2022 (U.S. Publication No. 2022 / 0235042), subtitled Imidazo[l,2-a]pyridines as IRAK 1 / 4 and FLT3 Inhibitors, International Patent Application No. PCT / US2021 / 044089, filed July 31, 2021 (International Publication No. WO 2022 / 026935), subtitled Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, International Patent Application No. PCT / US2021 / 065037, filed December 23, 2021, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, U.S. Patent Application No. 63 / 285,663, filed December 3, 2021, IRAK Inhibitors Combination Therapies, International Patent Application No. PCT / US2022 / 038902, filed July 29, 2022, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, U.S. Patent Application No. 63 / 289,341, filed December 14, 2021, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, U.S. Patent Application No. 63 / 394,118, filed August 1, 2022, Multi-Cyclic IRAK1 and IRAK4 Inhibiting Compounds and Uses Thereof, U.S. Patent Application No. 63 / 377,812, filed September 30, 2022, Multi-Cyclic IRAK1 and IRAK4 Inhibiting Compounds and Uses Thereof, U.S. Patent Application No. 63 / 378, filed October 4, 2022No. 300, "Multi-Cyclic IRAK1 and IRAK4 Inhibiting Compounds and Uses Thereof," and U.S. Patent Application No. 63 / 378,306, "Multi-Cyclic IRAK1 and IRAK4 Inhibiting Compounds and Uses Thereof," filed October 4, 2022.

[0034] While embodiments embodying the general inventive concept may take a variety of forms, various embodiments will be described herein with the understanding that the disclosure is to be considered merely exemplary and that the general inventive concept is not intended to be limited to the disclosed embodiments.

[0035] Some embodiments of the present invention include compounds of the present invention (e.g., compounds of Formula (I)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising compounds of the present invention. Still other embodiments of the present invention include compositions for treating certain diseases, e.g., using compounds of the present invention. Some embodiments include methods of using compounds of the present invention (e.g., in compositions or pharmaceutical compositions) for administration and treatment. Further embodiments include methods for making compounds of the present invention. Still further embodiments include methods for determining whether a particular patient is likely to respond to such treatment with compounds and compositions of the present invention.

[0036] Unless otherwise noted, terms are understood according to conventional usage by those of ordinary skill in the art.

[0037] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0038] Where substituents are designated by their conventional chemical formula written from left to right, they equally encompass chemically identical substituents that would result from writing the structure from right to left, e.g., -CHO- is equivalent to -OCH-.

[0039] As used herein, with respect to compounds of Formula (I), (II), (III), etc., the term "attached" means a stable covalent bond, with certain preferred points of attachment being apparent to those skilled in the art.

[0040] As used herein (unless otherwise specified), the term "alkyl" refers to alkyl groups that may be fully saturated, monounsaturated, or polyunsaturated and have a specified number of carbon atoms (i.e., C-C 10 means 1 to 10 carbons). For example, the terms "C1-C7 alkyl" or "C1-C4 alkyl" refer to a linear or branched saturated hydrocarbon group having 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7) or 1 to 4 (e.g., 1, 2, 3, or 4) carbon atoms, respectively. Examples of C1-C7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, and n-heptyl. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl.

[0041] As used herein (unless otherwise specified), the term "alkenyl" refers to a monovalent straight or branched hydrocarbon chain containing one or more (e.g., 1, 2, 3, or 4) double bonds. The double bond may occur at any stable point along the chain, and the carbon-carbon double bond may have either a cis or trans configuration. For example, this definition includes, but is not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, 1-pentenyl-3-cyclohexenyl, and the like. Similarly, "heteroalkenyl" refers to a heteroalkyl having one or more double bonds. Further examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0042] As used herein (unless otherwise specified), the term "alkynyl" means a monovalent straight or branched hydrocarbon chain that contains one or more (e.g., 1, 2, 3, or 4) triple bonds and may optionally contain one or more (e.g., 1, 2, 3, or 4) double bonds within the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0043] As used herein (unless otherwise specified), the term "alkoxy" means any of the above alkyl, alkenyl, or alkynyl groups attached to the remainder of the molecule by an oxygen atom (alkyl-O-). Examples of alkoxy groups include, but are not limited to, methoxy (sometimes designated as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy.

[0044] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, exemplified by, but not limited to, -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms.

[0045] As used herein (unless otherwise specified), the term "cycloalkyl" refers to a monovalent, monocyclic or bicyclic 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon group. The ring can be saturated or partially unsaturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyl (e.g., bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds). For monocyclic cycloalkyls, the ring is not aromatic. For bicyclic cycloalkyls, if one ring is aromatic, the other is not aromatic. For bicyclic cycloalkyls, one or both rings can be substituted.

[0046] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, stable linear or branched chains, or combinations thereof, which consist of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heteroatom(s) O, N, P, S, and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two heteroatoms may be consecutive, such as -CH2-NH-OCH3.

[0047] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups, as used herein, include groups attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and / or -SOR'. Where "heteroalkyl" is mentioned followed by a specific heteroalkyl group, such as -NR'R", it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is mentioned for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, such as -NR'R".

[0048] As used herein (unless otherwise specified), the term "halogen" or "halo" means monovalent Cl, F, Br, or I. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0049] As used herein (unless otherwise specified), the term "aryl" refers to a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic hydrocarbon group, and also refers to a polyvalent, unsaturated, aromatic, hydrocarbon substituent that may be fused together (i.e., fused-ring aryl) or covalently linked, single ring or multiple rings (preferably 1 to 3 rings). Fused-ring aryl refers to multiple rings fused together, where at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. For bicyclic aryls, one or both rings may be substituted.

[0050] As used herein (unless otherwise specified), the term "heteroaryl" refers to a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon group, in which 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic ring system is aromatic. The heteroaryl group (or ring) can contain 1 to 4 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, where at least one of the fused rings is a heteroaromatic ring). A 5,6-fused-ring heteroarylene refers to two rings fused together, one ring having 5 members and the other having 6 members, and at least one ring being a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 6 members, and at least one ring is a heteroaryl ring. Also, a 6,5-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Examples of heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisoxazolyl, 1H-pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl. For bicyclic heteroaryls, if one ring is aryl, the other is heteroaryl. For bicyclic heteroaryls, one or both rings can have one or more heteroatoms. For bicyclic heteroaryls, one or both rings can be substituted.

[0051] "Arylene" and "heteroarylene," alone or as part of another substituent, refer to divalent radicals derived from aryl and heteroaryl, respectively. Thus, the term "aryl" can refer to unsubstituted, monosubstituted, disubstituted, or trisubstituted monocyclic, polycyclic, biaryl, and heteroaromatic groups covalently attached at any ring position capable of forming a stable covalent bond, with certain preferred points of attachment apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl). Aryl substituents can be independently selected from halo, nitro, cyano, trihalomethyl, C 1-16 Alkyl, aryl C 1-16 Alkyl, C0- 16 Alkyloxy C0- 16 Alkyl, aryl C0- 16 Alkyloxy C0- 16 Alkyl, C0- 16 AlkylthioC0- 16 Alkyl, aryl C0- 16 AlkylthioC0- 16 Alkyl, C0- 16 Alkylamino C0- 16 Alkyl, aryl C0- 16 Alkylamino C0- 16 Alkyl, di(aryl C1- 16 Alkyl)aminoC0- 16 Alkyl, C1- 16 Alkylcarbonyl C0- 16 Alkyl, aryl C 1-16 Alkylcarbonyl C0- 16 Alkyl, C1- 16 Alkyl carboxy C0- 16 Alkyl, aryl C1- 16 Alkyl carboxy C0- 16 Alkyl, C 1-16 AlkylcarbonylaminoC0- 16 Alkyl, aryl C1- 16 AlkylcarbonylaminoC0- 16 Alkyl, -C0- 16 Alkyl COOR4, -C0- 16alkylCONR5R6, wherein R4, R5, and R6 are independently selected from the group consisting of hydrogen, C1-C 11 Alkyl, aryl C0-C 11 alkyl, or R5 and R6 together with the nitrogen to which they are attached form one C 1-16 Alkyl, aryl C0-C 16 Alkyl, or C0-Cl 16 With or without alkylaryl substituents, forming a ring system containing 3 to 8 carbon atoms. Aryl includes, but is not limited to, pyrazolyl and triazolyl.

[0052] For brevity, the term "aryl," when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the terms "arylalkyl," "aralkyl," and the like are intended to include radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like), and include alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like) or a sulfur atom. Thus, terms such as "arylalkyl" (e.g., (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represent an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.

[0053] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, may also be referred to as "heterocyclyl," and refer to cyclic versions of "alkyl" and "heteroalkyl," respectively, unless otherwise specified. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. As used herein (unless otherwise specified), the term "heterocycloalkyl" or "heterocyclyl" means a monovalent monocyclic or bicyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon ring in which 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic ring system is not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or pyrrolidinyl). Examples of bicyclic heterocyclyls include, but are not limited to, piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, or piperazin-4-yl), piperidinyl (e.g., piperadin-1-yl, piperadin-2-yl, piperadin-3-yl, or piperadin-4-yl), and morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl). For bicyclic heterocyclyls, when one ring is aromatic (e.g., monocyclic aryl or heteroaryl), the other ring is not aromatic.For bicyclic heterocyclyls, one or both rings can have one or more heteroatoms. For bicyclic heterocyclyls, one or both rings can be substituted, etc. "Cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0054] As used herein (unless otherwise specified), the term "heteroatom" means an atom selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0055] As used herein (unless otherwise specified), the term "hydroxy" or "hydroxyl" refers to the monovalent --OH group.

[0056] The term "acyl," unless otherwise indicated, means -C(O)R, in which R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0057] As used herein, the term "oxo" means an oxygen that is double bonded to a carbon atom.

[0058] As used herein, the term "alkylsulfonyl" means a moiety having the formula -S(O2)-R', where R' is an alkyl group as defined above. R' can have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0059] The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge.

[0060] In the above definitions, the terms "alkyl" and "alkenyl" may be used interchangeably, as long as a stable chemical entity is formed, as will be apparent to one skilled in the art.

[0061] The term "linker" refers to an attachment group interposed between substituents. In some embodiments, the linker is an amide (-CONH-R n or -NHCO-R n ), thioamide (-CSNH-R n Or -NHCS-R n ), carboxyl (-CO2-R n Rn or -OCOR n ), carbonyl (-CO-R n ), urea (-NHCONH-R n ), thiourea (-NHCSNH-R n ), sulfonamide (-NHSO2-R n or -SO2NH-R n ), ether (-OR n ), sulfonyl (-SO2-R n ), sulfoxyl (-SO-R n ), carbamoyl (-NHCO2-R n or -OCONH-R n ), or amino (-NHR n ) including the connecting portion.

[0062] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl," and "heteroaryl," etc.) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein.

[0063] As used herein (unless otherwise specified), the term "substituted" (e.g., as in substituted alkyl) means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from a specified selection. The replacement can occur at one or more positions. The term "optionally substituted" means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) can be, but need not be, replaced.

[0064] As used herein, "substituents" means non-hydrogen substituents that may be, and preferably are, groups selected from the following moieties: (A) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), -CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) C-C alkyl, C-C heteroalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from the following: (i) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) C-C alkyl, C-C heteroalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituted with at least one substituent selected from the following: (a) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from the following: -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-S03H), CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

[0065] The terms "size-limited substituent" or "size-limited substituent group" as used herein mean, for example, a group selected from all of the substituents described above for substituents, wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 4- to 8-membered heterocycloalkyl.

[0066] As used herein, the terms "lower substituent" or "lower substituent group" refer, for example, to a group selected from all of the substituents described above for a substituent, wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C5-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5- to 7-membered heterocycloalkyl.

[0067] The term "about" when used in the context of a numerical value indicates a range of + / - 10% of that numerical value, unless expressly indicated otherwise.

[0068] Some compounds of the present invention may have one or more chiral centers, and may exist in optically active and racemic forms with respect to any of the one or more chiral centers, and may be isolated in such forms.Some compounds may exhibit polymorphism.The compounds of the present invention (e.g., Formula I) encompass any optically active racemate, stereoisomeric form, polymorph, or mixture thereof.If a chiral center does not provide an indication of its configuration (i.e., R or S) in the chemical structure, it should be considered to represent R, S, or racemate.

[0069] As used herein, the term "sample" encompasses samples obtained from a subject or patient. A sample can be of any biological tissue or fluid. Such samples include, but are not limited to, sputum, saliva, buccal samples, oral samples, blood, serum, mucus, plasma, urine, blood cells (e.g., white blood cells), circulating cells (e.g., stem cells or endothelial cells in blood), tissue, core needle or fine needle biopsy samples, cell-containing body fluids, suspended nucleic acids, urine, stool, ascites, and pleural fluid, tears, or cells therefrom. A sample can also include a section of tissue, such as a frozen or fixed section taken for histological purposes, or a microdissected cell or extracellular portion thereof. The sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch resection, or by any other surgical method resulting in biopsy or excised cellular material. Such a sample can contain cells obtained from a subject or patient. In some embodiments, the sample is a bodily fluid, for example, but not limited to, blood fluid, serum, mucus, plasma, lymph, ascites, gynecological tract, or urine, hi some embodiments, the sample can be a non-invasive sample, such as, for example, a saline swish, buccal scrape, buccal swab, or the like.

[0070] As used herein, blood can include, for example, plasma, serum, whole blood, blood lysate, and the like.

[0071] As used herein, the term "evaluating" includes any form of measurement and includes determining whether an element is present. The terms "determining," "measuring," "evaluating," "assessing," "analyzing," and "assaying" may be used interchangeably and may include quantitative and / or qualitative determinations.

[0072] As used herein, the term "monitoring" with respect to a type of cancer refers to a method or process of determining the severity or extent of that type of cancer, or stratifying that type of cancer based on the risk and / or probability of death. In some embodiments, monitoring relates to a method or process of determining the therapeutic effectiveness of a treatment administered to a patient.

[0073] As used herein, "outcome" may refer to the outcome studied. In some embodiments, "outcome" may refer to survival / mortality over a given analysis period. For example, "outcome" may refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or more. In some embodiments, an increased risk of a poor outcome indicates that the therapy had poor efficacy, and a decreased risk of a poor outcome indicates that the therapy had good efficacy.

[0074] As used herein, the term "high-risk clinical trial" refers to one in which the investigational agent poses "more than minimal risk" (as defined by the terminology used by an Institutional Review Board or IRB). In some embodiments, a high-risk clinical trial is a clinical trial.

[0075] As used herein, the term "low-risk clinical trial" refers to one in which the test agent has "minimal risk" (as defined by the terminology used by the IRB). In some embodiments, a low-risk clinical trial is one that is not a clinical trial. In some embodiments, a low-risk clinical trial involves the use of monitors or clinical practice processes. In some embodiments, a low-risk clinical trial is an observational clinical trial.

[0076] As used herein, the terms "modulated" or "modulation," or "regulated" or "regulation," and "differentially regulated" can refer to both upregulation (i.e., activation or stimulation, e.g., by agonism or enhancement) and downregulation (i.e., inhibition or suppression, e.g., by antagonism, reduction, or inhibition), unless otherwise specified or apparent from the context of the particular use.

[0077] As used herein, the term "subject" refers to any suitable (e.g., treatable) member of the animal kingdom. In the methods, the subject is preferably a mammal. In the methods, the subject is preferably a human patient. In the methods, the subject may be a pediatric mammalian patient. In the methods, a pediatric patient is a mammalian (e.g., preferably human) patient under the age of 18, while an adult patient is 18 years of age or older.

[0078] As used herein, the term "treating" (and variations thereof, such as "treatment," "treating," "treat") should be considered in its broadest context unless otherwise specified and refers to obtaining a desired pharmacological and / or physiological effect. Specifically, for example, the term "treating" does not necessarily imply or may not require that an animal be treated until complete recovery. Thus, "treating" includes amelioration of symptoms, relief from symptoms or effects associated with a condition, reduction in the severity of a condition, or prevention of symptoms, prophylactic amelioration, or otherwise reducing the risk of developing a particular condition. In some aspects, "treating" does not require or include prevention. As used herein, reference to "treating" an animal includes, but is not limited to, prophylactic and therapeutic treatment. The effect may be prophylactic, in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic, in terms of a partial or complete cure of a disease and / or adverse effects resulting from a disease. As used herein, "treatment" encompasses any treatment of a disease in a subject, preferably a mammal (e.g., a human), and may include one or more of: (a) preventing the disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed with it; (b) inhibiting the disease, i.e., halting its development; and (c) relieving the disease, i.e., causing regression or elimination of the disease and / or alleviating one or more disease symptoms. In certain aspects of the method, such as for conditions or disorders characterized by dysregulated IRAK expression or a dysregulated (e.g., hyperactive) IRAK-mediated signaling pathway, treatment may be or may include reducing such expression or signaling. "Treatment" can also encompass the delivery of an agent or administration of a therapy to provide a pharmacological effect even in the absence of a disease or condition. Any of the compositions (e.g., pharmaceutical compositions) described herein can be used to treat a suitable subject.

[0079] A "therapeutically effective amount" refers to an amount effective to achieve a desired and / or beneficial effect. An effective amount can be administered in one or more administrations. In the methods, a therapeutically effective amount is an amount adequate to treat an indication. Treating an indication means achieving any desired effect, such as, for example, one or more of palliating, ameliorating, stabilizing, reversing, slowing, or delaying disease progression, improving quality of life, or extending lifespan. Such achievement can be measured by any suitable method, such as measuring tumor size or blood counts, or any other suitable measurement.

[0080] As used herein, the term "marker" or "biomarker" refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, etc., whose presence or concentration can be detected and correlated with a known condition, such as a disease state. It can also be used to refer to differentially expressed genes whose expression patterns can be utilized as part of a predictive, prognostic, or diagnostic process in healthy or disease states, or alternatively, can be used in methods to identify useful therapeutic or preventative therapies.

[0081] As used herein, an mRNA "isoform" is an alternative transcript of a particular mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, truncated, or aberrant mRNA, modified mRNA (e.g., containing any residue modifications, capping variants, polyadenylation variants, etc.), etc.

[0082] "Antibody" or "antibody peptide" refers to an intact antibody or a binding fragment thereof that competes with the intact antibody for specific binding; this definition also encompasses monoclonal and polyclonal antibodies. Binding fragments are produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies. An antibody other than a "bispecific" or "bifunctional" antibody is understood to have each of its binding sites identical. An antibody substantially inhibits the adhesion of a receptor to a counterreceptor when, for example, the excess antibody reduces the amount of receptor bound to the counterreceptor by at least about 20%, 40%, 60%, or 80%, more usually by more than about 85% (as measured in an in vitro competitive binding assay).

[0083] Embodiments of the invention described herein include compounds of the invention (e.g., compounds of Formula (I), such as compounds of Formula (II) and Formula (III)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising compounds of the invention. Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) for treating certain diseases, for example, using compounds of the invention. Some embodiments include methods of administering and using compounds of the invention (e.g., in compositions or pharmaceutical compositions) to treat (e.g., diseases such as cancer or blood disorders). Some embodiments include methods of determining whether a patient is suitable for or likely to respond favorably to a particular treatment. Further embodiments include methods for making compounds of the invention. Additional embodiments of the invention are also contemplated herein.

[0084] Compounds and compositions, including pharmaceutical compositions Some embodiments of the present invention provide a compound having a structure according to formula (I-5008): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. In some embodiments, the compound is a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative of a compound of Formula (I-5008). In some embodiments, the compound is not an ester, is not a solvate, or is not a prodrug.

[0085] In an exemplary embodiment, R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; and is independently selected from amido, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl. The alkyl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), nitro (—NO), —NH, —NHCH, —N(CH), cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH, —CONHCH, —CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl.

[0086] In some embodiments, R 1can be H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; and amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl can be H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl. optionally substituted by one or more of methyl, methanoyl (—COH), carboxy (—COH), nitro (—NO), —NH, —NHCH, —N(CH), cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH, —CONHCH, —CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; 2can be H, halogen, hydroxy, oxo, -CN, amino, -O-aryl, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, heteroaryl, or fused-ring heteroaryl, and amino, -O-aryl, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl can be H, halogen, hydroxy, oxo, methanoyl (-COH), ), carboxy (—COH), nitro (—NO), —NH, —NHCH, —N(CH), cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SOH), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH, —CONHCH, —CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C-C alkyl substituted with cycloalkyl; 3 , R 4 , and R 5can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl can be H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl. and optionally substituted with one or more of methyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl.

[0087] R 6 teeth, [ka] It can be,

[0088] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; and R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 may be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; Alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl are optionally substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x can be 0, 1, 2, 3, 4, or 5; q+r+s+t is at least 1; and u+v+w+x is at least 1.

[0089] In some embodiments, R 1is H, halogen, -CONH2, -CONHCH3, -CON(CH3)2, benzyl, C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl, wherein the C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl is optionally substituted with one or more halogen, hydroxyl, C1-C7 alkyl, or C1-C7 haloalkyl. 1 is H, Cl, -CONH2, -CONHCH3, methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl, wherein methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl is optionally substituted with one or more F, -OH, methyl, or CF3. In some embodiments, R 1 is not H.

[0090] In some embodiments, R 2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, and is O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl In some embodiments, R is optionally substituted with one or more of halogen, hydroxy, —CN, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused ring aryl, fused ring heteroaryl, pyrrolyl, piperidyl, piperazinyl, C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. 2is H, halogen, hydroxy, O-aryl, amino, C-C alkyl, C-C alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl, wherein the O-aryl, amino, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, R 2 is H, Cl, hydroxy, -NHCH, -N(CH), -OCH, -OCF, -OCHF, -OPh, -CF, -CHF, unsubstituted C-C alkyl, substituted amino, substituted C-C alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl. In some embodiments, R 2 is not H.

[0091] In some embodiments, R 3is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, or C-C alkoxy, wherein the C-C alkyl or C-C alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, R 3 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0092] In some embodiments, R 4 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, or C-C alkoxy, wherein the C-C alkyl or C-C alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, R 4 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0093] In some embodiments, R5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, or C-C alkoxy, wherein the C-C alkyl or C-C alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, R 5 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0094] In some embodiments, R 4 is methyl or -CF3, and R 3 and R 5 At least one of is H or halogen.

[0095] In some embodiments, R 6 There is a chiral center at the attached carbon. In some embodiments, the chiral center is an R chiral center. In some embodiments, the chiral center is an S chiral center. In certain embodiments, the chiral center is located at the bond [ka] As will be appreciated by those skilled in the art, where chiral centers are possible at other positions in compounds according to formula (I), the linear bond shown may also be represented by [ka] It could be.

[0096] In some embodiments, R 6 teeth, [ka] is.

[0097] In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl may be one or more; optionally substituted with halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), nitro (—NO), —NH, —N(CH), cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH, —CONHCH, —CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl, with the proviso that R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 provided that at least one of R15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and each of methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; or optionally substituted with halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), nitro (—NO), —NH, —N(CH), cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH, —CONHCH, —CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5; and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0098] In one embodiment, R 7 , R 8 , R 9 , R10 , R 11 , R 12 , R 13 , and R 14 At least one of R is not H. In another embodiment, 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 Each of, if present, is H.

[0099] In one embodiment, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 At least one of R is not H. In another embodiment, 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 Each of, if present, is H.

[0100] In some embodiments, R 6 teeth, [ka] is.

[0101] In some embodiments, R 6 teeth, [ka] is.

[0102] Some embodiments of the present invention provide a compound having a structure according to formula (I): [ka] wherein Y to R 6 wavy line coupling to (i.e., [ka] ) is, in some cases, R 6 indicates that there is a chiral center at the attached carbon. In some embodiments, R 6 If there is a chiral center at the attached carbon, the wavy bond can indicate an R chiral center, an S chiral center, or a racemate. [ka] teeth, [ka] As will be appreciated by those skilled in the art, where chiral centers are possible at other positions in compounds according to formula (I), the linear bond shown may also be [ka] It could be.

[0103] In some embodiments, R 6 is (Ia) which results in the structure of formula (II) as follows: [ka]

[0104] In some embodiments according to Formula (II), m is 0 or 1, n is 0 or 1, o is 0 or 1, and p is 0 or 1.

[0105] In some embodiments, R 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14 is not H and / or R 11 , R 12 , R 13 , and R 14 is H and R 7 , R 8 , R 9 , and R 10 At least one of R is not H. In certain embodiments, 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkoxy, or spirofused cycloalkyl, wherein methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, or spirofused cycloalkyl is optionally substituted with one or more halogens. 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14At least one of R is halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), C-C alkyl, C-C alkoxy, or spirofused cycloalkyl, wherein the methanoyl (—COH), carboxy (—COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, or spirofused cycloalkyl is optionally substituted with one or more halogens. 11 , R 12 , R 13 , and R 14 is H and R 7 , R 8 , R 9 , and R 10 At least one of R is halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), C-C alkyl, C-C alkoxy, or spirofused cycloalkyl, wherein the methanoyl (—COH), carboxy (—COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, or spirofused cycloalkyl is optionally substituted with one or more halogens. 7 , R 8 , R 9 , and R 10 At least one of R is halogen, hydroxyl, C-C alkyl, C-C haloalkyl, C-C alkoxy, or spiro-fused cycloalkyl. 7 , R 8 , R 9 , and R 10 At least one of R is F, hydroxyl, methyl, methoxy, —CHF, —CF, spirofused cyclopropyl, spirofused cyclobutyl, or spirofused cyclopentyl. 7 and R 8 Both or R 9 and R 10 Both are F or R 7 and R 8 Both or R 9 and R10 and R are both methyl. 11 , R 12 , R 13 , and R 14 At least one of R is halogen, hydroxyl, C-C alkyl, C-C haloalkyl, C-C alkoxy, or spiro-fused cycloalkyl. 11 , R 12 , R 13 , and R 14 At least one of R is F, hydroxyl, methyl, methoxy, —CHF, —CF, spirofused cyclopropyl, spirofused cyclobutyl, or spirofused cyclopentyl. 11 and R 12 Both or R 13 and R 14 Both are F or R 11 and R 12 Both or R 13 and R 14 Both of the groups are methyl.

[0106] In addition to any of the embodiments above in which the compound has the structure of formula (II), the compound can have a structure according to any of (IIa)-(IIe), where V, W, X, Y, and Z are independently selected from R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , or R 14 and at least one of V, W, X, Y, and Z is not H. [ka]

[0107] In one embodiment, the compound of formula (II) is a compound of formula (IIf) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20f is selected from H, halogen, C-C alkyl, C-C alkoxy, C-C cycloalkyl, and —O—(C-C cycloalkyl), wherein the C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, and the C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 21f , R 22f , and R 23f are each independently selected from H and halogen; R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms.

[0108] In one embodiment, R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb Each of is H.

[0109] In one embodiment, R 20f is H. In another embodiment, R 20fis not H. In one embodiment, R 20f is halogen. In one embodiment, R 20f is Cl. In another embodiment, R 20f is unsubstituted C1-C6 alkoxy. In one embodiment, R 20f teeth, [ka] In another embodiment, R 20f is C1-C6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20f teeth, [ka] In one embodiment, R 21g is C1-C6 alkyl substituted with one or more -OH. In one embodiment, R 20f teeth, [ka] In another embodiment, R 20f is C-C cycloalkyl. In one embodiment, R 20f is an unsubstituted C cycloalkyl. In one embodiment, R 20f teeth, [ka] is.

[0110] In one embodiment, R 21f , R 22f , and R 23f Each of R is H. In one embodiment, 21f and R 23f are each independently a halogen, and R 22f is H. In one embodiment, R 21f and R 23f are F and R, respectively. 22f is H. In one embodiment, R 21f and R 23f are H and R 22fis halogen. In one embodiment, R 21f and R 23f are H and R 22f is F.

[0111] In one embodiment, R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb Each of R is H. In one embodiment, 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa and / or R 24fb is halogen. In one embodiment, R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa is F. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa and R 24fb Each of R is F. In one embodiment, 25fa , R 25fb , R 26fa , and R 26fb are H and R 24fa and / or R 24fb is C1-C6 alkyl. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa and R 24fb Each of R is -CH3. 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa is -CH3.

[0112] In one embodiment, the compound of formula (IIf) has one or more stereocenters. In one embodiment, the compound of formula (IIf) has the moiety [ka] contains a stereocenter at which R is attached to the remainder of formula (IIf). In one embodiment, the compound of formula (IIf) 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and / or R 26fb In one embodiment, the compound of formula (IIf) contains a stereocenter at one or more of R 20f Contains a stereocenter above.

[0113] In one embodiment, the compound of formula (II) is a compound of formula (IIg) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20g is selected from H and C1-C6 alkoxy; R 21g is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C6-C 12 aryl), C3-C9 heterocyclyl, and -NR 28ga R 28gb wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; and C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R 22g , R 23g , and R 24gare each independently selected from H and halogen; R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; R 28ga and R 28gb are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0114] In one embodiment, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H.

[0115] In one embodiment, R 20g is H. In one embodiment, R 20g is unsubstituted C1-C6 alkoxy. In one embodiment, R 20g -OCH3, -OCH2CH3, and [ka] is selected from.

[0116] In one embodiment, R 21g is halogen. In one embodiment, R 21g is Cl. In one embodiment, R 21gis unsubstituted C1-C6 alkyl. In one embodiment, R 21g is t-butyl. In one embodiment, R 21g is C1-C6 alkyl substituted with one or more F and / or -OH. In one embodiment, R 21g is -CF3, [ka] In another embodiment, R 21g is unsubstituted C1-C6 alkoxy. In one embodiment, R 21g is —OCH3. In another embodiment, R 21g is C1-C6 alkoxy substituted with one or more halogen atoms. 21g is -O-(C6-C 12 aryl). In one embodiment, R 21g is -O-phenyl. In another embodiment, R 21g is unsubstituted C-C cycloalkyl. In one embodiment, R 21g is an unsubstituted C cycloalkyl. In one embodiment, R 21g is a C cycloalkyl substituted with one or more fluorine atoms. 21g teeth, [ka] In another embodiment, R 21g is an unsubstituted C-C heterocyclyl. In one embodiment, R 21g is morpholinyl, azetidinyl, piperdinyl, isoxazolyl, pyrazolyl, [ka] wherein G is N or CH, and [ka] wherein c is 1 or 2. In another embodiment, R 21gis C-C alkyl, C-C cycloalkyl, C-C-heterocyclyl, —OH, and C-C heterocyclyl substituted with one or more substituents selected from halogen. 21g teeth, [ka] where R 29g is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens and / or —OH. 21g teeth, [ka] where R 29g is H. In one embodiment, R 21g teeth, [ka] where R 29g is unsubstituted C1-C6 alkyl. In one embodiment, R 21g teeth, [ka] where R 29g is selected from -CH3 and isopropyl. In one embodiment, R 21g teeth, [ka] where R 29g is C1-C6 alkyl substituted with one or more -OH and / or F. In one embodiment, R 21g teeth, [ka] where R 29g teeth, [ka] In another embodiment, R 21g teeth, [ka] where R 29g is selected from unsubstituted C cycloalkyl, azetidinyl, and tetrahydropyranyl. 21g teeth, [ka] wherein a is 1, 2, or 3, G is N or CH, and each X is independently a halogen. 21g teeth, [ka] In another embodiment, R 21g teeth, [ka] wherein b is 0, 1, 2, 3, 4, 5, or 6, c is 1 or 2, and each R 220g is independently C1-C6 alkyl. In one embodiment, R 21g teeth, [ka] In another embodiment, R 21g is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R 21g is isoxazolyl monosubstituted with -CH3. In another embodiment, R 21g is -NR 28ga R 28gb where R 28ga is H and R 28gb is selected from —CH3, cyclobutyl, and cyclohexyl. 21g is -NR 28ga R 28gb where R 28ga and R28gb are each independently C1-C6 alkyl. In one embodiment, R 21g is -NR 28ga R 28gb where R 28ga and R 28gb are each -CH3.

[0117] In one embodiment, R 22g , R 23g , and R 24g are each H. In one embodiment, R 22g and R 24g are each independently a halogen, and R 23g is H. In one embodiment, R 22g and R 24g are F and R, respectively. 23g is H. In one embodiment, R 22g and R 24g are H and R 23g is halogen. In one embodiment, R 22g and R 24g are H and R 23g is F.

[0118] In one embodiment, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of R is H. In one embodiment, 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga and / or R 25gb is halogen. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga is F. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25gaand R 25gb Each of R is F. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb are H and R 25ga and / or R 25gb is C1-C6 alkyl. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb are H and R 25ga and R 25gb Each is —CH. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga is -CH3. In another embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga is selected from substituted C1-C6 alkyl and —OH. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga is —OH. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga is -CF3 and [ka] In another embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga is unsubstituted C1-C6 alkoxy. In one embodiment, R 25gb , R 26ga , R26gb , R 27ga , and R 27gb is H and R 25ga is -OCH3.

[0119] In one embodiment, R 25ga , R 25gb , R 26gb , R 27ga , and R 27gb is H and R 26ga is unsubstituted C1-C6 alkyl. In one embodiment, R 25ga , R 25gb , R 26gb , R 27ga , and R 27gb is H and R 26ga is -CH3.

[0120] In one embodiment, R 25ga , R 25gb , R 26ga , and R 26gb is H and R 27ga and R 27gb Each of R is an unsubstituted C-C alkyl. 25ga , R 25gb , R 26ga , and R 26gb is H and R 27ga and R 27gb Each of is —CH3.

[0121] In one embodiment, the compound of formula (IIg) contains one or more stereocenters. In one embodiment, the compound of formula (IIg) contains R 21g In one embodiment, the compound of formula (IIg) comprises the moiety [ka] contains a stereocenter at which R is attached to the remainder of formula (IIg). In one embodiment, the compound of formula (IIg) contains a stereocenter at which R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and / or R 27gbcontains one or more stereocenters.

[0122] In one embodiment, the compound of Formula (IIf) or (IIg) is selected from compounds 1-4, 9-14, 21-24, 26-30, 52-57, 59, 60, 64, 68-72, 74, 77-83, 87-99, 103, 107, 109-116, 119, 121, 124, 126, 129, 133, 135, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.

[0123] In one embodiment, the compound of formula (II) is a compound of formula (IIh) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20h is selected from H and C1-C6 alkoxy; R 21h is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen; R 22ha , R 22hb , R 23ha , and R 23hb are each independently selected from H and C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more halogen atoms; R 24h , R 25h , and R 26h are each independently selected from H and halogen;

[0124] In one embodiment, R 20h is H.

[0125] In one embodiment, R 21h is a C3-C9 heterocyclyl substituted with one or more substituents selected from C1-C6 alkyl, —OH, and halogen. 21h is pyrazolyl substituted with C-C alkyl and F. In one embodiment, R 21h teeth, [ka] In one embodiment, R 21h teeth, [ka] is.

[0126] In one embodiment, R 22ha , R 22hb , R 23ha , and R 23hb and one or more of R are independently optionally substituted C-C alkyl. 22ha , R 22hb , R 23ha , and R 23hb Each of R is H. In one embodiment, 22ha , R 22hb is H and R 23ha and / or R 23hb is C1-C6 alkyl. In one embodiment, R 22ha , R 22hb , and R 23ha is H and R 23hb is -CH3. In another embodiment, R 22ha and R 22hb is H and R 23ha and R 23hb Each of is —CH3.

[0127] In one embodiment, R 24h , R 25h , and R 26h are each H. In one embodiment, R 24h and R 26h are each independently a halogen, and R25h is H. In one embodiment, R 24h and R 26h are F and R, respectively. 25h is H. In one embodiment, R 24h and R 26h are H and R 25h is halogen. In one embodiment, R 24h and R 26h are H and R 25h is F.

[0128] In one embodiment, the compound of formula (IIh) contains one or more stereocenters. In one embodiment, the compound of formula (IIh) contains R 21h In one embodiment, the compound of formula (IIh) comprises the moiety [ka] contains a stereocenter at which R is attached to the remainder of formula (IIh). 22ha , R 22hb , R 23ha , and / or R 23hb One or more of the groups contains a stereocenter.

[0129] In one embodiment, the compound of formula (IIh) is [ka] is.

[0130] In one embodiment, the compound of formula (II) is a compound of formula (IIi) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, [ka] teeth, [ka] is selected from R 20i is selected from H and C1-C6 alkoxy; R 21i is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9-heterocyclyl, -OH, -C=O, and halogen; R 22i , R 23i , and R 24i are each independently selected from H and halogen; R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib are each independently selected from H, halogen, —OH, or C1-C6 alkyl.

[0131] In one embodiment, R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is independently selected from halogen, —OH, and C1-C6 alkyl. 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R28ia , R 28ib , R 29ia , and R 29ib Each of is H.

[0132] In one embodiment, R 20i is H. In another embodiment, R 20i is unsubstituted C1-C6 alkoxy. In one embodiment, R 20i is -OCH3.

[0133] In one embodiment, R 21i is C1-C6 alkyl substituted with one or more F and / or -OH. In one embodiment, R 21i teeth, [ka] In another embodiment, R 21i is unsubstituted C-C cycloalkyl. In one embodiment, R 21i is an unsubstituted C cycloalkyl. In one embodiment, R 21i is a C cycloalkyl substituted with C-C alkyl. 21i teeth, [ka] In one embodiment, R 21i is a C cycloalkyl substituted with one or more C-C alkyl and one or more fluorine atoms. 21i teeth, [ka] In another embodiment, R 21i is an unsubstituted C-C heterocyclyl. In one embodiment, R 21i is pyrazolyl. In one embodiment, R 21i teeth, [ka] wherein J is N or CH. In another embodiment, R 21i is C-C alkyl, C-C cycloalkyl, C-C heterocyclyl, C-C heterocyclyl substituted with one or more substituents selected from -OH, -C=O, and halogen. 21i is pyrrolidinyl monosubstituted with -C=O. In one embodiment, R 21i teeth, [ka] In one embodiment, R 21i teeth, [ka] where R 220i is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens and / or —OH. 21i teeth, [ka] where R 220i is H. In one embodiment, R 21i teeth, [ka] where R 220i is unsubstituted C1-C6 alkyl. In one embodiment, R 21i teeth, [ka] where R 220i is —CH3. In one embodiment, R 21i teeth, [ka] where R 220iis C1-C6 alkyl substituted with one or more -OH and / or F. In one embodiment, R 21i teeth, [ka] where R 220i teeth, [ka] In another embodiment, R 21i teeth, [ka] where R 220i is an unsubstituted C3 cycloalkyl.

[0134] In one embodiment, R 22i , R 23i , and R 24i Each of R is H. In one embodiment, 22i and R 24i are each independently a halogen, and R 23i is H. In one embodiment, R 22i and R 24i are F and R, respectively. 23i is H. In one embodiment, R 22i and R 24i are H and R 23i is halogen. In one embodiment, R 22i and R 24i are H and R 23i is F.

[0135] In one embodiment, [ka] teeth, [ka] and R 25ia , R 25ib , R 26ia , R 26ib , R27ia , R 27ib , R 28ia , and R 28ib Each of R is H. In one embodiment, 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H and R 25ia and / or R 25ib is halogen. In one embodiment, R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H and R 25ia and R 25ib Each of R is F. In one embodiment, R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H and R 25ib is F.

[0136] In one embodiment, [ka] teeth, [ka] and R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib Each of R is H. In one embodiment, 25ia , R 25ib , R 27ia , R 27ib , R 29ia , and R 29ib is H and R 28ia and / or R 28ib is halogen. In one embodiment, R25ia , R 25ib , R 27ia , R 27ib , R 29ia , and R 29ib is H and R 28ia and R 28ib Each of R is F. In one embodiment, R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 29ia , and R 29ib is H and R 28ib is F. In another embodiment, R 25ia , R 25ib , R 28ia , R 28ib , R 29ia , and R 29ib is H and R 27ia and / or R 27ib is halogen. In one embodiment, R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib is H and R 27ib is F. In one embodiment, R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib is H and R 27ia and R 27ib Each of is F.

[0137] In one embodiment, the compound of formula (IIi) contains one or more stereocenters. In one embodiment, the compound of formula (IIi) contains R 20i In one embodiment, the compound of formula (IIi) contains a stereocenter at R 21i In one embodiment, the compound of formula (IIi) comprises the moiety [ka] contains a stereocenter at which R is attached to the remainder of formula (IIi). 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R2 8ia , R2 8ib , R2 9ia , and / or R 29ib One or more of the groups contains a stereocenter.

[0138] In one embodiment, the compound of formula (IIi) is one of compounds 5-8, 15-20, 73, 76, 84-86, 101, 102, 104-106, 108, 117, 118, 120, 122, 123, 125, 127, 128, 130-132, 134, 136, or 137.

[0139] In one embodiment, the compound of formula (II) is a compound of formula (IIj) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, [ka] teeth, [ka] is selected from R 20j is selected from H and C1-C6 alkoxy; R 21j is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and —OH, and the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 22j , R 23j, and R 24j are each independently selected from H and halogen.

[0140] In one embodiment, R 20j is H. In another embodiment, R 20j is optionally substituted C1-C6 alkoxy. In one embodiment, R 20j is unsubstituted C1-C6 alkoxy. In one embodiment, R 20j is -OCH3.

[0141] In one embodiment, R 21j is an optionally substituted C-C cycloalkyl. In one embodiment, R 21j is an optionally substituted C cycloalkyl. In one embodiment, R 21j is an unsubstituted C3 cycloalkyl.

[0142] In one embodiment, R 22j , R 23j , and R 24j are each H. In one embodiment, R 22j and R 24j are each independently a halogen, and R 23j is H. In one embodiment, R 22j and R 24j are F and R, respectively. 23j is H. In one embodiment, R 22j and R 24j are H and R 23j is halogen. In one embodiment, R 22j and R 24j are H and R 23j is F.

[0143] In one embodiment, [ka] teeth, [ka] is.

[0144] In one embodiment, the compound of formula (IIj) contains one or more stereocenters. In one embodiment, the compound of formula (IIj) contains R 21j In one embodiment, the compound of formula (IIj) comprises the moiety [ka] contains a stereogenic center that bonds to the remainder of formula (IIj).

[0145] In one embodiment, the compound of formula (IIj) is Compound 75, Compound 100, or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof.

[0146] In one embodiment, the compound of formula (I) is a compound of formula (IIk) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20k is selected from H, halogen, C-C alkyl, C-C alkoxy, C-C cycloalkyl, and —O—(C-C cycloalkyl), wherein the C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, and the C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 21k , R 22k , and R 23k are each independently selected from H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl is optionally substituted with one or more halogens; R 24ka , R 24kb , R 25ka , R 25kb , R 26ka , and R26kb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms.

[0147] In one embodiment, R 24ka , R 24kb , R 25ka , R 25kb , R 26ka , and R 26kb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

[0148] In one embodiment, R 21k , R 22k , and R 23k At least one of R is C-C alkyl. 21k , R 22k , and R 23k are each H. In one embodiment, R 22k is H and R 21k and R 23k are each independently F or -CH3. In another embodiment, R 21k and R 22k are H and R 23k is F or -CH3. In another embodiment, R 22k and R 23k are H and R 21k is F or -CH3. In another embodiment, R 21k and R 23k are H and R 22k is F or -CH3.

[0149] In one embodiment, R 20k is -OCH3 and [ka] is selected from.

[0150] In one embodiment, R 24ka , R 24kb , R 25ka , R 25kb , R 26ka , and R 26kb are each H. In another embodiment, R 25ka , R 25kb , R 26ka , and R 26kb are H and R 24ka and / or R 24kb is F.

[0151] In one embodiment, the compound of formula (IIk) is [ka] is selected from.

[0152] In another embodiment, the compound of formula (I) is a compound of formula (IIm) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20m is selected from C1-C6 alkyl and C1-C6 alkoxy, each of which is optionally substituted with one or more substituents selected from —OH and halogen; R 21m is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C5-C 12 Spiro-fused cycloalkyl, -O-(C6-C 12 aryl), C3-C9 heterocyclyl, and -NR 28ma R 28mbwherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; the C1-C6 alkyl is optionally substituted with one or more -OH; and the C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R 22m , R 23m , and R 24m are each independently selected from H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl is optionally substituted with one or more halogens; R 25ma , R 25mb , R 26ma , R 26mb , R 27ma , and R 27mb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; R 28ma and R 28mb are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0153] In one embodiment, R 25ma , R 25mb , R 26ma , R 26mb , R 27ma , and R 27mb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 25ma , R 25mb , R 26ma , R 26mb , R 27ma , and R 27mbare each H. In another embodiment, R 26ma , R 26mb , R 27ma , and R 27mb are H and R 25ma and / or R 25mb is F.

[0154] In one embodiment, R 22m , R 23m , and R 24m At least one of R is C-C alkyl. 22m , R 23m , and R 24m In another embodiment, at least one of R 22m , R 23m , and R 24m are each H. In another embodiment, R 23m is H and R 22m and R 24m are each independently F, —CH, or —OCH. In another embodiment, R 22m and R 23m are H and R 24m is F, —CH, or —OCH. In another embodiment, R 23m and R 24m are H and R 22m is F, —CH, or —OCH. In another embodiment, R 22m and R 24m are H and R 23m is F, —CH3, or —OCH3.

[0155] In one embodiment, R 20m is -OCH3 and [ka] is selected from.

[0156] In one embodiment, R 21m is unsubstituted C3-C6 cycloalkyl, [ka] is selected from.

[0157] In one embodiment, the compound of formula (IIm) is [ka] [ka] [ka] is selected from.

[0158] In one embodiment, the compound of formula (I) is a compound of formula (IIn) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, [ka] teeth, [ka] is selected from R 20n is selected from H, halogen, C-C alkyl, C-C alkoxy, C-C cycloalkyl, and —O—(C-C cycloalkyl), wherein the C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, and the C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 21n , R 22n , and R 23n are each independently selected from H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl is optionally substituted with one or more halogens; R 25na , R 25nb , R 26na , R 26nb , R 27na , R 27nb , R 28na , R 28nb , R 29na , and R 29nb are each independently selected from H, halogen, —OH, or C1-C6 alkyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms.

[0159] In one embodiment, R 25na , R 25nb , R 26na , R 26nb , R 27na , R 27nb , R 28na , R 28nb , R 29na , and R 29nb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

[0160] In one embodiment, R 21n , R 22n , and R 23n At least one of is C1-C6 alkyl.

[0161] In one embodiment, R 20n is -OCH3 and [ka] is selected from.

[0162] In one embodiment, R 21n , R 22n , and R 23n are each H. In another embodiment, R 22n is H and R 21n and R 23n are each independently F or -CH3. In another embodiment, R 21n and R22n are H and R 23n is F or -CH3. In another embodiment, R 22n and R 23n are H and R 21n is F or -CH3. In another embodiment, R 21n and R 23n are H and R 22n is F or -CH3.

[0163] In one embodiment, [ka] teeth, [ka] and R 25na , R 25nb , R 27na , R 27nb , R 28na , R 28nb、 R 29na , and R 29nb Each of is H. In another embodiment, [ka] teeth, [ka] and R 25na , R 25nb , R 27na , R 27nb , R 28na , R 29na , and R 29nb is H and R 28nb is F.

[0164] In one embodiment, the compound of formula (IIn) is [ka] is selected from.

[0165] In another embodiment, the compound of formula (I) is a compound of formula (IIp) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, [ka] teeth, [ka] is selected from R 20p is selected from C1-C6 alkyl and C1-C6 alkoxy, each of which is optionally substituted with one or more substituents selected from —OH and halogen; R 21p is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C5-C 12 Spiro-fused cycloalkyl, -O-(C6-C 12 aryl), C3-C9 heterocyclyl, and -NR 220pa R 220pb wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; and the C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R 22p , R 23p , and R 24p are each independently selected from H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl is optionally substituted with one or more halogens; R 25pa , R 25pb , R26pa , R 26pb , R 27pa , R 27pb , R 28pa , R 28pb , R 29pa , and R 29pb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R 220pa and R 220pb are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0166] In one embodiment, R 25pa , R 25pb , R 26pa , R 26pb , R 27pa , R 27pb , R 28pa , R 28pb , R 29pa , and R 29pb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

[0167] In one embodiment, R 22p , R 23p , and R 24p At least one of R is C-C alkyl. 22p , R 23p , and R 24pi are each H. In one embodiment, R 23p is H and R 22p and R 24p are each independently F, —CH, or —OCH. In another embodiment, R 22p and R 23p are H and R 24p is F, —CH, or —OCH. In another embodiment, R 23p and R 24p are H and R 22pis F, —CH, or —OCH. In another embodiment, R 22p and R 24p are H and R 23p is F, —CH3, or —OCH3.

[0168] In one embodiment, R 20p is -OCH3 and [ka] is selected from.

[0169] In one embodiment, R 21p is unsubstituted C3-C6 cycloalkyl, [ka] is selected from.

[0170] In one embodiment, [ka] teeth, [ka] and R 25pa , R 25pb , R 27pa , R 27pb , R 28pa , R 28pb , R 29pa , and R 29pb Each of is H. In another embodiment, [ka] teeth, [ka] and R 25pa , R 25pb , R 27pa , R 27pb , R 28pa , R 29pa , and R 29pb is H and R28pb is F.

[0171] In one embodiment, the compound of formula (IIp) is [ka] [ka] [ka] [ka] [ka] is selected from.

[0172] In one embodiment, the compound of formula (I) is a compound of formula (IIq) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, [ka] teeth, [ka] is selected from R 20q is C1-C6 alkoxy optionally substituted with one or more substituents selected from -OH and halogen; R 21q is a C3-C6 cycloalkyl optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 22q and R 23q are each independently a halogen.

[0173] In one embodiment, [ka] teeth, [ka] is.

[0174] In one embodiment, R 20q is unsubstituted C1-C6 alkoxy. In one embodiment, R 20q is -OCH3.

[0175] In one embodiment, R 21q is unsubstituted C-C cycloalkyl. In one embodiment, R 21q is an unsubstituted C3 cycloalkyl.

[0176] In one embodiment, R 22q and R 23q are F respectively.

[0177] In yet another embodiment, the compound of formula (I) is a compound of formula (IIr) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20r is C1-C6 alkoxy optionally substituted with one or more substituents selected from -OH and halogen; R 21r and R 23r are each independently a halogen; R 22r is H, R 24ra , R 24rb , R 25ra , R 25rb , R 26ra , and R 26rb are each independently selected from H and halogen; R 24ra , R 24rb , R 25ra , R 25rb, R 26ra , and R 26rb One or more of the groups is a halogen.

[0178] In one embodiment, R 20r is C1-C6 alkoxy substituted with two halogen atoms. In one embodiment, R 20r is a C substituted with two fluorine atoms 1- In one embodiment, R 20r is a C2 alkoxy substituted with two fluorine atoms. In one embodiment, R 20r teeth, [ka] is.

[0179] In one embodiment, R 21r and R 23r Each is a halogen. In one embodiment, R 21r and R 23r are F respectively.

[0180] In one embodiment, R 25ra , R 25rb , R 26ra , R 24ra , and R 26rb are H and R 24rb is halogen. In one embodiment, R 25ra , R 25rb , R 26ra , R 24ra , and R 26rb are H and R 24rb is F.

[0181] In one embodiment, the compound of formula (IIr) is [ka] or a pharmaceutically acceptable salt thereof.

[0182] In yet another embodiment, the compound of formula (I) is a compound of formula (IIs) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20s is selected from C1-C6 alkyl, C1-C6 alkoxy, and —OH, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more substituents selected from —OH and halogen; R 21s is C1-C6 alkyl, C3-C6 cycloalkyl, C5-C 12 spirofused cycloalkyl, and C3-C9 heterocyclyl, wherein each C1-C6 alkyl is optionally substituted with one or more substituents selected from —OH and halogen, and wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 22s , R 23s , and R 24s are each independently H, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more halogens; R 25sa , R 25sb , R 26sa , R 26sb , R 27sa , and R 27sb are each independently selected from H and halogen; R 25sa , R 25sb , R2 6sa , R2 6sb , R 27sa , and R 27sb One or more of the groups is a halogen.

[0183] In one embodiment, R 20s is unsubstituted C1-C6 alkoxy. In one embodiment, R 20s is -OCH3.

[0184] In one embodiment, R 20s is -OCH3 and R 21s is unsubstituted C3 cycloalkyl or [ka] If (i) R 22s , R 23s , and R 24s At least one of the groups may be CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), or (ii) R 22s is a halogen and R 23s is H, and R 24s is H, or (iii) R 22s is H and R 23s is H and R 24s is halogen. In one embodiment, R 20s is -OCH3 and R 21s but, [ka] If R 22s , R 23s , and R 24s At least one of R is not H. In one embodiment, 20s is -OCH3, R 21s teeth, [ka] isn't it.

[0185] In one embodiment, R 21s is unsubstituted C3-C6 cycloalkyl, [ka] In one embodiment, R 21s is C1-C6 alkyl substituted with one -OH. In one embodiment, R21s is a C alkyl substituted with one -OH. In one embodiment, R 21s teeth, [ka] In one embodiment, R 21s is a C1-C6 alkyl substituted with one -OH and three halogen atoms. 21s is a C alkyl substituted with one -OH and three fluorine atoms. 21s teeth, [ka] In one embodiment, R 21s is a C-C cycloalkyl substituted with one or more C-C alkyls. 21s is substituted with one or more C1-C6 alkyl C4 In one embodiment, R 21s is a C4 cycloalkyl substituted with two -CH3. In one embodiment, R 21s teeth, [ka] is.

[0186] In one embodiment, R 22s , R 23s , and R 24s are each H. In another embodiment, R 23s is H and R 22s , and R 24s Each is a halogen. In one embodiment, R 23s is H and R 22s and R 24s are each F. In another embodiment, R 22s is a halogen and R 23s and R 24s are each H. In one embodiment, R 22s is F and R 23s and R 24sare each H. In another embodiment, R 24s is a halogen and R 22s and R 23s are each H. In one embodiment, R 24s is F and R 22s and R 23s are each H.

[0187] In one embodiment, R 22s , R 23s , and R 24s At least one of the groups is CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), wherein the C1-C6 alkyl is optionally substituted with one or more halogens. 23s is H and R 22s and R 24s are each independently selected from -CH, -OCH, CN, Ccycloalkyl, phenyl, and -O-phenyl. 22s is selected from -CH, -OCH, CN, Ccycloalkyl, phenyl, and -O-phenyl; R 23s and R 24s are each H. In another embodiment, R 24s is selected from -CH, -OCH, CN, Ccycloalkyl, phenyl, and -O-phenyl; R 22s and R 23s are each H.

[0188] In one embodiment, R 25sa , R 26sa , R 26sb , R 27sa , and R 27sb are H and R 25sb is halogen. In one embodiment, R 25sa , R 26sa , R 26sb , R 27sa , and R 27sb are H and R 25sb is F.

[0189] In one embodiment, the compound of formula (IIs) is [ka] [ka] [ka] [ka] and a pharmaceutically acceptable salt of any one of them.

[0190] In one embodiment, the compound of formula (IIs) is one of the following compounds: [ka] or a pharmaceutically acceptable salt thereof.

[0191] In yet another embodiment, the compound of formula (I) is a compound of formula (IIt) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, [ka] teeth, [ka] is selected from R 20t is C1-C6 alkoxy optionally substituted with one or more substituents selected from -OH and halogen; R 21t and R 23t are each independently a halogen; R 22t is H, R24ta , R 24tb , R 25ta , R 25tb , R 26ta , R 26tb , R 27ta , R 27tb , R 28ta , R 28tb , R 29ta , and R 29tb are each independently selected from H and halogen.

[0192] In one embodiment, [ka] teeth, [ka] is.

[0193] In one embodiment, R 20t is C1-C6 alkoxy substituted with two halogen atoms. In one embodiment, R 20t is a C substituted with two fluorine atoms 1- In one embodiment, R 20t is a C2 alkoxy substituted with two fluorine atoms. In one embodiment, R 20t teeth, [ka] is.

[0194] In one embodiment, R 21t and R 23t are F respectively.

[0195] In one embodiment, [ka] teeth, [ka] and R 25ta , R 25tb , R27ta , R 27tb , R 28ta , R 28tb , R 29ta , and R 29tb Each of is H. In another embodiment, [ka] teeth, [ka] and R 25ta , R 25tb , R 27ta , R 27tb , R 28ta , R 28tb , and R 29ta is H and R 29tb is a halogen. [ka] teeth, [ka] and R 25ta , R 25tb , R 27ta , R 27tb , R 28ta , R 28tb , and R 29ta is H and R 29tb is F.

[0196] In one embodiment, the compound of formula (IIt) is [ka] and a pharmaceutically acceptable salt of any one of them.

[0197] In yet another embodiment, the compound of formula (I) is a compound of formula (IIu) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, [ka] teeth, [ka] is selected from R 20u is selected from C1-C6 alkyl, C1-C6 alkoxy, and —OH, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more substituents selected from —OH and halogen; R 21u is C1-C6 alkyl, C3-C6 cycloalkyl, C5-C 12 spirofused cycloalkyl, and C3-C9 heterocyclyl, wherein each C1-C6 alkyl is optionally substituted with one or more substituents selected from —OH and halogen, and wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 22u , R 23u , and R 24u are each independently H, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more halogens; R 25ua , R 25ub , R 26ua , R 26ub , R 27ua , R 27ub , R 28ua , R 28ub , R 29ua , and R 29ubare each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms.

[0198] In one embodiment, [ka] teeth, [ka] is.

[0199] In one embodiment, R 20u is -OCH3 and R 21u is unsubstituted C3 cycloalkyl or [ka] If (i) R 22u , R 23u , and R 24u At least one of the groups may be CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), or (ii) R 22u is a halogen and R 23u is H and R 24u is H, or (iii) R 22u is H and R 23u is H and R 24u is halogen. In one embodiment, R 20u is -OCH3 and R 21u but, [ka] If R 22u , R 23u , and R 24u At least one of R is not H. In one embodiment, 20s is -OCH3, R 21steeth, [ka] isn't it.

[0200] In one embodiment, R 20u is unsubstituted C1-C6 alkoxy. In one embodiment, R 20u is -OCH3.

[0201] In one embodiment, R 21u is unsubstituted C3-C6 cycloalkyl, [ka] In one embodiment, R 21u is C1-C6 alkyl substituted with one -OH. In one embodiment, R 21u is a C alkyl substituted with one -OH. In one embodiment, R 21u teeth, [ka] In one embodiment, R 21u is a C1-C6 alkyl substituted with one -OH and three halogen atoms. 21u is a C alkyl substituted with one -OH and three fluorine atoms. 21u teeth, [ka] In one embodiment, R 21u is a C-C cycloalkyl substituted with one or more C-C alkyls. 21u is a C4 cycloalkyl substituted with one or more C1-C6 alkyls. In one embodiment, R 21u is a C4 cycloalkyl substituted with two -CH3. In one embodiment, R 21u teeth, [ka] is.

[0202] In one embodiment, R 22u , R 23u , and R 24u are each H. In another embodiment, R 23u is H and R 22u and R 24u Each is a halogen. In one embodiment, R 23u is H and R 22u and R 24u are each F. In another embodiment, R 22u is a halogen and R 23u and R 24u are each H. In one embodiment, R 22u is F and R 23u and R 24u are each H. In another embodiment, R 24u is a halogen and R 22u and R 23u are each H. In one embodiment, R 24u is F and R 22u and R 23u are each H.

[0203] In one embodiment, R 22u , R 23u , and R 24u At least one of the groups is CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 12 Aryl, and -O-(C6-C 12 aryl), wherein the C1-C6 alkyl is optionally substituted with one or more halogens. 23u is H and R 22u and R 24u are each independently selected from -CH, -OCH, CN, Ccycloalkyl, phenyl, and -O-phenyl. 22u is selected from -CH, -OCH, CN, Ccycloalkyl, phenyl, and -O-phenyl; R 23u and R 24uare each H. In another embodiment, R 24u is selected from -CH, -OCH, CN, Ccycloalkyl, phenyl, and -O-phenyl; R 22u and R 23u are each H.

[0204] In one embodiment, [ka] teeth, [ka] and R 25ua , R 25ub , R 27ua , R 27ub , R 28ua , R 28ub , R 29ua , and R 29ub Each of is H. In another embodiment, [ka] teeth, [ka] and R 25ua , R 25ub , R 27ua , R 27ub , R 28ua , R 29ua , and R 29ub is H and R 28ub is a halogen. [ka] teeth, [ka] and R 25ua , R 25ub , R 27ua , R 27ub , R 28ua , R 29ua , and R 29ub is H and R28ub is fluorine.

[0205] In one embodiment, the compound of formula (IIu) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] and a pharmaceutically acceptable salt of any one of them.

[0206] In one embodiment, the compound of formula (IIu) is one of the following compounds: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0207] In one embodiment, a compound of Formula (IIr), (IIs), (IIt), or (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, is an inhibitor of at least one of IRAK1, IRAK4, and FLT3. In one embodiment, a compound of Formula (IIr), (IIs), (IIt), or (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, is an inhibitor of IRAK1 and IRAK4. In one embodiment, a compound of Formula (IIr), (IIs), (IIt), or (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, is an inhibitor of IRAK1, IRAK4, and FLT3.

[0208] In another aspect, the disclosure provides a composition comprising a compound of any one of formula (IIr), (IIs), (IIt), or (IIu), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein the composition further comprises a formulating ingredient, adjuvant, or carrier.

[0209] In some embodiments, R 6 is (Ib) which results in the structure of formula (II) as follows: [ka]

[0210] In some embodiments according to Formula (III), q, r, s, t, u, v, w, and x are independently 0, 1, or 2. In some embodiments, q is 0 or 1, r is 0 or 1, s is 0 or 1, t is 0 or 1, u is 0 or 1, v is 0 or 1, w is 0 or 1, and x is 0 or 1.

[0211] In some embodiments, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkoxy, or spirofused cycloalkyl, wherein methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, or spirofused cycloalkyl is optionally substituted with one or more halogens. 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 and one or more of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 All of the are R.

[0212] In addition to any of the embodiments described above in which the compound has the structure of formula (III), the compound may have a structure according to any of (IIIa)-(IIIp), as follows: [ka] [ka] [ka]

[0213] In one embodiment, the compound of formula (III) is a compound of formula (IIIq) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 30q is selected from H and C1-C6 alkoxy; R 31q is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 32q , R 33q , and R 34q are each independently selected from H and halogen.

[0214] In one embodiment, R 30q is H.

[0215] In one embodiment, R 31q is an unsubstituted C-C heterocyclyl. In one embodiment, R 31qis pyrazolyl. In one embodiment, R 31q teeth, [ka] wherein K is N or CH; [ka] wherein d is 1 or 2. In one embodiment, R 31q teeth, [ka] wherein d is 2. In another embodiment, R 31q is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9-heterocyclyl, C6-C 12 and C3-C9 heterocyclyl substituted with one or more substituents selected from aryl, -OH, -C=O, and halogen. 31q teeth, [ka] where R 35q is H, unsubstituted C1-C6 alkyl, unsubstituted C6-C 12 aryl, and unsubstituted C-C heterocyclyl. In one embodiment, R 31q teeth, [ka] where R 35q is H. In one embodiment, R 31q teeth, [ka] where R 35q is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. 31q is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R 31qis isoxazolyl monosubstituted with —CH. In one embodiment, R 31q teeth, [ka] In another embodiment, R 31q teeth, [ka] wherein e is 1, 2, or 3, K is N or CH, and each X is independently a halogen. 31q teeth, [ka] is.

[0216] In one embodiment, R 32q , R 33q , and R 34q are each H. In one embodiment, R 32q and R 34q are each independently a halogen, and R 33q is H. In one embodiment, R 32q and R 34q are F and R, respectively. 33q is H. In one embodiment, R 32q and R 34q are H and R 33q is halogen. In one embodiment, R 32q and R 34q are H and R 33q is F.

[0217] In one embodiment, the compound of formula (IIIq) contains one or more stereocenters.

[0218] In one embodiment, the compound of formula (IIIq) is compounds 32-37, 58, 61, and 65-67, or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof.

[0219] In one embodiment, the compound of formula (III) has the formula (IIIr) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 30r is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 31r is selected from H and C1-C6 alkoxy; R 32r , R 33r , and R 34r are each independently selected from H and halogen.

[0220] In one embodiment, R 30r is an unsubstituted C-C heterocyclyl. In one embodiment, R 30r is unsubstituted pyrazolyl. In one embodiment, R 30r teeth, [ka] wherein L is N or CH; [ka] wherein f is 1 or 2. In one embodiment, R 30r teeth, [ka] wherein f is 2. In another embodiment, R 30r is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9-heterocyclyl, C6-C 12 and C3-C9 heterocyclyl substituted with one or more substituents selected from aryl, -OH, -C=O, and halogen. 30r teeth, [ka] where R 35r is H, unsubstituted C1-C6 alkyl, unsubstituted C6-C 12 aryl, and unsubstituted C-C heterocyclyl. In one embodiment, R 30r teeth, [ka] where R 35r is H. In one embodiment, R 30r teeth, [ka] where R 35r is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. 30r is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R 30r is isoxazolyl monosubstituted with —CH. In one embodiment, R 30r teeth, [ka] In another embodiment, R 30r teeth, [ka] wherein g is 1, 2, or 3, L is N or CH, and each X is independently a halogen. 30r teeth, [ka] is.

[0221] In one embodiment, R 31r is H.

[0222] In one embodiment, R 32r , R 33r , and R 34r are each H. In one embodiment, R 32r and R 34r are each independently a halogen, and R 33r is H. In one embodiment, R 32r and R 34r are F and R, respectively. 33r is H. In one embodiment, R 32r and R 34r are H and R 33r is halogen. In one embodiment, R 32r and R 34r are H and R 33r is F.

[0223] In one embodiment, the compound of formula (IIIr) contains one or more stereocenters.

[0224] In one embodiment, the compound of formula (IIIr) is one of compounds 38-44 and 62, or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof.

[0225] In one embodiment, the compound of formula (III) is a compound of formula (IIIs) [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 30s is selected from H and C1-C6 alkoxy; R 31sis selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 32s , R 33s , and R 34s are each independently selected from H and halogen.

[0226] In one embodiment, R 30s is H.

[0227] In one embodiment, R 31q is an unsubstituted C-C heterocyclyl. In one embodiment, R 31s is pyrazolyl. In one embodiment, R 31s teeth, [ka] wherein M is N or CH; [ka] wherein h is 1 or 2. In one embodiment, R 31s teeth, [ka] wherein h is 2. In another embodiment, R 31s is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9-heterocyclyl, C6-C 12and C3-C9 heterocyclyl substituted with one or more substituents selected from aryl, -OH, -C=O, and halogen. 31s teeth, [ka] where R 35s is H, unsubstituted C1-C6 alkyl, unsubstituted C6-C 12 aryl, and unsubstituted C-C heterocyclyl. In one embodiment, R 31s teeth, [ka] where R 35s is H. In one embodiment, R 31s teeth, [ka] where R 35s is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. 31s is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R 31s is isoxazolyl monosubstituted with —CH. In one embodiment, R 31s teeth, [ka] In another embodiment, R 31s teeth, [ka] wherein i is 1, 2, or 3, M is N or CH, and each X is independently a halogen. 31s teeth, [ka] is.

[0228] In one embodiment, R32s , R 33s , and R 34s are each H. In one embodiment, R 32s and R 34s are each independently a halogen, and R 33s is H. In one embodiment, R 32s and R 34s are F and R, respectively. 33s is H. In one embodiment, R 32s and R 34s are H and R 33s is halogen. In one embodiment, R 32s and R 34s are H and R 33s is F.

[0229] In one embodiment, the compounds of formula (IIIs) contain one or more stereocenters.

[0230] In one embodiment, the compound of formula (IIIs) is selected from compounds 45-51 and 63, or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof.

[0231] In some embodiments, a compound of Formula (I), such as a compound of Formula (II) or Formula (III), is an IRAK inhibitor. In one embodiment, a compound of Formula (I) is an IRAK1, IRAK4, IRAK1 / 4, and / or FLT3 inhibitor. In one embodiment, a compound of Formula (I) is an IRAK1 / 4, panFLT3 inhibitor.

[0232] In some embodiments, the compound of Formula (I), such as a compound of Formula (II) or Formula (III), can be any of Compounds 1-137 or Compounds 1a-84a, as listed in Tables 1-11. In some embodiments, the compound can be Compound 1, Compound 9, Compound 19, Compound 20, Compound 21, Compound 26, Compound 31, Compound 38, Compound 45, Compound 56, Compound 60, Compound 61, Compound 62, Compound 63, Compound 81, Compound 84, Compound 96, Compound 97, or Compound 99.

[0233] In some embodiments, compounds of Formula (I), such as compounds of Formula (II) or Formula (III), may be in the form of salts, optical and geometric isomers, and salts of isomers. In other embodiments, the compounds may be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including, but not limited to, hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates. In some cases, for acidic compounds, salts may include metals, amines, or organic cations (e.g., quaternary ammonium). In still other embodiments, simple derivatives of compounds (e.g., ethers, esters, or amides) may be used that have desirable retention and release characteristics but are easily hydrolyzed by body pH, enzymes, or other suitable means.

[0234] In some embodiments, compounds of the present disclosure having chiral centers exist in and can be isolated in optically active and racemic forms. In other embodiments, compounds may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form of the compounds described herein, including isotopically and radiolabeled compounds, or mixtures thereof. See, e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be isolated by standard resolution techniques, including, for example, fractional crystallization, chiral chromatography, and the like. See, e.g., Eliel, EL & Wilen SH, 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. Preparation of optically active forms can be achieved by any suitable method, including, but not limited to, resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0235] In some embodiments, the compounds disclosed herein have asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, and all isomeric forms and mixtures thereof are contemplated for use in the compounds and methods described herein. Compounds contemplated for use in the compounds and methods described herein do not include those known in the art to be too unstable to synthesize and / or isolate.

[0236] The compounds disclosed herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope contemplated.

[0237] In some embodiments, metabolites of the compounds disclosed herein are useful in the methods disclosed herein.

[0238] In some embodiments, compounds contemplated herein may be provided in the form of a prodrug. The term "prodrug" refers to a compound that can be converted in vivo to a compound described herein (e.g., a biologically active compound). Prodrugs may be useful for a variety of reasons known in the art, including ease of administration, such as by enhancing oral bioavailability. Prodrugs may also have improved solubility in pharmaceutical compositions relative to the biologically active compound. One example, without limitation, of a prodrug is a compound that is administered as an ester (i.e., a "prodrug") to facilitate transport across cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the active carboxylic acid once inside the cell, where water solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in *Design of Prodrugs* (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference for the limited purpose of describing the procedures and preparation of suitable prodrug derivatives.

[0239] Certain compounds disclosed herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the contemplated compounds. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.

[0240] In certain embodiments, one or more compounds of the present disclosure (e.g., Formula (I)) may be part of a composition and may be at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 15 ... %, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, or about 99.99% or less, 0.0001% to about 99%, 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75% (by weight of the total composition).

[0241] In some embodiments, one or more compounds of the present disclosure (e.g., Formula (I)) are present in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35 ... It may be purified or isolated in an amount of about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, about 99.99% or less, 0.0001% to about 99%, 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75% (by weight of the total composition).

[0242] Processes for preparing compounds of formula (I) Some embodiments of the present disclosure include methods for the preparation of compounds of Formula (I). In certain embodiments, compounds of Formula (I) can be prepared comprising one or more of the steps described in Examples 2-15 herein. The synthetic routes shown and described in Examples 2-15 can be used to prepare, for example, compounds 1-137 or compounds 1a-84a, and structurally related compounds, described in Tables 1-11.

[0243] Combination therapy In one embodiment, the compound of formula (I) is administered with one or more therapeutic agents.Exemplary therapeutic agents include CDK inhibitors, BCL2 inhibitors, PTEFb inhibitors, DNA polymerase inhibitors, cytidine deaminase inhibitors, DNA methyltransferase (DNMT) inhibitors, immunomodulatory imides, cereblon modulators, purine nucleoside antimetabolites, type II topoisomerase inhibitors, DNA intercalators, hedgehog antagonists, IDH2 inhibitors, IDH1 inhibitors, ribonucleotide reductase inhibitors, adenosine deaminase inhibitors, Mek 1 / 2 inhibitors, ERK inhibitors, and the like. 1 / 2 inhibitors, AKT inhibitors, PTPN11 inhibitors, SHP2 inhibitors, glucocorticoid steroids, menin inhibitors, MDM2 inhibitors, BTK inhibitors, mutated / inactivated p53 reactivators, chemotherapeutic agents, BCL2 inhibitors, immunomodulators, DNA hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAb / immunotherapy, Plk inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, smoothened receptor agonists agonists, ERK1 inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura These include, but are not limited to, EGFR inhibitors, Aurora kinase inhibitors, EGFR inhibitors, Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT 1, 2, and / or 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, menin-KMT2A / MLL inhibitors, and multikinase inhibitors.

[0244] In one embodiment, a compound of Formula (I) or a composition comprising a compound of Formula (I) is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof; the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them; the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitor BAY1251152 and atubeciclib, or a pharmaceutically acceptable salt of any one of them; or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.

[0245] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a salt thereof. In one embodiment, the therapeutic agent comprises a DNA polymerase inhibitor. In one embodiment, the DNA polymerase inhibitor is cytidine. In one embodiment, the therapeutic agent comprises a cytidine deaminase inhibitor. In one embodiment, the cytidine deaminase inhibitor is zebularine. In one embodiment, the therapeutic agent comprises a DNMT inhibitor. In one embodiment, the DNMT inhibitor is zebularine, decitabine, or azacytidine. In one embodiment, the therapeutic agent comprises an immunomodulatory imide (cereblon-modulating agent). In one embodiment, the immunomodulatory imide (cereblon-modulating agent) is lenalidomide. In one embodiment, the therapeutic agent comprises a purine nucleoside antimetabolite. In one embodiment, the purine nucleoside antimetabolite is clofarabine. In one embodiment, the therapeutic agent comprises a type II topoisomerase inhibitor / DNA intercalator. In one embodiment, the type II topoisomerase inhibitor / DNA intercalator is vosaroxin. In one embodiment, the therapeutic agent comprises a hedgehog antagonist. In one embodiment, the hedgehog antagonist is glasdegib. In one embodiment, the therapeutic agent comprises an IDH1 inhibitor. In one embodiment, the IDH1 inhibitor is ivosidenib. In one embodiment, the therapeutic agent comprises an IDH2 inhibitor. In one embodiment, the IDH2 inhibitor is enasidenib. In one embodiment, the therapeutic agent comprises a ribonucleotide reductase inhibitor. In one embodiment, the ribonucleotide reductase inhibitor is gemcitabine. In one embodiment, the therapeutic agent comprises an adenosine deaminase inhibitor. In one embodiment, the adenosine deaminase inhibitor is cladribine. In one embodiment, the therapeutic agent comprises a Mek1 / 2 inhibitor. In one embodiment, the Mek1 / 2 inhibitor is trametinib. In one embodiment, the therapeutic agent comprises an ERK1 / 2 inhibitor. In one embodiment, the ERK1 / 2 inhibitor is ulixertinib. In one embodiment, the therapeutic agent comprises an AKT inhibitor. In one embodiment, the AKT inhibitor is capivasertib (AZD5363). In one embodiment, the therapeutic agent comprises a PTPN11 / SHP2 inhibitor.In one embodiment, the PTPN11 / SHP2 inhibitor is TNO-155. In one embodiment, the therapeutic agent comprises a glucocorticoid steroid. In one embodiment, the glucocorticoid steroid is prednisolone. In one embodiment, the therapeutic agent comprises a menin inhibitor. In one embodiment, the menin inhibitor is SNDX-5613. In one embodiment, the therapeutic agent comprises an MDM2 inhibitor. In one embodiment, the MDM2 inhibitor is nabtemadrine (AMG 232, KRT-232). In one embodiment, the therapeutic agent comprises a BTK inhibitor. In one embodiment, the BTK inhibitor is selected from ibrutinib, acalabrutinib, and zanubrutinib. In one embodiment, the therapeutic agent comprises a mutated / inactivated p53 reactivator. In one embodiment, the mutated / inactivated p53 reactivator is eprenetapopt (APR-246).

[0246] In one embodiment, the therapeutic agent comprises a CDK inhibitor. The CDK inhibitor can be any CDK inhibitor known to those skilled in the art. In one embodiment, the CDK inhibitor is a CKD1, CKD2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13 inhibitor, or a combination thereof.

[0247] In one embodiment, the CDK inhibitor comprises an inhibitor described in one of the following patents or patent applications: US 2021 / 0332071, US 2021 / 0330653, WO 2021 / 214253, WO 2021 / 178595, WO 2021 / 207632, US 8685660, US 2020 / 0361906, US 10695346, US 11142507, WO 2021 / 198439, WO 2021 / 201170, US 8153632, US 11013743, US 11135198, US 2021 / 0299111, WO 2021 / 190637, WO 2021 / 188855, WO 2021 / 188849, US 2021 / 0292299, US 11124836, US 10961527, US 2021 / 0284629, US 2021 / 0283265, WO 2021 / 183994, WO 2021 / 181233, US 11116755, WO 2021 / 176045, WO 2021 / 177816, WO 2021 / 176049, WO 2021 / 176349, US 2021 / 0275522, US 2021 / 0275491, US 2021 / 0277037, US 11111250, WO 2021 / 142448, WO 2021 / 172359, WO 2021 / 174195, US 2021 / 0260209, US 2021 / 0261609, US 2021 / 0261636, US 2021 / 0261546, WO 2021 / 168341, US 11014911, US 9932344, US 8415355, US 11091485, US 11091490, US 2021 / 0246422, US 2021 / 0246138, US 2021 / 0244715, US 11083722, US 11083728, US 2021 / 0238226, US 2019 / 0142835, WO 2021 / 155006, WO 2021 / 152107, WO 2021 / 155192, US 10294234, US 11077156, WO 2021 / 148793, WO 2021 / 149817, US 2021 / 0228529, US 2021 / 0228546, US 2021 / 0228723, US 10568887, US 2019 / 0209549, US11072596、US 2021 / 0222133、US 10336760、WO 2021 / 144302、US 2021 / 0196796、US 11066404、US 2021 / 0213029、US 2021 / 0213012、US 9642835、US 8673972、US 2021 / 0205304、WO 2021 / 108648、WO 2020 / 140054、US 11053238、US 11052087、US 10245251、WO 2021 / 133601、WO 2021 / 133957、WO 2021 / 127133、WO 2021 / 124106、WO 2021 / 122745、US 10849903、US 2021 / 0186979、US 11040957、WO 2021 / 115335、US 11034710、WO 2021 / 110136、WO 2021 / 110731、WO 2021 / 108927、WO 2021 / 110122、US 2021 / 0171554、US 10966977、US 2021 / 0171498、US 11028087、US 2021 / 0161909、WO 2021 / 108581、US 10300073、WO 2021 / 102234、WO 2021 / 102410、US 11014906、US 11013728、WO 2021 / 092672、US 2021 / 0147424、US 2018 / 0147202、US 2021 / 0145974、US 11007174、US 2021 / 0139459、US 2021 / 0139474、US 2021 / 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0238745、US 2008 / 0312223、US 7465728、US 6710227、US 2008 / 0293785、US 7456191、US 6916798、WO 2008 / 137139、US 2008 / 0280906、US 7449544、US 2008 / 0275063、US 7446195、US 7446105、WO 2008 / 130569、US 7442697、WO 2008 / 120098、WO 2008 / 115499、US 7388015、US 7427626、WO2008 / 073304、US 7329799、US 7407745、US 7393953、US 2008 / 0153822、US 2008 / 0146555、WO 2007 / 044401、US 6821990、US 7041824、US 7354946、US 7348335、US 7335674、WO 2008 / 021210、US 2008 / 0026992、US 2008 / 0027052、US 7312225、US 2007 / 0287718、WO 2007 / 139732、WO 2007 / 110649、US 2007 / 0275382、US 7300943、WO 2007 / 123686、US 7288547、US 7279473、WO 2007 / 022241、US 7268231、WO 2007 / 098090、WO 2007 / 098089、WO 2007 / 097109、WO 2007 / 095389、US 7258981、WO 2007 / 054725、US 2007 / 0179161、US 7250515、WO 2007 / 081060、US 2007 / 0167466、US 2007 / 0155816、US 7232826、US 7081454、US 7208598、US 6645990、US 6822097、US 2007 / 0021419、US 7166602、US 2007 / 0004684、US 7153964、US 6914062、US 2006 / 0269482、US 2006 / 0252748、US 2004 / 0147561、US 2006 / 0241297、US 2006 / 0239973、WO 2006 / 106046、WO 2006 / 105386、US 7109220、US 2006 / 0194883、US 2006 / 0148828、US 2006 / 0147922、WO 2006 / 070202、WO 2004 / 066935、US 7008953、US 2006 / 0142312、US 6838464、US 2006 / 0135589、US 2005 / 0125054、US 2006 / 0078535、US 6635640、US 2006 / 0111378、WO 2006 / 051951、WO 2006 / 024945、US 7026313、US 6982260、US2004 / 0077601、US 2005 / 0288307、US 2005 / 0277656、US 2005 / 0276866、US 2005 / 0272755、US 2004 / 0029151、US 2005 / 0267066、US 6627633、US 2005 / 0261260、US 2005 / 0136177、US 2004 / 0219214、US 2005 / 0222163、US 6953783、US 2005 / 0222054、US 6949558、US 6667311、WO 2005 / 002576、WO 2005 / 083096、WO 2004 / 078925、US 6939872、US 2005 / 0175592、US 6927031、US 6899731、US 2005 / 0164976、US 2005 / 0153991、US 6838558、WO 2005 / 044274、US 2005 / 0090529、US 2004 / 0082613、US 2005 / 0070591、US 2004 / 0180844、US 2003 / 0157704、US 6863647、US 6858709、US 6849631、US 2005 / 0004120、WO 2004 / 113353、US 2004 / 0254094、US 2004 / 0248905、WO 2004 / 107240、US 2004 / 0242869、US 2004 / 0225077、US 6812232、US 6720427、US 2004 / 0185506、US 2004 / 0186288、US 6747046、US 2004 / 0180043、US 2004 / 0180848、US 2004 / 0176431、US 2004 / 0156826、US 2004 / 0152651、US 2004 / 0138245、US 6756385、US 2004 / 0110775、US 2004 / 0110770、US 6747128、US 6743785、WO 2004 / 004730、WO 2004 / 031158、US 6720332、WO 2004 / 028571、US 6716831、US 6713267、US 6710052、US 6706718、US 2004 / 0048849、US 2003 / 0187007、US 6696546、US 6683095、US2004 / 0010027, US 6677345, US 6630464, US 2003 / 0229105, US 6569878, US 2003 / 0215861, US 6649608, US 2003 / 0064426, WO 2003 / 091700, US 6642231, US 6632820, US 6620818, US 2003 / 0166016, US 6596694, US 6586203, US 2003 / 0119816, US 2003 / 0113897, US 2003 / 0114504, US 6579903, US 6576647, US 6573044, US 6043030, US 2003 / 0049602, US 2003 / 0100477, US 2003 / 0032177, WO 2003 / 030909, US 6319918, WO 2003 / 027299, US 2003 / 0060397, US 6504034, WO 2002 / 074742, WO 2002 / 053096, US 2003 / 0018005, US 6500846, WO 2002 / 100401, US 6486166, WO 2002 / 072085, US 6462069, US 6451618, US 6420345, WO 2002 / 051849, US 6413974, US 6414013, US 6407103, WO 2001 / 083716, US 5672508, US 6291504, WO 2001 / 038532, WO 2001 / 027080, US 6303618, US 6290951, WO 2001 / 055148, WO 2001 / 053293, US 6001868, US 6197804, WO 1999 / 066055, US 6013646, WO 1999 / 043676, US 5767258, US 5733920, and any INPADOC family member of each of the above references (each of which is incorporated herein by reference in its entirety). In another embodiment, the CDK inhibitor comprises an inhibitor described in: Alsofouk, A., Journal of Enzyme Inhibition and Medicinal Chemistry, 2021, 36(1):693-706; Goel, B. et.al.,Curr.Top.Med.Chem.,2020,20(17):1535-1563, Heptinstall,ABet al.,Future Med.Chem.,2018,10(11):1369-1388, Sanchez-Martinez,C.et al.,Bioorganic & Medicinal Chemistry Letters,2019,29:126637, Di Sante,G.et al.,Expert Review of Anticancer Therapy,2019,19(7):569-587,Whittaker,SRet al.,Pharmacology & Therapeutics,2017,173:83-105,Chou,J.et al.,Cancer Discovery,2020,10:351-370,Galbraith,MDet al., Transcription, 2019, 10(2):118-136; Goel, B. et al., Current Topics in Medicinal Chemistry, 2020, 20:1535-1563; Heptinstall, A. B. et al., Future Medicinal Chemistry, 2018, 10(11):1369-1388 (each of which is incorporated herein by reference in its entirety).

[0248] In one embodiment, the CDK inhibitor is a CDK9 inhibitor. In one embodiment, the CDK9 inhibitor is atubeciclib (BAY-1143572) or BAY-1251152 (VIP152). In one embodiment, BAY-1251152 (VIP152) is a selective CDK9 inhibitor, while atubeciclib (BAY-1143572) is a CDK9 / PTEFb inhibitor. In one embodiment, the CDK inhibitor is a CDK4 / 6 inhibitor. In one embodiment, the CDK4 / 6 inhibitor is palbociclib. In one embodiment, the CDK inhibitor is a CDK7 inhibitor. In one embodiment, the CDK7 inhibitor is THZ1.

[0249] Exemplary CDK inhibitors include, but are not limited to, Compound 21 (PMID 27326333), CYC065, YKL-1-116, i-CDK9, JH-VII-49, JH-XI-10-02, SEL120-34A, MM-D37K, PF-06873600, BEY-1007, BEY-1107, vilociclib (XZP-3297), FCN-437, TP-1287, BEBT-209, TQB-3616, AMG-925 (FLX -925), CS3002, HS-10342, Terameprocol (EM-1421), NU-6102, CGP-60474, BMS-265246, NU-6027, Purvalanol A, Purvalanol B, RGB-286147, Indirubin, 7-hydroxystaurosporine, BS-194, PHA-690509, Cdk4 / 6 inhibitor IV, FCN437c, [ka] dinaciclib (SCH 727965), [ka] CDKI-73 (LS-007), [ka] flavopiridol (alvocidib), [ka] ginaciclib, [ka] SNS-032 (BMS-387032), [ka] (RGB286638), [ka] (zortiraciclib, TG02, SB1317), [ka] (atubeciclib, BAY-1143572), [ka] (AZD4573), [ka] Abemaciclib (LY2835219, Verzenio), [ka] palbociclib (PD-0332991, Ibrance), [ka] ribociclib (LEE-011, Kisqali), [ka] PF-06873600, [ka] Trilaciclib (G1T28), [ka] Relociclib (G1T38), [ka] SHR-6390, [ka] Milciclib (PHA-848125), [ka] FN-1501, [ka] Inditinib (AGM-130), [ka] (+)-BPI-16350, [ka] AT-7519, [ka] AZD-4573, [ka] voruciclib (P-1446A-05), [ka] BCD-115, [ka] CT7001 (ICEC 0942), [ka] CYC-065, [ka] Seliciclib (R-roscovitine, CY-202), [ka] SY-1365, [ka] Roniciclib (BAY-1000394), [ka] THZ1, [ka] THZ2, [ka] THZ531, [ka] E9, [ka] FMF-04-159-2, [ka] YKL-5-124, [ka] NU6300, [ka] SY-314, [ka] SY-351, [ka] dabrafenib, [ka] Rebastinib, [ka] K03861, [ka] MC180295, [ka] BRD6989, [ka] SR-3029, [ka] nordihydroguaiaretic acid (NDGA), [ka] Protaglandin E1, [ka] Adapalene, [ka] Fluspirilene, [ka] Candesartan cilexil, [ka] indocyanine green, [ka] Rafoxanide, [ka] HSD922, [ka] 20-223(CP668863), [ka] Roxyl-zhc-84, [ka] Abemaciclib, [ka] vorinostat, [ka] Cabozantinib, [ka] cortistatin A, [ka] MSC2530818, [ka] CCT251545, [ka] CCT251921, [ka] ZK-304709, [ka] Ribiciclib (P276-00), [ka] R547, [ka] AZD5438, [ka] AG-024322, [ka] LDC3140, [ka] LDC4297, [ka] Wogonin, [ka] CMPD14, [ka] LDC000067, [ka] CMPD 93, [ka] sorafenib, [ka] Senexin A, [ka] Senexin B, [ka] CMPD 20, [ka] CMPD 32, [ka] SEL120, [ka] PHA-793887, [ka] IIIM-290, [ka] Olomoucine, [ka] Rohitskin, [ka] fascaplysin, [ka] Hymenialdisine, [ka] Variolin B, [ka] Kombuacidin A, [ka] staurosporine, [ka] LY2857785, [ka] BS-181, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] BS-181, [ka] [ka] (Wherein, Ar is [ka] ), [ka] wherein X is N, Y is —C(═O)H, and Ar is [ka] X is N, Y is —CHOH, and Ar is [ka] or X is CH, Y is —CHOH, and Ar is [ka] ), [ka] wherein X is NH or O; [ka] wherein X is NH or O; [ka] (Wherein R1 is [ka] ), [ka] wherein R is H or -CH3; [ka] wherein R is -CH3, X is F, R is H, and X is F, or R is -CH3, and X is Cl; [ka] wherein R is tetrahydro-pyran-4-yl and R ’ is H or R is -CH2CH3 and R ’ is -OCH3, or R is isopropyl and R' is H, or R is -CH2CH3 and R' is F), [ka] wherein R is t-butylcarboxyl and n is 1, or R is H and n is 2; [ka] wherein X is NH or O; [ka] wherein R is H and R' is F, or R is F and R' is F, or R is H and R' is H, [ka] wherein R is -OCH3 and R' is F, or R is F and R' is SF5, or R is -OCH3 and R' is -SF5, [ka] wherein R is F and R' is -CH3, or R is -SF5 and R' is H; [ka] wherein R is —CF and R′ is —CH, or R is H and R′ is cyclopropyl; [ka] wherein R is 3-fluoroailin-1yl and R' is F, or R is phenyl and R' is -CH; [ka] wherein R is H or F, and alkyl is —CH or —CHCH, [ka] wherein R is 3-fluorophenyl or morpholin-4-yl; [ka] wherein R is cyclopropan-1-ol-1-yl, X is Cl, and n is 1, or R is tetrahydrofuran-3-yl, X is Cl, and n is 1, or R is -CH3, X is F, and n is 2, or R is cyclopropan-1-1-yl, X is F, and n is 1, or oxatan-3-yl, X is -CH3, and n is 1, [ka] wherein R is 1,2-oxazol-3yl or 3,4-difluorobenzene-1yl, [ka] wherein R is H, C(=O)NHCH3, -SO2NH2, SO2CH3, or 2,3-dihydroxpropan-1yl; [ka] wherein R is H, CH, 2-aminoethyan-1yl, 3-aminopropan-1yl, or 2,3-dihydroxpropan-1yl; [ka] wherein R is H or -CH3; [ka] wherein R is H, C(=O)NHCH3, or -SO2CH3; [ka] wherein R is 3-fluorobenzyl or 3-fluoropyridin-3yl, [ka] wherein aryl is 4-fluorophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 4-methylphenyl, 2-ethylphenyl, or 3-pyridyl, and R is H, cyclopropyl, cylcopentyl, or cycloheptyl; [ka] wherein R is 2-phenylethan-1yl or (furan-2-yl)methyl; [ka] wherein R is H or —C(═O)CHOH, [ka] wherein R is —NHC(═O)CH or —NHSOCH, [ka] wherein R is H or isobutyl; [ka] wherein R is H and R' is -CH3, or R is -CN and R' is H; [ka] wherein R is 3,4-dimethyl-1H-pyrazol-4-yl and R' is -CH3, or R is piperazin-1yl and R' is H, [ka] wherein R is 2,6-dichlorophenyl, 2,3,4,5,6-tetrafluorophenyl, or 3-fluorophenyl; [ka] wherein R is —CHNCH or H, [ka] wherein R is —CHN(CH) or H; [ka] wherein R is H, —SO2CH3, —CH2C(═O)N(CH3)2, 4-carboxylic acid-cyclobutan-1yl, or (2(hydroxymethy)pyrrolidin-1-yl)-2-one-ethan-1yl, R′ is H or F, and R″ is H or —CH2CH3, [ka] (wherein R1 is -OH, R2 is H, R3 is H, and R4 is H (meridianin A); R1 is -OH, R2 is H, R3 is Br, and R4 is H (meridianin B); R1 is H, R2 is Br, R3 is H, and R4 is H (meridianin C); R1 is H, R2 is H, R3 is Br, and R4 is H (meridianin D); or R1 is -OH, R2 is H, R3 is H, and R4 is Br (meridianin E)), and [ka] wherein R is piperidin-3yl, pyrrolidin-3yl, or morpholin-2yl.

[0250] In one embodiment, the therapeutic agents comprise a BCL2 inhibitor and a DNMT inhibitor. In one embodiment, the therapeutic agents comprise venetoclax, or a salt thereof, and azacitidine, or a salt thereof.

[0251] In some embodiments, one or more therapeutic agents may be in the form of salts, optical and geometric isomers, and salts of isomers. In other embodiments, the therapeutic agent may be in various forms, such as an uncharged molecule, a component of a molecular complex, or a non-irritating pharmacologically acceptable salt, including, but not limited to, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some cases, for acidic compounds, salts may include metal, amine, or organic cations (e.g., quaternary ammonium). In still other embodiments, simple derivatives (e.g., ethers, esters, or amides) of the therapeutic agent may be used that have desirable retention and release characteristics but are easily hydrolyzed by body pH, enzymes, or other suitable means.

[0252] In some embodiments, a therapeutic agent has a chiral center and exists in and can be isolated in optically active and racemic forms. In other embodiments, a therapeutic agent may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form of the compounds described herein, including isotopically and radiolabeled compounds, or mixtures thereof. See, e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be isolated by standard resolution techniques, including, for example, fractional crystallization, chiral chromatography, and the like. See, e.g., Eliel, EL & Wilen SH, 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. Preparation of optically active forms can be accomplished by any suitable method, including, but not limited to, resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0253] In some embodiments, therapeutic agents possess asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, and all isomeric forms, as well as mixtures thereof, are contemplated for use in the compounds and methods described herein. Compounds contemplated for use in the compounds and methods described herein do not include those known in the art to be too unstable to synthesize and / or isolate.

[0254] The therapeutic agents disclosed herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope contemplated.

[0255] In some embodiments, metabolic products of the therapeutic agents disclosed herein are useful in the methods disclosed herein.

[0256] In some embodiments, therapeutic agents contemplated herein may be provided in the form of a prodrug. The term "prodrug" refers to a compound that can be converted in vivo to a compound described herein (e.g., a biologically active compound). Prodrugs may be useful for a variety of reasons known in the art, including ease of administration, such as by enhancing oral bioavailability. Prodrugs may also have improved solubility in pharmaceutical compositions relative to the biologically active compound. One example, without limitation, of a prodrug is a compound that is administered as an ester (i.e., a "prodrug") to facilitate transport across cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the active carboxylic acid once inside the cell, where water solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in *Design of Prodrugs* (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference for the limited purpose of describing the procedures and preparation of suitable prodrug derivatives.

[0257] Certain therapeutic agents disclosed herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the contemplated compounds. Certain therapeutic agents of the present disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.

[0258] Pharmaceutical Compositions and Formulations In one embodiment, the present disclosure further relates to a composition comprising a compound of Formula (I) and a composition comprising a therapeutic agent. Exemplary therapeutic agents are described elsewhere herein. In another embodiment, the compound of Formula (I) and the therapeutic agent are co-formulated into a single composition. In one embodiment, the compound of Formula (I) and the therapeutic agent are administered together in a single dose or in a single composition. In another embodiment, the compound of Formula (I) and the therapeutic agent are administered separately in two or more doses or in two or more compositions. In one embodiment, the composition comprising a compound of Formula (I) and the composition comprising a therapeutic agent are administered simultaneously to a subject. In another embodiment, the composition comprising a compound of Formula (I) and the composition comprising a therapeutic agent are administered sequentially to a subject. In one embodiment, the composition comprising a compound of Formula (I) and the composition comprising a therapeutic agent are administered simultaneously (or within a defined period of time) such that the subject is exposed to both inhibitors over a period of time during which they can act synergistically.

[0259] Some embodiments of the present disclosure include compositions comprising one or more compounds of the present disclosure (e.g., Formula (I)). In one embodiment, a composition comprising a compound of the present disclosure further comprises one or more therapeutic agents described elsewhere herein. In one embodiment, the present disclosure includes a separate composition comprising one or more of the therapeutic agents described elsewhere herein. In certain embodiments, the composition is a pharmaceutical composition, such as a composition suitable for administration to an animal (e.g., a mammal, a primate, a monkey, a human, a dog, a cat, a pig, a mouse, a rabbit, a rat, etc.). In some embodiments, a pharmaceutical composition is provided comprising a compound disclosed herein and a pharmaceutically acceptable excipient. The compound can be any compound of Formulas (I)-(III) disclosed herein, a compound described in Tables 1-11, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof. In some embodiments, the compound is described in any of Tables 1-11 herein.

[0260] Further embodiments of the present disclosure relate to compositions comprising the above-described compounds. In some embodiments, the amount of compound may be from about 0.0001% (by weight of the total composition) to about 99%. In some embodiments, the composition may further comprise a formulation ingredient, adjuvant, or carrier. In some embodiments, the composition may further comprise a BCL2 inhibitor. In some embodiments, the composition may be used in combination with a second composition comprising a BCL2 inhibitor. In some embodiments, the BCL2 may be venetoclax, or a salt, isomer, derivative, or analog thereof.

[0261] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound disclosed herein contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfate, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0262] The compounds disclosed herein may exist as salts with pharmaceutically acceptable acids, etc. Thus, the compounds contemplated herein include such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts containing amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0263] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0264] Pharmaceutically acceptable salts of the above compounds in which a basic or acidic group is present in the structure are also included within the scope of the compounds contemplated herein. When acidic substituents such as -NHSOH, -COOH, and -P(O)(OH) are present, ammonium, sodium, potassium, calcium salts, and the like can be formed for use as dosage forms. Acidic salts such as amino or basic heteroaryl radicals or pyridyl, and hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like can be used as dosage forms.

[0265] In embodiments where R—COOH is present, pharmaceutically acceptable esters may also be used, such as methyl, ethyl, tert-butyl, pivaloyloxymethyl, etc., and esters known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0266] In some cases, pharmaceutical compositions are non-toxic, do not cause side effects, or both, while in some embodiments, there may be inherent side effects (e.g., they may be harmful to the patient or may be toxic or harmful to some extent in some patients).

[0267] In some embodiments, one or more compounds of the present disclosure (e.g., Formula (I)) may be part of a pharmaceutical composition, and may be at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, The amount of the pharmaceutical composition may be 0.001%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, about 99.99% or less, 0.001% to about 99%, 0.001% to about 50%, about 0.1% to about 99%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%. In some embodiments, the pharmaceutical composition may be presented in a dosage form suitable for topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, dermal, nasal, vaginal, or ocular administration. In other embodiments, the pharmaceutical composition may be presented in a dosage form suitable for parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. The pharmaceutical composition may be, for example, a tablet, capsule, pill, granule, suspension, emulsion, solution, gel (including hydrogel), paste, ointment, cream, plaster, drench, delivery device, suppository, enema, injectable, implant, spray, aerosol, or other suitable form.

[0268] In some embodiments, the compounds disclosed herein can be orally administered as tablets, aqueous or oily suspensions, drops, lozenges, powders, granules, emulsions, capsules, syrups, or elixirs. Compositions for oral use can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to produce pharmaceutically elegant and palatable preparations. Thus, pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein are also provided.

[0269] In some embodiments, tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate; (2) granulating and disintegrating agents such as corn starch or alginic acid; (3) binders such as starch, gelatin, or acacia; and (4) lubricants such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used.

[0270] For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powder, tablets, pills, capsules, cachets, suppositories and dispersible granules.Solid carriers can be one or more substances that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0271] For in vivo applications, the compounds disclosed herein, in the form of free compounds or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts, can be administered parenterally by injection or by gradual perfusion over time. Administration can be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavity, or transdermal. For in vitro studies, the compounds can be added or dissolved in an appropriate biologically acceptable buffer and added to cells or tissues.

[0272] In powders, the carrier is a finely divided solid in admixture with the finely divided active component. In tablets, the active component is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0273] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound containing an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier, thereby associating it with the carrier. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0274] For preparing suppositories, a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein as by stirring, etc. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0275] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0276] When parenteral application is required or desired, particularly suitable mixtures for the compounds disclosed herein are injectable sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. These suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles, carriers, and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables. Specifically, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, etc. Ampoules are convenient unit doses. The compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical mixtures suitable for use in the pharmaceutical compositions and methods disclosed herein include, for example, those described in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of both of which are incorporated herein by reference.

[0277] In some embodiments, preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol, and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water, alcohol, glycerol, and polyols. Intravenous vehicles include fluid and nutrient replenishers. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose, and sodium chloride. Intravenous vehicles for lactated Ringer's include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, growth factors, and inert gases and the like.

[0278] Preservatives include antibacterial agents, antioxidants, chelating agents, and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions and non-toxic excipients, including salts, preservatives, buffers, etc., as described, for example, in Remington's Pharmaceutical Sciences, 15th ed., Easton: Mack Publishing Co., pp. 1405-1412, 1461-1487 (1975) and The National Formulary XIV., 14th ed., Washington: American Pharmaceutical Association (1975), the contents of which are incorporated herein by reference. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine techniques in the art. See, for example, Goodman and Gilman (eds.), 1990, The Pharmacological Basis for Therapeutics (7th ed.).

[0279] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers and thickeners as needed.Aqueous suspensions suitable for oral use can be prepared by dispersing finely divided active ingredients in water using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.Aqueous suspensions usually contain the active substance mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients may be (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; (2) dispersing or wetting agents which may be (a) a naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, e.g., polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, e.g., heptadecaethyleneoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, e.g., polyoxyethylene sorbitol monooleate; or (e) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, e.g., polyoxyethylene sorbitan monooleate.

[0280] Also included are solid form preparations intended to be converted immediately before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0281] Pharmaceutical preparations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form may be a packaged preparation, the package containing discrete amounts of preparations such as packets of tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or drop itself, or the appropriate number of any of these in packaged form.

[0282] In some embodiments, the pharmaceutical composition may include one or more formulary ingredients. The "formulary ingredients" may be any suitable ingredients (e.g., appropriate for the drug, drug dosage, drug release timing, disease state, or delivery route), and may include water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water containing chloroform), sugars (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made therefrom), ethanol, glycerol, glycols (e.g., propylene glycol), acetone, ethers, DMSO, surfactants (e.g., anionic surfactants, cationic surfactants, zwitterionic surfactants), or the like. The additives include, but are not limited to, an antioxidant, such as a surfactant, or a non-ionic surfactant (e.g., polysorbate), an oil (e.g., animal oil, vegetable oil (e.g., coconut oil or peanut oil), or mineral oil), an oil derivative (e.g., ethyl oleate, glyceryl monostearate, or hydrogenated glycerides), an excipient, a preservative (e.g., cysteine, methionine, an antioxidant (e.g., vitamins (e.g., A, E, or C), selenium, retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens (e.g., methylparaben or propylparaben)), or a combination thereof.

[0283] In certain embodiments, pharmaceutical compositions can be formulated to release the active ingredient (e.g., one or more compounds of the present disclosure, such as Formula (I)) substantially immediately upon administration, or at any substantially predetermined time or time after administration. Such formulations can include controlled-release formulations, such as, for example, various controlled-release compositions and coatings.

[0284] Other formulations (eg, formulations of pharmaceutical compositions) may, in certain embodiments, include incorporating the drug (or controlled release formulation) into a food, foodstuff, feed, or beverage.

[0285] Some compounds may have limited water solubility and therefore may require a surfactant or other suitable cosolvent in the composition. Such cosolvents include polysorbates 20, 60, and 80, Pluronic® F-68, F-84, and P-103, cyclodextrin, and polyoxyl 35 castor oil. Such cosolvents are typically used at levels of about 0.01% to about 2% by weight.

[0286] A viscosity greater than that of a simple aqueous solution may be desirable to reduce variability in dispensing of the formulation, to reduce physical separation of the formulation's suspension or emulsion components, and / or to otherwise improve the formulation. Examples of such viscosity-enhancing agents include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing. Such agents are typically used at levels of about 0.01% to about 2% by weight.

[0287] The compositions disclosed herein may additionally contain components to provide sustained release and / or comfort. Such components include high molecular weight anionic mucus-mimetic polymers, gelling polysaccharides, and micronized drug carrier substrates. These components are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes.

[0288] Various pharmaceutical compositions useful for ameliorating certain diseases and disorders are provided. In one embodiment, pharmaceutical compositions are prepared by formulating the compounds disclosed herein in the form of free compounds, either alone or together with other pharmaceutical agents, or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts suitable for administration to a subject using carriers, excipients, and additives or adjuvants. Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol, and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water, alcohol, glycerol, and polyols. Intravenous vehicles include fluid and nutrient replenishers.

[0289] Various pharmaceutical compositions useful for ameliorating certain diseases and disorders are provided. In one embodiment, pharmaceutical compositions are prepared by formulating the compounds disclosed herein in the form of free compounds, either alone or together with other pharmaceutical agents, or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts suitable for administration to a subject using carriers, excipients, and additives or adjuvants. Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol, and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water, alcohol, glycerol, and polyols. Intravenous vehicles include fluid and nutrient replenishers.

[0290] Methods for treating and preventing diseases Further embodiments of the present disclosure relate to methods for providing a compound to a subject, comprising one or more administrations of one or more compositions comprising the compound described above, wherein the compositions, if two or more administrations are present, can be the same or different. In some embodiments, at least one of the one or more compositions further comprises a formulation component. In some embodiments, at least one of the one or more compositions comprises a composition comprising the compound described above. In some embodiments, at least one of the one or more administrations comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. In some embodiments, if two or more administrations are present, at least one composition used in at least one administration is different from at least one other administration. In some embodiments, at least one compound of the one or more compositions may be administered to a subject in an amount of about 0.005 mg / kg to about 50 mg / kg of subject body weight. In some embodiments, the subject is a mammal, preferably a human, rodent, or primate.

[0291] Further embodiments of the present disclosure relate to methods for treating a disease or disorder, the method comprising one or more administrations to a subject of one or more compositions comprising the compounds described above, wherein the compositions, if administered more than once, may be the same or different. In some embodiments, the disease or disorder may respond to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition. In some embodiments, at least one of the one or more compositions further comprises a formulating ingredient. In some embodiments, at least one of the one or more compositions comprises the composition described above.

[0292] In some embodiments, at least one of the one or more administrations comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, transdermal, oral, sublingual, intranasal, or intramuscular administration. In some embodiments, at least one of the one or more administrations comprises oral administration. In some embodiments, when there are two or more administrations, at least one composition used in at least one administration is different from the composition used in at least one other administration. In some embodiments, at least one compound of the one or more compositions is administered to the subject in an amount of about 0.005 mg / kg to about 50 mg / kg of the subject's body weight. In some embodiments, the subject may be a mammal, preferably a human, rodent, or primate. In some embodiments, the subject is in need of treatment.

[0293] In some embodiments, the method is for treating a hematopoietic cancer. In some embodiments, the method is for treating myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML). In some embodiments, the method is for treating at least one of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MYD88-mutated DLBCL, follicular lymphoma, or marginal zone lymphoma. In some embodiments, the method is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof. In some embodiments, the method is for treating one or more inflammatory or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof. In some embodiments, the method is for treating myelofibrosis, in some embodiments, the method is for treating colitis, in some embodiments, the method is for treating Crohn's disease.In some embodiments, the method is for treating MDS, MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations, or the method is for treating AML with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or AML that is not driven by a FLT3 mutation but expresses IRAK4-Long. In some embodiments, the method is for treating DLBCL, wherein the DLBCL comprises the L265P MYD88-mutated (ABC) subtype of DLBCL.

[0294] In some embodiments, the method further comprises administering a composition comprising a BTK inhibitor. In some embodiments, the BTK inhibitor comprises ibrutinib.

[0295] In some embodiments, the subject is predisposed to AML and / or MDS and / or the method prevents or ameliorates future AML and / or MDS. In some embodiments, the method occurs after one or more of having a myelodysplastic syndrome, having a myeloproliferative disorder, developing a chemical exposure, exposure to ionizing radiation, or treatment for cancer.

[0296] In some embodiments, the method further comprises administering a composition comprising a BCL2 inhibitor, or at least one of the compositions comprising the above-mentioned compound further comprises a BCL2 inhibitor. In some embodiments, the above-mentioned compound and the BCL2 inhibitor may be administered together or separately in one or more administrations of one or more compositions. In some embodiments, the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0297] In some embodiments, the method further comprises administration of one or more additional therapies selected from one or more chemotherapeutics, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (anti-metabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof. In some embodiments, the DNA methyltransferase inhibitor / hypomethylating agent comprises azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin at a fixed 5:1 molar ratio); and the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, , valproic acid, and / or pracinostat; purine nucleoside analogs (anti-metabolites) include fludarabine, cladribine, and / or clofarabine; isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; antibody-drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab), mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, casatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)), Plk inhibitors include volasertib and / or rigosertib, MEK inhibitors include trastuzumab, ... CDK9 inhibitors include alvocidib and / or voruciclib; CDK8 inhibitors include SEL120; retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); TP53 activators include APR-246 (eprenetapopt); smoothened receptor antagonists include glasdegib; ERK inhibitors include ulixertinib, SCH772984, lavokipsin, and rituximab. ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors include certinib, MK-8353, and / or VTX-11e; PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-2 3573), everolimus, and / or bistusertib (AZD2014), and the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricorant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15), and / or the EZH2 inhibitor comprises tazemetostat.

[0298] Further embodiments of the present disclosure relate to the compounds described above for use in a method for treating a disease or disorder, the method comprising inhibiting at least one of IRAK and FLT3 by administering one or more compositions comprising the compound, wherein the compositions, if two or more administrations are present, can be the same or different. In some embodiments, the disease or disorder may respond to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition. In some embodiments, at least one of the one or more compositions further comprises a formulating ingredient. In some embodiments, at least one of the one or more compositions comprises the composition described above. In some embodiments, at least one of the one or more administrations comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, transdermal, oral, sublingual, intranasal, or intramuscular administration. In some embodiments, at least one of the one or more administrations comprises oral administration. In some embodiments, if two or more administrations are present, at least one composition used in at least one administration is different from the composition used in at least one other administration.

[0299] In some embodiments, at least one compound of one or more compositions may be administered to a subject in an amount of about 0.005 mg / kg to about 50 mg / kg of the subject's body weight. In some embodiments, the subject is a mammal, preferably a human, rodent, or primate. In some embodiments, the subject is in need of treatment.

[0300] In some embodiments, the method is for treating a hematopoietic cancer. In some embodiments, the method is for treating MDS and / or AML. In some embodiments, the method is for treating at least one of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MYD88-mutated DLBCL, follicular lymphoma, or marginal zone lymphoma. In some embodiments, the method is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof. In some embodiments, the method is for treating one or more inflammatory or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof. In some embodiments, the method is for treating MDS, MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations, or the method is for treating AML with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or AML that is not driven by a FLT3 mutation but expresses IRAK4-Long. In some embodiments, the method is for treating DLBCL, wherein the DLBCL comprises the L265P MYD88-mutated (ABC) subtype of DLBCL.

[0301] In some embodiments, the method further comprises administering a composition comprising a BTK inhibitor. In some embodiments, the BTK inhibitor comprises ibrutinib.

[0302] In some embodiments, the subject is predisposed to AML and / or MDS, and / or the method prevents or ameliorate future AML and / or MDS. In some embodiments, the method occurs after one or more of having a myelodysplastic syndrome, having a myeloproliferative disorder, experiencing chemical exposure, exposure to ionizing radiation, or treatment for cancer. In some embodiments, the method further comprises administering a composition comprising a BCL2 inhibitor, or at least one of the compositions comprising the compound of any one of claims 1-39 further comprises a BCL2 inhibitor. In some embodiments, the compound of any one of claims 1-39 and the BCL2 inhibitor may be administered together or separately in one or more administrations of one or more compositions. In some embodiments, the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0303] In some embodiments, the method further comprises administration of one or more additional therapies selected from one or more chemotherapeutics, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (anti-metabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof. In some embodiments, the DNA methyltransferase inhibitor / hypomethylating agent comprises azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin at a fixed 5:1 molar ratio); and the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, , valproic acid, and / or pracinostat; purine nucleoside analogs (anti-metabolites) include fludarabine, cladribine, and / or clofarabine; isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; antibody-drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab), mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, casatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)), Plk inhibitors include volasertib and / or rigosertib, MEK inhibitors include trametinib, coxsackievirus (CVS), CDK9 inhibitors include alvocidib and / or voruciclib; CDK8 inhibitors include SEL120; retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); TP53 activators include APR-246 (eprenetapopt); smoothened receptor antagonists include glasdegib; ERK inhibitors include ulixertinib, SCH772984, labiophen ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors including xertinib, MK-8353, and / or VTX-11e; PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573); The glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricorant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15), and / or the EZH2 inhibitor comprises tazemetostat.

[0304] In one aspect, the disclosure relates to a method of treating and / or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of a CDK inhibitor. In one embodiment, a composition comprising a therapeutically effective amount of a compound of Formula (I) is administered to the subject. In one embodiment, a composition comprising a therapeutically effective amount of a CDK inhibitor is administered to the subject. In one embodiment, the compound of Formula (I) inhibits FLT3 (wild-type FLT3 and / or mutant FLT3) and IRAK4, IRAK1, or both IRAK4 and IRAK1 to treat and / or prevent a disease or disorder in a subject in need thereof. In one embodiment, the CDK inhibitor inhibits one or more of CKD1, CKD2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13 to treat and / or prevent a disease or disorder in a subject in need thereof.

[0305] In addition to the ability to inhibit IRAK, IRAK inhibitors have been demonstrated to have selectivity toward multiple kinases. In some embodiments, compounds described herein according to Formula (I), such as compounds 1-137 or compounds 1a-84a as listed in Tables 1-11, exhibit and have inhibitory activity against one or more kinases, such as interleukin-1 receptor-associated kinase (IRAK) and FMS-like tyrosine kinase 3 (FLT3). The inhibitory effect on one or more kinases, such as IRAK and FLT3, may enable the use of compounds of the present disclosure (e.g., Formula (I)) to treat and / or prevent diseases in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cows, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans), including, but not limited to, hematopoietic cancers (e.g., disorders of hematopoietic stem cells in the bone marrow or disorders related to the myeloid lineage), MDS, AML, myeloproliferative disorders, and diseases (e.g., hematopoietic cancers) associated with mutations in IRAK1, IRAK4, and / or FLT3 (e.g., a mutation in the juxtamembrane region of FLT3, a mutation in the kinase domain of FLT3, a FLT3 point mutation, a FLT3 internal tandem duplication mutation, a FLT3-ITD mutation, a D835Y FLT3 mutation, a D835V FLT3 mutation, a F691L FLT3 mutation, or a R834Q FLT3 mutation).

[0306] In some embodiments, compounds of the present disclosure can inhibit the activity of one or more of FLT3, a FLT3 mutation (e.g., a FLT3 juxtamembrane region mutation, a FLT3 kinase domain mutation, a FLT3 point mutation, a FLT3 internal tandem duplication mutation, a FLT3-ITD mutation, a D835Y FLT3 mutation, a D835V FLT3 mutation, a F691L FLT3 mutation, or a R834Q FLT3 mutation), IRAK4 (interleukin-1 receptor-associated kinase 4), an isoform of IRAK4, a mutation of IRAK4, IRAK1 (interleukin-1 receptor-associated kinase 1), an isoform of IRAK1, and / or a mutation of IRAK1. In some embodiments, compounds of the present disclosure can inhibit the activity of one or both of FLT3 and FLT3 mutations (e.g., FLT3 juxtamembrane region mutations, FLT3 kinase domain mutations, FLT3 point mutations, FLT3 internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and optionally inhibit one or more of IRAK4, an isoform of IRAK4, a mutation of IRAK4, IRAK1, an isoform of IRAK1, or a mutation of IRAK1. In some embodiments, compounds of the present disclosure can inhibit the activity of one or both of FLT3 and FLT3 mutations (e.g., FLT3 juxtamembrane region mutations, FLT3 kinase domain mutations, FLT3 point mutations, FLT3 internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and optionally inhibit one or both of IRAK4 and IRAK1, or isoforms or mutations thereof. In some embodiments, compounds of the present disclosure can inhibit FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1.

[0307] In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3 of ≧1 μM, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 nM, or even higher. In some embodiments, compounds exhibit inhibitory activity against IRAK and / or FLT-3 with an activity of 0.1 nM to 1 nM, e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 nM. In some embodiments, compounds described herein exhibit inhibitory activity against IRAK and / or FLT-3 with an activity of ≦0.1 μM, e.g., about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of values using any combination of the values recited herein as upper and / or lower limits are also contemplated, for example, but not limited to, 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM. In some embodiments, the inhibitory activity is in the range of about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or even 500-1000 μM. For purposes of quantification, it is understood that the terms "activity," "inhibitory activity," "biological activity," "IRAK activity," "IRAK1 activity," "IRAK4 activity," "FLT-3 activity," and the like, in the context of the inhibitory compounds disclosed herein, can be quantified in a variety of ways known in the art.Unless otherwise indicated, such terms, when used herein, are used in their customary sense (i.e., IC50 concentration to achieve half-maximal inhibition). 50 Refers to...

[0308] In some embodiments, hematopoietic cancers that may be treated in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using compounds of the present disclosure (e.g., Formula (I)) include, but are not limited to, hematopoietic cancers and cancers of the myeloid lineage of blood cells, cancers at high risk of developing due to other blood disorders, chemical exposure (e.g., anti-cancer therapy or occupational chemical exposure), ionizing radiation (e.g., anti-cancer therapy), cancers progressing from myelodysplastic syndromes, cancers progressing from myeloproliferative disorders, and cancers of B cells.

[0309] In some embodiments, hematopoietic cancers that may be treated include, but are not limited to, MDS, AML, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid carcinoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., ABC DLBCL with a MYD88 mutation (e.g., L265P)), follicular lymphoma, or marginal zone lymphoma, or a combination thereof.

[0310] In some embodiments, cancers characterized by dysregulated IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling may be treated, including, but not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer, and the like, and combinations thereof.

[0311] In some embodiments, compounds of the present disclosure can be used to inhibit targets in the context of additional conditions characterized by overactive IRAK1 and / or IRAK4. According to certain aspects of the present disclosure, compounds of the present disclosure can be used to inhibit overactive IRAK1 and / or IRAK4 under conditions such as inflammatory and autoimmune diseases, which are characterized by overactive IRAK1 and / or IRAK4. In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling can be treated, including, but not limited to, chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, and the like, and combinations thereof.

[0312] In certain embodiments, MDS that may be treated in a subject (e.g., mammals, pigs, dogs, birds (e.g., chickens), cows, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the present disclosure (e.g., Formula (I)) include MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations, refractory cytopenias with single lineage dysplasia (e.g., refractory These include, but are not limited to, refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ringed sideroblasts, and animals / humans with pathological changes not limited to erythrocytes such as prominent proleukocyte and proplatelet (megakaryocyte) dysplasia), refractory anemia with excess blasts I and II, 5q-syndrome, megakaryocytic dysplasia with fibrosis, and refractory cytopenia in children. In some embodiments, MDS that may be treated include, but are not limited to, inherited MDS, MDS at high risk due to genetic predisposition, MDS at high risk due to other blood disorders, MDS at high risk due to chemical exposure, MDS at high risk due to ionizing radiation, MDS at high risk due to cancer treatment (e.g., radiation in combination with radiomimetic alkylating agents such as busulfan, nitrosoureas, or procarbazine (with a 5-7 year latency period), or DNA topoisomerase inhibitors), MDS progressing from acquired aplastic anemia and Fanconi anemia after immunosuppressive treatment, MDS at high risk due to splicing factor mutations, MDS at high risk due to isocitrate dehydrogenase 1 mutations, and MDS at high risk due to isocitrate dehydrogenase 2 mutations. Animals that may be treated include, but are not limited to, mammals, rodents, primates, monkeys (e.g., macaques, rhesus monkeys, pig-tailed monkeys), humans, dogs, cats, pigs, birds (e.g., chickens), cows, mice, rabbits, and rats. In the methods, the term "subject" can refer to both human and non-human subjects.In some cases, the subject is in need of treatment (eg, by exhibiting symptoms of a disease, such as MDS, AML, cancer, an autoimmune disease, an inflammatory condition, etc., or by having a low blood count).

[0313] In some embodiments, MDS that can be treated in a subject (e.g., a mammal, pig, dog, bird (e.g., chicken), cow, cat, primate, rodent, monkey, rabbit, mouse, rat, and human) using a compound of the present disclosure (e.g., Formula (I)) include, but are not limited to, MDS that can be treated by inhibiting one or more of FLT3 (e.g., using a FLT3 inhibitor), FLT3 mutation (e.g., using an inhibitor of a FLT3 mutant), IRAK4 (e.g., using an IRAK4 inhibitor), IRAK4 mutation (e.g., using an inhibitor of a IRAK4 mutant), IRAK1 (e.g., using an IRAK1 inhibitor), and / or IRAK1 mutation (e.g., using an inhibitor of a IRAK1 mutant). In certain embodiments, MDS that can be treated include, but are not limited to, MDS that can be treated by inhibiting IRAK4 (or mutations thereof), MDS that can be treated by inhibiting IRAK1 (or mutations thereof), or MDS that can be treated by inhibiting IRAK4 (or mutations thereof) and IRAK1 (or mutations thereof). In some embodiments, MDS that can be treated include, but are not limited to, MDS that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that can be, or become, resistant to FLT3 inhibitors due to, for example, adaptive resistance mechanisms driven by IRAK.In some embodiments, MDS that may be treated is characterized by MDS with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or MDS that is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entireties)).

[0314] In some embodiments, AML that may be treated in a subject (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the present disclosure (e.g., Formula (I)) includes inherited AML, AML at high risk of development due to genetic predisposition, AML with one or more recurrent genetic abnormalities (e.g., AML with inversion or translocation, e.g., MLLT3 / MLL (“MLL”) with a translocation between chromosomes 9 and 11, AML with a translocation between chromosomes 8 and 21, and AML with a translocation between chromosomes 9 and 21). L, AML with translocation or inversion of chromosome 16, AML with translocation between chromosomes 9 and 11, APL with translocation between chromosomes 15 and 17 (M3), AML with translocation between chromosomes 6 and 9, AML with translocation or inversion of chromosome 3, etc.), AML with translocation between chromosomes 1 and 22 (megakaryoblastic), AML with myelodysplasia-related changes, AML related to previous chemotherapy or radiation (e.g., alkylating agent-associated AML, topoisomerase II inhibitor-associated AML, etc.), AML not elsewhere classified (see above). Not falling within the above categories (similar to the FAB classification), e.g., minimally differentiated AML (M0), AML with minimal maturation (M1), AML with maturation (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroleukemia (M6), acute megakaryoblastic leukemia (M7), acute basophilic leukemia, acute panmyelosis with fibrosis, etc.), myeloid sarcoma (also known as granulocytic sarcoma, chloroma, or extramedullary myeloblastoma), undifferentiated and mixed acute leukemia (also known as mixed phenotype acute leukemia), AML at high risk of development due to other blood disorders, and AML due to exposure to chemicals. AML with high risk of progression, AML with high risk of development due to ionizing radiation, AML progressing from myelodysplastic syndrome, AML progressing from myeloproliferative disorder, AML with high risk due to FLT3 mutation, AML with high risk due to FLT3 mutation in the juxtamembrane region of FLT3, AML with high risk due to FLT3 mutation of internal tandem duplication in the juxtamembrane region of FLT3, AML with high risk due to FLT3 mutation in the kinase domain of FLT3, AML with high risk due to FLT3 mutation D835Y, AML with high risk due to FLT3 mutation D835V,These include, but are not limited to, high-risk AML due to the FLT3 mutation F691L and high-risk AML due to the FLT3 mutation R834Q. In some embodiments, AML that can be treated includes AML by inhibiting one or more of FLT3 (e.g., using an FLT3 inhibitor), FLT3 mutation (e.g., using an inhibitor of an FLT3 mutant), IRAK4 (e.g., using an IRAK4 inhibitor), IRAK4 mutation (e.g., using an inhibitor of an IRAK4 mutant), IRAK1 (e.g., using an IRAK1 inhibitor), and / or IRAK1 mutation (e.g., using an inhibitor of an IRAK1 mutant). In certain embodiments, AML that can be treated includes, but is not limited to, AML that can be treated by inhibiting IRAK4 (or a mutation thereof), MDS that can be treated by inhibiting IRAK1 (or a mutation thereof), or AML that can be treated by inhibiting IRAK4 (or a mutation thereof) and IRAK1 (or a mutation thereof). In some embodiments, AML that may be treated includes, but is not limited to, AML that may be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that may be, or may become, resistant to FLT3 inhibitors due to, for example, adaptive resistance mechanisms driven by IRAK. In some embodiments, AML that may be treated is characterized as AML with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or AML that is not driven by FLT3 mutations but expresses IRAK4-Long based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g.,As described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entirety).

[0315] In some embodiments, hematopoietic cancers that may be treated in a subject (e.g., mammal, pig, dog, bird (e.g., chicken), cow, cat, primate, rodent, monkey, rabbit, mouse, rat, and human) using a compound of the present disclosure (e.g., Formula (I)) include, but are not limited to, hematopoietic cancers (e.g., MDS, AML, DLBCL, etc., as described above) that may be treated by inhibiting (e.g., reducing the activity or expression of) one or more of FLT3 (e.g., using a FLT3 inhibitor), a mutation of FLT3 (e.g., using an inhibitor of a mutant FLT3), IRAK4 (e.g., using an IRAK4 inhibitor), an isoform of IRAK4, a mutation of IRAK4 (e.g., using an inhibitor of a mutant IRAK4), IRAK1 (e.g., using an IRAK1 inhibitor), an isoform of IRAK1, or a mutation of IRAK1 (e.g., using an inhibitor of a mutant IRAK1). In certain embodiments, hematopoietic cancers that may be treated include, but are not limited to, cancers that may be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof) and IRAK4 (or mutations thereof), or by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof) and IRAK1 (or mutations thereof), or by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof), IRAK4 (or isoforms or mutations thereof), and IRAK1 (or isoforms or mutations thereof). In some embodiments, hematopoietic cancers that may be treated include, but are not limited to, hematopoietic cancers that may be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that may be, or may become, resistant to FLT3 inhibitors due to, for example, adaptive resistance mechanisms driven by IRAK.In some embodiments, hematopoietic cancers that may be treated are characterized by hematopoietic cancers with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or hematopoietic cancers that are not driven by FLT3 mutations but express IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entireties)).

[0316] In some embodiments, cancers that may be treated include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer, which may be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1, and combinations thereof. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that may be, or may become, resistant to FLT3 inhibitors due to, for example, adaptive resistance mechanisms driven by IRAK. In some embodiments, cancers that may be treated are characterized by cancers with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or cancers that are not driven by FLT3 mutations but express IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entireties)).

[0317] In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling that can be treated include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, and the like, and combinations thereof, which can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for inflammatory and autoimmune diseases with FLT3 mutations that may be, or may become, resistant to FLT3 inhibitors due to, for example, adaptive resistance mechanisms driven by IRAK. In some embodiments, inflammatory and autoimmune diseases that may be treated are characterized by inflammatory and autoimmune diseases having enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or inflammatory and autoimmune diseases that are not driven by FLT3 mutations but express IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entireties)).

[0318] In relation to the treatment of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2), treatment can include, but is not limited to, prophylactic and therapeutic treatments. Thus, treatments include preventing MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS), reducing the risk of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS), improving or alleviating the symptoms of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS), inducing a physical response to MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS), and improving or alleviating the symptoms of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS). inhibiting the onset or progression of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); inhibiting or preventing the onset of symptoms associated with MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); reducing the severity of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); causing regression of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) or one or more symptoms associated with MDS (e.g., increased blood counts);These effects may include, but are not limited to, causing remission of MDS (e.g., MDS with a splicing factor mutation, MDS with a isocitrate dehydrogenase 1 mutation, or MDS with an isocitrate dehydrogenase 2 mutation) by preventing or minimizing FLT3 mutations (e.g., an internal tandem duplication mutation or a D835Y mutation), preventing the recurrence of MDS (e.g., MDS with a splicing factor mutation, MDS with an isocitrate dehydrogenase 1 mutation, or MDS with an isocitrate dehydrogenase 2 mutation), or preventing the recurrence of MDS (e.g., MDS with a splicing factor mutation, MDS with an isocitrate dehydrogenase 1 mutation, or MDS with an isocitrate dehydrogenase 2 mutation) in animals / humans with intrinsic or acquired resistance to other MDS treatments. In some embodiments, treating does not include prophylactic treatment of MDS (e.g., preventing or ameliorating future MDS).

[0319] In relation to the treatment of hematopoietic cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow carcinoma, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation (e.g., ABC DLBCL with MYD88 mutation L265P), follicular lymphoma, or marginal zone lymphoma, and combinations thereof), treatment can include, but is not limited to, prophylactic and therapeutic treatments. Thus, treatment includes preventing cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); reducing the risk of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, and combinations thereof)ameliorating or alleviating symptoms of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, eliciting a bodily response to cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, and combinations thereof; inhibiting the onset or progression of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, inhibiting or preventing the onset of symptoms associated with cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, and combinations thereof);reducing the severity of cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, and combinations thereof); causing regression of one or more symptoms associated with cancer (e.g., reduction in tumor size), cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, leukemia ... and inducing remission of cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), and combinations thereof) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations). Inducing remission in acute myeloid leukemia by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations), inducing remission in cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL,preventing recurrence of cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, in animals / humans with intrinsic or acquired resistance to other cancer therapies (e.g., from some FLT3 inhibitors or from MLL); In some embodiments, treating does not include preventative treatment of cancer (e.g., preventing or ameliorating future cancers).

[0320] Treatment of a subject can be carried out using any suitable method of administration (such as those disclosed herein) and using any suitable amount of a compound of the present disclosure (e.g., Formula (I)). In some embodiments, the method of treatment includes treating an animal or human for MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2). In some embodiments, the therapeutic methods include treating an animal or human for a hematopoietic cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid carcinoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutated, follicular lymphoma, or marginal zone lymphoma, and combinations thereof). Other embodiments include treatment following one or more of having a blood disorder, having a myelodysplastic syndrome, having a myeloproliferative disorder, developing a chemical exposure, exposure to ionizing radiation, or treatment for a hematopoietic cancer (e.g., chemotherapy, ionizing radiation, or both). Some embodiments of the present disclosure include methods for treating a subject (e.g., an animal such as a human or a primate) with a composition (e.g., a pharmaceutical composition) comprising a compound of the present disclosure (e.g., Formula (I)), which comprises one or more administrations of one or more such compositions, which, if two or more administrations are present, may be the same or different.

[0321] In some embodiments, the method of treatment comprises administering to a subject an effective amount of a composition comprising a compound of the present disclosure (eg, Formula (I)). As used herein, the term "effective amount" refers to a dose or series of doses sufficient to affect therapy in a subject (e.g., for treating MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) or for treating a hematopoietic cancer such as, but not limited to, acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid carcinoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutations, follicular lymphoma, or marginal zone lymphoma, and combinations thereof). In some embodiments, an effective amount can encompass a therapeutically effective amount as disclosed herein. In certain embodiments, the effective amount may vary depending on the subject and the particular treatment being affected. The exact amount required may vary from subject to subject, depending, for example, on the subject's age and general condition, the particular adjuvant (if any) used, the administration protocol, etc. Thus, the effective amount may vary, for example, based on the particular circumstances, and an appropriate effective amount may be determined in each particular case. The effective amount may include, for example, any of the dosages or composition amounts disclosed herein.In some embodiments, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, Compounds 1-137 or Compounds 1a-84a as listed in Tables 1-11) (which may be administered to a subject, such as a mammal, primate, monkey, or human) is about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 The amount can be about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, or about 15 mg / kg. For some embodiments, the dosage can be about 0.5 mg / kg or about 6.5 mg / kg body weight. In some cases, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, Compounds 1-137 or Compounds 1a-84a as listed in Tables 1-11) (which may be administered to a subject such as a mammal, rodent, mouse, rabbit, cat, pig, or dog) may be an amount of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 80 mg / kg, about 100 mg / kg, or about 150 mg / kg.In some embodiments, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, Compounds 1-137 or Compounds 1a-84a as listed in Tables 1-11) (which may be administered to an animal, such as a mammal, primate, monkey, or human) is about 1 to about 1000 mg / kg body weight, about 5 to about 500 mg / kg body weight, about 10 to about 200 mg / kg body weight, about 25 to about 100 mg / kg body weight, about 30 to about 400 mg / kg body weight, about 40 to about 500 mg / kg body weight, about 50 to about 600 mg / kg body weight, about 60 to about 800 mg / kg body weight, about 70 to about 900 mg / kg body weight, about 80 to about 900 mg / kg body weight, about 90 to about 10 ... For some conditions, the dosage may be about 20 mg / kg human body weight or about 100 mg / kg human body weight. In some cases, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, Compounds 1-137 or Compounds 1a-84a as listed in Tables 1-11) (which may be administered to an animal, such as a mammal, rodent, mouse, rabbit, cat, pig, or dog) is about 1 to about 1000 mg / kg body weight, about 5 to about 500 mg / kg body weight, about 10 to about 200 mg / kg body weight, about 25 to about 300 mg / kg body weight, about 30 to about 400 mg / kg body weight, about 40 to about 500 mg / kg body weight, about 50 to about 600 mg / kg body weight, about 50 to about 700 mg / kg body weight, about 50 to about 800 mg / kg body weight, about 50 to about 900 mg / kg body weight, about 50 to about 1000 mg / kg body weight, about 50 to about 15 ... The amount can be about 100 mg / kg body weight, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1000 mg / kg.

[0322] In some embodiments, treatment may also include one or more of surgical intervention, chemotherapy, radiation therapy, hormone therapy, immunotherapy, and adjuvant systemic therapy. Adjuvants may include, but are not limited to, chemotherapy (e.g., temozolomide), radiation therapy, antiangiogenic therapy (e.g., bevacizumab), and hormone therapy such as administration of LHRH agonists, antiestrogens such as tamoxifen, high-dose progestogens, aromatase inhibitors, and / or adrenalectomy. Chemotherapy may be used as a single agent or in combination with known or new therapies.

[0323] In some embodiments, administration of at least one compound of the present disclosure (e.g., Formula (I)) to a subject is an adjuvant cancer therapy or part of an adjuvant cancer therapy. Adjuvant therapy includes the treatment of cancers disclosed herein, including but not limited to tumors, by the mechanisms disclosed herein. Corresponding primary therapy may include, but is not limited to, surgery, chemotherapy, or radiation therapy. In some cases, adjuvant therapy may be a combination of a chemokine receptor antagonist with a conventional chemotoxic agent or with an immunotherapy, which may enhance treatment specificity for cancer and limit additional systemic side effects. In yet other embodiments, a compound of the present disclosure (e.g., Formula (I)) may be used as an adjuvant with other chemotherapeutic agents. The use of a compound of the present disclosure (e.g., Formula (I)) may, in some cases, reduce the duration of the dose of both the drug and the drug combination, reducing side effects.

[0324] In some embodiments, administration to a subject may reduce the incidence of one or more symptoms associated with MDS / AML / certain types of hematopoietic cancer, hi some embodiments, administration may reduce bone marrow failure, immune dysfunction, transformation to overt leukemia, or a combination thereof in the subject compared to a subject who does not receive the composition.

[0325] In some embodiments, the method may reduce a marker of viability of MDS cells, AML cells, or cancer cells in the subject. In one aspect, the method may reduce a marker of viability of MDS, AML, and / or cancer cells. The marker may be selected from survival over time, proliferation, growth, migration, colony formation, chromosome assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or a combination thereof.

[0326] In one embodiment, the compounds of Formula (I) described herein and / or compositions comprising the compounds of Formula (I) described herein are used in one or more doses together or in combination with a CDK inhibitor. Various CDK isoforms play important roles in controlling cell cycle progression in various cell types, and these pathways are dysregulated in hematopoietic cancers and solid tumors. Non-selective CDK inhibitors have shown efficacy in various blood cancer models (Whittaker SR et al., Pharmacology & Therapeutics (2017) 173:83-105). In one embodiment, the CDK inhibitor is a CDK9 inhibitor.

[0327] The cyclin-dependent kinase 9 (CDK9) pathway is dysregulated in AML, and therefore targeting this pathway is an attractive approach for treating AML. Inhibition of CDK9 leads to downregulation of cell survival genes controlled by super-enhancers, such as MCL-1, MYC, and cyclin D1. Because first-generation CDK9 inhibitors are nonselective, predictive biomarkers are now being utilized that can help identify patients most likely to respond to CDK9 inhibitors in order to improve efficacy and safety. In one embodiment, the CDK9 inhibitor is alvocidib, a multiserine-threonine cyclin-dependent kinase inhibitor with demonstrable in vitro and clinical activity in AML when combined in a timed sequential chemotherapy regimen. In another embodiment, the CDK9 inhibitor is BAY1143752 (atubeciclib), which has demonstrated antiproliferative activity in HeLa and MOLM-12 AML cells in vitro. BAY1143752 also significantly reduced the growth of MOLM-13 and MV4-11 tumor xenografts in nude mice and rats, respectively, and was well tolerated in both models. In another embodiment, the CDK9 inhibitor is NVP-2, which exhibits antiproliferative activity against multiple leukemia cell lines and induces MCL-1 loss and apoptosis within 4 hours in MOLT4 ALL cells. In yet another embodiment, the CDK inhibitor is THAL-SNS-032, which has been shown to selectively induce CDK9 degradation with minimal effect on the protein levels of other CDKs, despite retaining the ability to block the kinase activity of other CDKs.

[0328] Combination therapy In some embodiments, the treatments disclosed herein may include the use of other drugs (e.g., antibiotics) or therapies to treat diseases, such as MDS / AML / certain types of hematopoietic cancer. For example, antibiotics can be used to treat infections and can be used in combination with compounds of the present disclosure to treat diseases (e.g., infections). In other embodiments, intravenous immunoglobulin (IVIG) therapy can be used as part of a treatment regimen (i.e., in addition to administering a compound of the present disclosure). For example, treatment regimens for various types of cancer can involve one or more elements selected from chemotherapy, targeted therapy, alternative therapy, immunotherapy, etc.

[0329] Thus, in some embodiments, the compounds and / or compositions described herein may be used in combination with one or more BCL2 inhibitors, BTK inhibitors, chemotherapy, targeted therapy, replacement therapy, immunotherapy, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (anti-metabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or the like, or one or more combinations thereof, in one or more administrations to a subject, and the compositions, if there are two or more administrations, may be the same or different. In some embodiments, when there is more than one administration, at least one composition used in at least one administration is different from the composition of at least one other administration.

[0330] Specifically, it has been demonstrated that IRAK inhibitors have synergistic effects when administered in combination with apoptosis regulators / inhibitors, such as BCL2 inhibitors.As described in U.S. Patent Application No. 16 / 804,518 (which is incorporated herein by reference in its entirety), exemplary apoptosis / BCL2 inhibitors have been shown to have synergistic effects when used in combination with exemplary IRAK inhibitors in multiple AML cell lines.Venetoclax is used as a representative apoptosis / BCL2 inhibitor.

[0331] When the concentration of an exemplary IRAK inhibitor was combined with venetoclax, the efficacy of venetoclax increased by approximately 50-fold, an unexpectedly high level. According to certain embodiments of the present disclosure, this synergistic combination allows for increased efficacy of venetoclax at lower doses, avoiding at least some of the toxicity observed in clinical trials. According to certain embodiments, the extent of the interaction depends on the dose ratio combination used, with lower concentrations of the exemplary IRAK inhibitor providing a greater shift in the venetoclax IC50. This unexpected and dramatic shift in the venetoclax IC50 is substantially greater than an additive response, demonstrating the unexpected synergistic interaction of the two drugs, even in cell lines that do not express activating FLT3 mutants.

[0332] Accordingly, the present disclosure encompasses methods for treating a disease or disorder responsive to inhibition of IRAK, the methods comprising administering to a subject a composition comprising an IRAK inhibitor compound, and some embodiments of the methods may further involve administering an apoptosis-modulating agent. The apoptosis-modulating agent may comprise a BTK inhibitor and / or a BCL2 inhibitor. The BTK inhibitor and BCL2 inhibitor may, for example, be those known in the art. In some embodiments, the method may comprise administering to the subject an apoptosis-modulating agent. In some embodiments, the apoptosis-modulating agent may comprise a BCL2 inhibitor selected from ABT-263 (navitoclax), ABT-737, ABT-199 (venetoclax), GDC-0199, GX15-070 (obatoclax) (all available from Abbott Laboratories), HA14-1, S1,2-methoxyantimycin A3, gossypol, AT-101, apogossypol, WEHI-539, A-1155463, BXI-61, BXI-72, TW37, MIM1, UMI-77, and the like, and combinations thereof. One of skill in the art will appreciate that there are many known BCL2 inhibitors that may be used in accordance with the present disclosure. In some embodiments, the BCL2 inhibitor comprises venetoclax.

[0333] In some embodiments, the administering step comprises administering to the subject a composition comprising an IRAK inhibitor compound and a BCL2 inhibitor, hi some embodiments, the administering step comprises administering a composition comprising an IRAK inhibitor compound in combination with a composition comprising a BCL2 inhibitor.

[0334] In some embodiments, the IRAK inhibitor compound is selected from compounds 1-137 or compounds 1a-84a, or a salt, isomer, derivative, or analog thereof, and the BCL2 inhibitor is venetoclax, or a salt, isomer, derivative, or analog thereof.

[0335] In some embodiments, the method may further involve administering to the subject an immunomodulatory agent. The immunomodulatory agent may include, for example, lenalidomide (Revlimid, Celgene Corporation). In some embodiments, the method may involve administering an epigenetic modulating agent. The epigenetic modulating agent may include, for example, a hypomethylating agent such as azacitidine, decitabine, or a combination thereof.

[0336] In some embodiments, the compounds and / or compositions described herein may be used with or in combination with one or more BTK inhibitors, such as, for example, ibrutinib, or salts, isomers, derivatives, or analogs thereof, in one or more administrations to a subject.

[0337] For example, the compounds and / or compositions described herein may be used in combination with other compounds, such as DNA methyltransferase inhibitors / hypomethylating agents, such as, for example, azacitidine, decitabine, cytarabine, and / or guadecitabine; anthracyclines, such as, for example, daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin at a fixed 5:1 molar ratio); or other compounds, such as, for example, vorinostat, panobinostat, valproic acid, histone deacetylase (HDAC) inhibitors, such as, for example, fludarabine, cladribine, and / or clofarabine; purine nucleoside analogs (antimetabolites), such as, for example, fludarabine, cladribine, and / or clofarabine; isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, such as, for example, ivosidenib and / or enasidenib; anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131- antibody-drug conjugates such as apamistamab; mAbs / immunotherapies such as anti-CD70 (e.g., ARGX-110, casatuzumab), bispecific antibodies (e.g., floteuzumab (CD123×CD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); Plk inhibitors such as volasertib and / or rigosertib; MEK inhibitors, such as trametinib, cobimetinib, selumetinib, pimasertib, and / or refametinib; CDK9 inhibitors, such as alvocidib and / or voruciclib; CDK8 inhibitors, such as SEL120; retinoic acid receptor agonists, such as ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); TP53 activators, such as APR-246 (eprenetapopt); smoothened receptor antagonists, such as glasdegib; ERK inhibitors such as ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors such as liquisertinib, SCH772984, lavoxertinib, MK-8353, and / or VTX-11e; PI3K inhibitors such as, for example, fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); for example, bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridafolil mTOR inhibitors such as mus (MK-8669, AP-23573), everolimus, and / or bistusertib (AZD2014); glucocorticoid receptor modulators such as agonists including prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or antagonists including mifepristone, milicholant, and / or onapristone, and / or another binding ligand including vamorolone (VBP15);and / or may be used in one or more doses together or in combination with an EZH2 inhibitor, such as tazemetostat. In some embodiments, the compounds and pharmaceutical compositions containing them, when used in combination with an EZH2 inhibitor, may be used in the prevention of secondary malignancies. Additional therapies are described below and are contemplated in combination therapy in the context of this disclosure.

[0338] Chemotherapy / targeted therapy / alternative therapy Cancer is commonly treated with chemotherapy and / or targeted therapy and / or alternative therapies. While chemotherapy works by indiscriminately targeting healthy cells and rapidly dividing cells, including tumor cells, targeted cancer therapies work by interfering with specific molecules or molecular targets involved in the growth and progression of cancer. Targeted therapies generally target only cancer cells, with minimal damage to normal cells. Chemotherapy and targeted therapies that are approved and / or in clinical trials are known to those skilled in the art. Any such compounds may be utilized in the practice of the present disclosure.

[0339] For example, approved chemotherapy drugs include Abitrexate (methotrexate injection), Abraxane (paclitaxel injection), Adcetris (brentuximab vedotin injection), Adriamycin (doxorubicin), Adrsil injection (5-FU (fluorouracil)), Afinitor (everolimus), Afinitor Disperse (everolimus), Alimta (pemetrexed), Alkeran injection (melphalan injection), Alkeran tablets (melphalan), Aredia (pamidronate), and Arimidex (anastrozole). ol), Aromasin (exemestane), Alanon (nelarabine), Arzera (ofatumumab injection), Avastin (bevacizumab), Beleodac (belinostat injection), Bexar (tositumomab), BiCNU (carmustine), Blenoxane (bleomycin), Bilincyto (blinatumomab injection), Bosulif (bosutinib), Busulfex injection (busulfan injection), Camptus (alemtuzumab), Camptosar (irinotecan), Caprelsa (vandetanib), Casodex (bicalutamide), CeeNU (lomustine), CeeNU Dose Pack (lomustine), Cervizin (daunorubicin), Chloral (clofarabine injection), Cometrik (cabozantinib), Cosmegen (dactinomycin), Cotellic (cobimetinib), Cyramza (ramucirumab injection), cytosarU (cytarabine), Cytoxan (cytoxan), Cytoxan injection (cyclophosphamide injection), Dacogen (decitabine), Daunoxome (daunorubicin lipid complex injection), Decadron (dexamethasone), Depocyt (cytarabine lipid complex injection), Dexamethasone Intensor (dexamethasone), Dexpac Taper Pack (dexamethasone), Docephres (docetaxel), Doxil (doxorubicin lipid complex injection), Droxia (hydroxyurea), DTIC (dacarbazine), Eligard (leuprolide), Elence (Elence (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Elspar (asparaginase), Emcyte (estramustine), Erbitux (cetuximab), Elibege (vismodegib),Erwinase (asparaginase derived from Erwinia chrysanthemi), Ethiol (amifostine), Etopofos (etoposide injection), Eurexin (flutamide), Fairston (toremifene), Farydak (panobinostat), Faslodex (fulvestrant), Femara (letrozole), Farmagon (degarelix injection), Fludara (fludarabine), Folex (methotrexate injection), Folotin (pralatrexate injection), FUDR (FUDR (floxuridine)), Gazyva (obinutuzumab injection), Gem Zar (gemcitabine), Giotrif (afatinib), Glivec (imatinib mesylate), Gliadelwafer (carmustine wafer), Halaven (eribulin injection), Herceptin (trastuzumab), Hexalen (altretamine), Hycamtin (topotecan), Hycamtin (topotecan), Hydrea (hydroxyurea), Ibrance (palbociclib), Iclusig (ponatinib), Idamycin PFS (idarubicin), Ifex (ifosfamide), Imbruvica (ibrutinib), Inlyta (aki) Citinib), IntronA alpha b (interferon alpha-2a), Iressa (gefitinib), Istodax (romidepsin injection), Ixempra (ixabepilone injection), Jakafi (ruxolitinib), Jevtana (cabazitaxel injection), Kadcyla (ado-trastuzumab emtansine), Keytruda (pembrolizumab injection), Kyprolis (carfilzomib), Lenvima (lenvatinib), Leukelan (chlorambucil), Leukine (sargramostim), Leustatin (cladribine), Lonsurf (trifluridine and tipiracil), Lupron (leuprolide), Lupron Depot (leuprolide), Lupron Depot PED (leuprolide), Lynparza (olaparib), Risodren (mitotane), Marquibokit (vincristine lipid complex injection), Matulane (procarbazine), Megase (megestrol), Mekinist (trametinib), Methunex (mesna), Methunex (mesna injection), Metastron (strontium-89 chloride), Mexate (methotrexate injection), Mastergen (mechlorethamine),Mutamycin (mitomycin), Myleran (busulfan), Mylotarg (gemtuzumab ozogamicin), Navelbine (vinorelbine), Neosar injection (cyclophosphamide injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (sorafenib), Nilandrone (nilandrone (nilutamide)), Nipent (pentostatin), Nolvadex (tamoxifen), Novantrone (mitoxantrone), Odomzo (sonidegib), Oncaspar ( Pegaspargase), Oncovin (vincristine), Ontak (denileukin diftitox), Onxol (paclitaxel injection), Opdivo (nivolumab injection), Panretin (alitretinoin), Paraplatin (carboplatin), Perjeta (pertuzumab injection), Platinol (cisplatin), Platinol (cisplatin injection), Platinol AQ (cisplatin), Platinol AQ (cisplatin injection), Pomalyst (pomalidomide), Prednisone Intensor (prednisone), Proleukin (Aldesro) Ikin), Purinetol (mercaptopurine), Liclast (zoledronic acid), Revlimid (lenalidomide), Actimid (pomalidomide), Rheumatrex (methotrexate), Rituxan (rituximab), Roferon A alpha a (interferon alpha-2a), Rubex (doxorubicin), Sandostatin (octreotide), Sandostatin LAR depot (octreotide), Soltamox (tamoxifen), Sprycel (dasatinib), Stellapred (prednisone), Stellapred DS (prednisone), Stibar Ga (regorafenib), Saplerin LA (histrelin implant), Sutent (sunitinib), Silatron (peginterferon alpha-2b injection (Silatron)), Silvant (siltuximab injection), Synribo (omacetaxine injection), Tabloid (thioguanine), Taflinar (dabrafenib), Tarceva (erlotinib), Targretin capsules (bexarotene), Tasigna (dacarbazine), Taxol (paclitaxel injection), Taxotere (docetaxel), Temodar (temozolomide),Temodar (temozolomide injection), Tepadina (thiotepa), Thalomid (thalidomide), TheraCys BCG (BCG), Thioprex (thiotepa), TICE BCG (BCG), Toposar (etoposide injection), Torisel (temsirolimus), Treanda (bendamustine hydrochloride), Trelstar (triptorelin injection), Trexal (methotrexate), Trisenox (arsenic trioxide), Tykerb (lapatinib), Unituxin (dinutuximab injection), Valstar (valrubicin intravesical), Vantas (histrelin implant), Vectibix (panitumumab), Balban (vinblastine), Belcad (bortezomib), Bepecid (etoposide injection) Toposide, Bepesid (etoposide injection), Besanoid (tretinoin), Vidaza (azacitidine), Vincasar PFS (vincristine), Vincrex (vincristine), Votrient (pazopanib), Bumon (teniposide), Wellcovorin IV (leucovorin injection), Xalkori (crizotinib), Xeloda (capecitabine), Xtandi (enzalutamide), Yervoy (ipilimumab injection), Yondelis (trabectedin injection), Zaltrap (Ziv-aflibercept injection) (streptozocin), Zanosar (streptozocin), Zelboraf (vemurafenib), Zevalin (ibritumomab tiuxetan), Zoladex (goserelin), Zolinza (vorinostat), Zometa (zoledronic acid), Zoltrex (everolimus), Zydelig (idelalisib), Zykadia (ceritinib), Zytiga (abiraterone), and their analogs and derivatives. For example, approved targeted therapies include ado-trastuzumab emtansine (Kadcyla), afatinib (Giotrif), and others. , aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campus), axitinib (Inlyta), belimumab (Benlysta), belinstat (Veleodac), bevacizumab (Avastin), bortezomib (Velcade), bosutinib (Bosulif), brentuximab vedotin (Adcetris), cabozantinib (Cabometyx [tablets], Cometrix [capsules]), canakinumab (Ilaris), carfilzomib (Kyprolis), ceritinib (Zykadia),Cetuximab (Erbitux), cobimetinib (Cotellic), crizotinib (Xalkori), dabrafenib (Tafinlar), daratumumab (Darazalex), dasatinib (Sprycel), denosumab (Zygeva), dinutuximab (Unituxin), elotuzumab (Empliciti), erlotinib (Tarceva), everolimus (Afinitor), gefitinib (Iressa), ibritumomab tiuxetan (Zevalin), ibrutinib (Imbruvica), idelalisib (Zygeva) Delig), imatinib (Gleevec), ipilimumab (Yervoy), ixazomib (Ninlaro), lapatinib (Tykerb), lenvatinib (Lenvima), necitumumab (Portraza), nilotinib (Tasigna), nivolumab (Opdivo), obinutuzumab (Gazyva), ofatumumab (Arzera, HuMax-CD20), olaparib (Lynparza), osimertinib (Tagrisso), palbociclib (Ibrance), panitumumab (Vectibix), panobinostat (Fu Alydak), pazopanib (Votrient), pembrolizumab (Keytruda), pertuzumab (Perjeta), ponatinib (Iclusig), ramucirumab (Cyramza), rapamycin, regorafenib (Stivarga), rituximab (Rituxan, MabThera), romidepsin (Istodax), ruxolitinib (Jakafi), siltuximab (Sylvanto), sipuleucel-T (Provenge), sirolimus, sonidegib (Odomzo), sorafenib (Nexavar), These include nitinib, tamoxifen, temsirolimus (Torisel), tocilizumab (Actemra), tofacitinib (Xeljanz), tositumomab (Bexar), trametinib (Mekinist), trastuzumab (Herceptin), vandetanib (Caprelsa), vemurafenib (Zelboraf), venetoclax (Venclexta), vismodegib (Elivege), vorinostat (Zolinza), ziv-aflibercept (Zaltrap), and analogs and derivatives thereof.

[0340] Those skilled in the art can determine appropriate chemotherapy and / or targeted therapy and / or alternative therapy options, including approved treatments and treatments in clinical trials or otherwise under development. Some targeted therapies are also immunotherapies. Any relevant chemotherapy, targeted therapy, and alternative therapy treatment strategies may be utilized in the practice of the present disclosure, alone or in combination with one or more additional cancer therapies.

[0341] immunotherapy In some embodiments, immunotherapies include cell-based immunotherapies, such as those involving cells that influence the immune response (e.g., lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTLs), antibodies and antibody derivatives, such as monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemically labeled antibodies, etc.), immune checkpoint inhibitors, vaccines (e.g., cancer vaccines (e.g., tumor cell vaccines), and the like). These include immunotherapy using immunomodulators (e.g., interleukins, antigen vaccines, dendritic cell vaccines, vector-based vaccines, etc., e.g., oncophage, sipuleucel-T, etc.), immunomodulators (e.g., interleukins, cytokines, chemokines, etc.), local immunotherapy (e.g., imiquimod, etc.), injectable immunotherapy, adoptive cell transfer, oncolytic virus therapy (e.g., talimogene laherparepvec (T-VEC), etc.), immunosuppressive drugs, helminth therapy, and other non-specific immunotherapies. Immune checkpoint inhibitor immunotherapy is an immunotherapy that inhibits PD-1, PD-L1, and CTLA- 4. Immune checkpoint inhibitor immunotherapies include ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), and the like. Non-specific immunotherapies include cytokines, interleukins, interferons, and the like. In some embodiments, the immunotherapy assigned or administered to a subject is an interleukin, and / or interferon (IFN), and / or denileukin. This may include administration of one or more suitable antibody-based reagents such as diftitox, and / or an antibody-based reagent selected from the group consisting of ado-trastuzumab emtansine, alemtuzumab, atezolizumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, catumaxomab, gemtuzumab, ibritumomab tiuxetan, iripimumab, natalizumab, nimotuzumab, nivolumab, fatumumab, panitumumab, pembrolizumab, rituximab, tositumomab, trastuzumab, bivatuxin, and the like.In some embodiments, the immunotherapy assigned or administered to the subject may include indoleamine 2,3-dioxygenase (IDO) inhibitors, adoptive T cell therapy, viral therapy (T-VEC), and / or any other immunotherapy whose efficacy broadly depends on anti-tumor immunity.

[0342] Those skilled in the art will be able to determine appropriate immunotherapeutic options, including approved treatments and treatments in clinical trials or otherwise under development. Any relevant immunotherapeutic treatment strategy, alone or in combination with one or more additional cancer therapies, may be utilized in the practice of the present disclosure.

[0343] Other cancer treatments In addition to chemotherapy, targeted therapy, alternative therapy, and immunotherapy, cancer may additionally be treated by other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplantation, precision medicine, etc. Such treatments and the compounds and compositions utilized therein are known to those skilled in the art. Any such treatment strategy may be utilized in the practice of the present disclosure.

[0344] Alternative treatment strategies have also been used for various types of cancer. Such treatments may be used alone or in combination with any other treatment modality. These include exercise, massage, relaxation techniques, yoga, acupuncture, aromatherapy, hypnosis, music therapy, dietary changes, nutritional and dietary supplements, and the like, and such treatments are known to those skilled in the art. Any such treatment strategy may be utilized in the practice of the present disclosure, alone or in combination with one or more additional cancer therapies.

[0345] Dosage and route of administration Other embodiments of the present disclosure may include methods of administering to or treating animals / humans, which may involve treatment with an amount of at least one compound of the present disclosure (e.g., Formula (I)) effective to treat a disease, condition, or disorder that the organism has, is suspected of having, or is susceptible to having, or to cause a desired physiological effect. In some embodiments, a composition or pharmaceutical composition comprising at least one compound of the present disclosure (e.g., Formula (I)) can be administered to an animal (a mammal, primate, monkey, or human) in an amount of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, or about 15 mg / kg. For some conditions, the dosage may be about 0.5 mg / kg human body weight or about 6.5 mg / kg human body weight. In some cases, some subjects (e.g., mammals, mice, rabbits, cats, pigs, or dogs) may be administered a dosage of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 80 mg / kg, about 100 mg / kg, or about 150 mg / kg. Of course, those skilled in the art will recognize that many concentrations are possible for use in the methods of the present disclosure. Also, using in part the guidance provided herein, any number of concentrations could be adjusted and tested to find one that achieves the desired result in a given situation.In some embodiments, the dose or therapeutically effective dose of a compound disclosed herein will be sufficient to achieve a plasma concentration of the compound or its active metabolite within the ranges described herein, e.g., 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or even 500-1000 μM, preferably about 1-10 nM, 10-100 nM, or 0.1-1 μM. Without wishing to be bound by any theory, it is believed that such compounds are indicated for the treatment or management of hematopoietic cancers, such as MDS and / or AML and / or DLBCL, other types of cancer, inflammatory conditions, and / or autoimmune diseases, as described herein.

[0346] In other embodiments, the compounds and / or pharmaceutical compositions of the present disclosure (e.g., compounds of Formula (I), and pharmaceutical compositions comprising same) may be administered in combination with one or more other therapeutic agents for a given disease, condition, or disorder.

[0347] The compounds and pharmaceutical compositions are preferably prepared and administered in dosage units.Solid dosage units are tablets, capsules, and suppositories.For the treatment of a subject, different daily doses can be used depending on the activity of the compound, the method of administration, the nature and severity of the disease or disorder, and the age and weight of the subject.

[0348] However, under certain circumstances, higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out both by single administration in the form of individual dose units or several smaller dose units, and by multiple administration of subdivided doses at specific intervals.

[0349] The compounds and pharmaceutical compositions contemplated herein can be administered locally or systemically at therapeutically effective doses.The effective amount for this use will naturally depend on the severity of disease or disorder, and the subject's wei...

Claims

1. Compound of formula (I) 【Chemistry 1】 or its salts, esters, solvates, optical isomers, geometric isomers, salts of isomers, prodrugs, or derivatives, During the ceremony, R １ is selected from H, halogen, hydroxy, oxo, -CN, amide, methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ alkyl, C ２ -C ７ alkenyl, C ２ -C ７ alkynyl, C １ -C ７ heteroalkyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein the amide, methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ alkyl, C ２ -C ７ alkenyl, C ２ -C ７ alkynyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO ２ H), nitro (-NO ２ ), -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO ３ H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , C １ -C ７ alkyl, C １ -C ７ heteroalkyl, C １ -C ７ haloalkyl, C １ -C ７ Perfluoroalkyl, C １ -C ７ Alkoxy, C １ -C ７ C substituted with haloalkoxy or cycloalkyl １ -C ７ It is optionally substituted with one or more alkyl groups. R ２ However, H, halogen, hydroxy, oxo, -CN, amino, -O-aryl, methyl(-COH), carboxy(-CO) ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Selected from alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, heteroaryl, or condensed ring heteroaryl, and the amino, -O-aryl, methyl(-CO), carboxy(-CO) ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Heteroalkyl, C １ -C ７ Alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be halogen, hydroxy, oxo, methanol (-COH), carboxy (-COH). ２ H), Nitro (-NO ２ ), -NH ２ , - NHCH ３ , -N(CH ３ ) ２ cyano(-CN), ethinyl(-CCH), propynyl, sulfo(-SO) ３ H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , C １ -C ７ Alkyl, C １ -C ７ Heteroalkyl, C １ -C ７ Haloalkyl, C １ -C ７ Perfluoroalkyl, C １ -C ７ Alkoxy, C １ -C ７ Haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused-ring aryl, heteroaryl, fused-ring heteroaryl, or cycloalkyl-substituted C １ -C ７ alkyl, optionally substituted with one or more of R ３ 、 R ４ 、 and R ５ are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ alkyl, C ２ -C ７ alkenyl, C ２ -C ７ alkynyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, -O-(C ６ -C １２ aryl), heteroaryl, or fused-ring heteroaryl, wherein the methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ alkyl, C ２ -C ７ alkenyl, C ２ -C<( ７ alkynyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO ２ H), nitro (-NO ２ [[ID=(50]]), -NH ２ , -NHCH ３ , -N(CH ３ )( ２ , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO ３ H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH ２ , -CONHCH ３ , -CON(CH ３ )( ２ , C １ -C ７ alkyl, C １ -C ７ haloalkyl, C １ -C ７ Perfluoroalkyl, C １ -C ７ Alkoxy, C １ -C ７ C substituted with haloalkoxy or cycloalkyl １ -C ７ It is optionally substituted with one or more alkyl groups. R ６ but, 【Chemistry 2】 And, R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ However, each is independent of H, halogen, hydroxyl, oxo, -CN, methanol (-COH), and carboxyl (-CO). ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Selected from alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the methanoly(-CO) and carboxy(-CO) compounds. ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl are optionally substituted with one or more halogens. R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２９ , R ２９ , and R ３０ However, each is independent of H, halogen, hydroxyl, oxo, -CN, methanol (-COH), and carboxyl (-CO). ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Selected from alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the methanoly(-CO) and carboxy(-CO) compounds. ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl are optionally substituted with one or more halogens. A compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, characterized in that m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, and q + r + s + t is at least 1 and u + v + w + x is at least 1.

2. Compounds of formula (IIr) 【Transformation 3】 or its salts, esters, solvates, optical isomers, geometric isomers, or salts of isomers, During the ceremony, R ２０ｒ However, C is optionally substituted with one or more substituents selected from -OH and halogens. １ -C ６ It is an alkoxy, R ２１ｒ and R ２３ｒ However, each is independently a halogen, R ２２ｒ However, it is H, R ２４ｒａ , R ２４ｒｂ , R ２５ｒａ , R ２５ｒｂ , R ２６ｒａ , and R ２６ｒｂ However, each is independently selected from H and halogen, R ２４ｒａ , R ２４ｒｂ , R ２５ｒａ , R ２５ｒｂ , R ２６ｒａ , and R ２６ｒｂ One or more of them are halogens, Compounds of formula (IIs) 【Chemistry 4】 or its salts, esters, solvates, optical isomers, geometric isomers, or salts of isomers, During the ceremony, R 20s is selected from C1-C6 alkyl, C1-C6 alkoxy, and -OH, and the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogens. R 21s is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spirocondensed cycloalkyl, and C3-C9 heterocyclyl, where each C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogens, and each C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens. R22s, R23s, and R24s are each independently selected from H, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(C6-C12 aryl), where the C1-C6 alkyl is optionally substituted with one or more halogens. R 25sa, R 25sb, R 26sa, R 26sb, R 27sa, and R 27sb are each independently selected from H and halogen, and one or more of R 25sa, R 25sb, R 26sa, R 26sb, R 27sa, and R 27sb are halogen. The compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof as described in claim 1.

3. When the compound is a compound of formula (IIr), (i) to (iii): (i) R ２０ｒ but, 【Transformation 5】 That is, (ii) R ２１ｒ and R ２３ｒ Each of these is F, and (iii) R ２５ｒａ , R ２５ｒｂ , R ２６ｒａ , R ２４ｒａ , and R ２６ｒｂ Each of these is H, and R ２４ｒｂ However, it is F. At least one of the following applies, or When the compound is a compound of formula (IIs), (i) to (x): (i) R 20s is -OCH 3, (ii) R 21s is an unsubstituted C3-C6 cycloalkyl, 【Transformation 6】 Selected from, (iii) R 22s, R 23s, and R 24s are each H. (iv) R 23s is H, and R 22s and R 24s are F, (v) R 22s is F, and R 23s and R 24s are each H. (vi) R 24s is F, and R 22s and R 23s are each H. (vii) R 23s is H, and R 22s and R 24s are each independently selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl. (viiii) R 22s is selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl, and R 23s And R 24s are each H. (ix) R 24s is selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl, and R 22s And R 23s are H, (x) R 25sa, R 26sa, R 26sb, R 27sa, and R 27sb are each H, and R 25sb is F. At least one of the following applies: The compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof as described in claim 2.

4. The compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof according to claim 2, wherein the compound is selected from the following compounds. 【Transformation 7】 【Transformation 8】 【Chemistry 9】

5. However, R 20s is -OCH3, and R 21s is an unsubstituted C3 cycloalkyl or 【Chemistry 10】 If so, (i) one or more of R 22s, R 23s, and R 24s are selected from CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(C6-C12 aryl), or (ii) R 22s is halogen, R 23s is H, and R 24s is H, or (iii) R 22s is H, R 23s is H, and R 24s is halogen; R 20s is -OCH 3, and R 21s is 【Chemistry 11】 If so, at least one of R 22s, R 23s, and R 24s is not H, and If R 20s is -OCH 3, then R 21s is 【Chemistry 12】 A compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, as described in claim 2, provided that it is not the case thereafter.

6. Compound of formula (IIt) 【Chemistry 13】 or its salts, esters, solvates, optical isomers, geometric isomers, or salts of isomers, During the ceremony, 【Chemistry 14】 but, 【Chemistry 15】 Selected from, R 20t is a C1-C6 alkoxy optionally substituted with one or more substituents selected from -OH and halogens. R21t and R23t are each independently halogens. R 22t is H, R 24ta, R 24tb, R 25ta, R 25tb, R 26ta, R 26tb, R 27ta, R 27tb, R 28ta, R 28tb, R 29ta, and R 29tb are each independently selected from H and halogen, or Compound of formula (IIu) 【Chemistry 16】 or its salts, esters, solvates, optical isomers, geometric isomers, or salts of isomers, During the ceremony, 【Chemistry 17】 but, [Chemistry 18] Selected from, R20u is selected from C1-C6 alkyl, C1-C6 alkoxy, and -OH, and the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogens. R21u is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spirocondensed cycloalkyl, and C3-C9 heterocyclyl, where each C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogens, and each C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens. R22u, R23u, and R24u are each independently selected from H, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(C6-C12 aryl), where the C1-C6 alkyl is optionally substituted with one or more halogens. R 25ua, R 25ub, R 26ua, R 26ub, R 27ua, R 27ub, R 28ua, R 28ub, R 29ua, and R 29ub are each independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, and the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms. The compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof as described in claim 1.

7. When the compound is a compound of formula (IIt), (i) to (iv): (i) R 20t, 【Chemistry 19】 That is, (ii) R 21t and R 23t are F, (iii) 【Chemistry 20】 but, 【Chemistry 21】 And each of R 25ta, R 25tb, R 27ta, R 27tb, R 28ta, R 28tb, R 29ta, and R 29tb is H. (iv) 【Chemistry 22】 but, 【Chemistry 23】 Therefore, R 25ta, R 25tb, R 27ta, R 27tb, R 28ta, R 28tb, and R 29ta are H, and each of R 29tb is F. At least one of the following applies, or When the compound is a compound of formula (IIu), (i) to (ix): (i) R 20u is -OCH 3, (ii) R 21u is an unsubstituted C3-C6 cycloalkyl, 【Chemistry 24】 Selected from, (iii) R 22u, R 23u, and R 24u are each H. (iv) R 23u is H, and R 22u and R 24u are each F. (v) R 22u is F, and R 23u and R 24u are each H. (vi) R 24u is F, and R 22u and R 23u are each H. (vii) R 23u is H, and R 22u and R 24u are each independently selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl. (viiii) R 22u is selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl, and R 23u And R 24u are each H. (ix) R 24u is selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl, and R 22u And R 23u are each H. (x) 【Chemistry 25】 but, 【Chemistry 26】 And each of R 25ua, R 25ub, R 27ua, R 27ub, R 28ua, R 28ub, R 29ua, and R 29ub is H, and (xi) 【Chemistry 27】 but, 【Chemistry 28】 And each of R 25ua, R 25ub, R 27ua, R 27ub, R 28ua, R 29ua, and R 29ub is H, and R 28ub is F. At least one of the following applies: The compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof as described in claim 6.

8. The compound is 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 A compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, selected from claim 6.

9. However, R20u is -OCH3, and R21u is an unsubstituted C3 cycloalkyl or 【Transformation 34】 If so, (i) one or more of R22u, R23u, and R24u are selected from CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(C6-C12 aryl), (ii) R22u is halogen, R23u is H, and R24u is H, or (iii) R22u is H, R23u is H, and R24u is halogen; R20u is -OCH3, and R21u is 【Chemistry 35】 In that case, at least one of R22u, R23u, and R24u is not H, and If R20u is -OCH3, then R21u is 【Transformation 36】 A compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, as described in claim 6, provided that it is not the case thereafter.

10. An inhibitor of at least one of IRAK1, IRAK4, and FLT3, and / or Inhibitors of IRAK1 and IRAK4, and / or A compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, which is an inhibitor of IRAK1, IRAK4, and FLT3, according to claim 1.

11. The compound described in Claim 1 or its salt, ester, solvate, optical isomer, geometric isomer, isomer salt, prodrug, or derivative, A composition comprising a formulation ingredient, an adjuvant, or a carrier.

12. A pharmaceutical composition for treating a disease or disorder in a subject, comprising a therapeutically effective amount of the compound described in Claim 1 or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof.

13. The pharmaceutical composition according to claim 12, further comprising a formulation component, an adjuvant, or a carrier.

14. The pharmaceutical composition according to claim 12, wherein the disease or disorder responds to at least one of interleukin-1 receptor-related kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition.

15. The disease or disorder is (i) Hematopoietic carcinoma, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular At least one cancer selected from lymphoma, marginal zone lymphoma, glioblastoma multiforme, myelofibrosis, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer, or (ii) The pharmaceutical composition according to claim 12, comprising at least one inflammatory disease or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic scleroderma, type 1 diabetes mellitus, Crohn's disease, and colitis.

16. The pharmaceutical composition according to claim 12, wherein the disease or disorder is BCL2 inhibitor-resistant acute myeloid leukemia (AML) and / or FLT3 inhibitor-resistant AML.

17. The disease or disorder is The effects of inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject are mitigated, and / or The effects of inhibiting IRAK1 and IRAK4 in the subject are mitigated, and / or The pharmaceutical composition according to claim 12, which is mitigated by inhibiting IRAK1, IRAK4, and FLT3 in the subject.

18. A pharmaceutical composition for increasing the viability of a subject diagnosed with or suspected of having acute myeloid leukemia (AML), comprising a therapeutically effective amount of the compound described in Claim 1 or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof.

19. The pharmaceutical composition according to claim 18, wherein the viability of the subject is increased compared to a subject treated with a standard therapeutic dose effective for AML.

20. The pharmaceutical composition according to claim 19, wherein the standard treatment for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition according to claim 18, wherein the subject is a human.

22. The pharmaceutical composition according to claim 19, wherein the survival of the subject is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with the standard treatment in a therapeutically effective amount for AML.

23. The pharmaceutical composition according to claim 18, wherein a therapeutically effective amount is administered to the subject approximately every 6 hours, every 12 hours, every 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week.

24. Chemotherapy agent, BCL2 inhibitor, immunomodulator, BTK inhibitor, DNA methyltransferase inhibitor / hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analog (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, antibody-drug conjugate, mAb / immunotherapy, Plk inhibitor, MEK inhibitor, CDK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, CELMoD, blunting receptor antagonist, ERK2 / MAPK1 Or ERK inhibitors including ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, Hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura The pharmaceutical composition according to claim 12 or 18, administered to the subject together with one or more additional therapies selected from A inhibitors, aurora kinase inhibitors, EGFR inhibitors, Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT 1, 2, and / or 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, menin-KMT2A / MLL inhibitors, and multi-kinase inhibitors.

25. The pharmaceutical composition according to claim 24, wherein the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococcorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.

26. The pharmaceutical composition according to claim 25, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or any one of these pharmaceutically acceptable salts, the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitor BAY1251152 and atubeciclib, or any one of these pharmaceutically acceptable salts, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.

27. ​​The pharmaceutical composition according to claim 18, wherein the AML is resistant to BCL2 inhibitors and / or FLT3 inhibitors.

28. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition is administered to a subject in a single dose or in a single composition together with the one or more additional therapies.

29. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition is administered to a target separately in two or more doses or in two or more compositions, in addition to the one or more additional therapies.

30. The survivability is Inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject increases and / or Inhibiting IRAK1 and IRAK4 in the subject increases, and / or The pharmaceutical composition according to claim 18, which increases by inhibiting IRAK1, IRAK4, and FLT3 in the subject.

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