Multi-cyclic IRAK and FLT3 inhibiting compounds and uses thereof

Abstract

Some embodiments of the disclosure include compounds of Formula (I) and Formula (la), and compositions thereof, e.g., pharmaceutical compositions, which inhibit IRAK and / or FLT3 and which can be used for treating, for example, certain diseases. Some embodiments include methods of using the compounds (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as hematopoietic cancers, myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), etc.). Additional embodiments provide disease treatment using combinations of the IRAK and / or FLT3 inhibiting compounds with other therapies, such as cancer therapies.

Description

MULTI-CYCLIC IRAK AND FLT3 INHIBITING COMPOUNDS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This International Application claims priority to U.S. Provisional Application No.63 / 612,654, filed December 20, 2023, which is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE

[0002] The present disclosure generally relates to compounds and compositions whichare kinase inhibitors and the use of the same in treating diseases and disorders, including cancers. GOVERNMENT RIGHTS

[0003] This invention was made in the performance of a Cooperative Research andDevelopment Agreement with the National Institutes of Health, an Agency of the Department ofHealth and Human Services. The Government of the United States has certain rights in thisinvention. BACKGROUND

[0004] Myelodysplastic syndromes (MDS) are malignant, potentially fatal blood diseasesthat arise from a defective hematopoietic stem / progenitor cell, confer a predisposition to acutemyeloid leukemia (AML) (Corey et al., 2007; Nimer, 2008), and often progress tochemotherapy-resistant secondary acute myeloid leukemia (sAML). A majority of patients having MDS die of marrow failure, immune dysfunction, and / or transformation to overt leukemia.

[0005] MDS are heterogeneous diseases with few treatment options, as there is a lack ofeffective medicines capable of providing a durable response. Current treatment options for MDS are limited but include allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapies (Ebert, 2010). While hemopoeitic stem cell (HSC) transplantation can be used as a curative treatment for MDS, this option is unavailable to many older patients, who instead receive supportive care and transfusions to ameliorate disease complications. Unfortunately, MDS clones can persist in the marrow even after HSC transplantation, and thedisease invariably advances (Tehranchi et al., 2010). For advanced disease or high-risk MDS, patients may also receive immunosuppressive therapy, epigenetic modifying drugs, and / or chemotherapy (Greenberg, 2010). Despite recent progress, most MDS patients exhibit treatment-related toxicities or relapse (Sekeres, 2010a). Overall, the efficacy of these treatments is variable, and generally life expectancies are only slightly improved as compared to supportive care. The complexity and heterogeneity of MDS, and the lack of human xenograft models areobstacles which are challenging for identifying and evaluating novel molecular targets for thisdisease.

[0006] Approximately 30% of MDS patients also develop aggressive AML due toacquisition of additional mutations in the defective hematopoietic stem / progenitor cell (HSPC) (Greenberg et al., 1997). AML is a cancer of the myeloid line 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. Although AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, its incidence is expected to increase as the population ages. Several risk factors and chromosomal abnormalities have been identified, but the specific cause is not clear. As an acute leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated. The prognosis for AMLthat arises from MDS is worse as compared to other types of AML.

[0007] Several compounds are known to treat blood disorders and cancers (e.g. MDS,AML), but do so inadequately. While some known compounds, such as Quizartinib, Gilteritinib, and Crenolanib, can be used to treat AML, some of these treatments do not result in complete remission or partial remission. In some instances, for example, treatment can result in adaptive resistance or selecting mutations that are resistant to inhibitors, as with Quizartinib, in particular, where repeated administration can lead to desensitization in tumor cell suppression ofproliferation (Melgar et al., 2019).

[0008] In treating MDS and / or AML, there is a need to develop therapies capable ofinhibiting the adaptive resistance mechanism, to improve survival in the context of AML and MDS. There is also an unmet need in AML for drugs that increase overall survival, decrease the length of hospital stay as well as hospital readmission rates, overcome acquired resistance toother treatments, and increase the success rate for hematopoietic stem cell transplant. There is additionally a need for drugs for treating MDS which can slow the conversion rate to AML, and decrease transfusion dependence.

[0009] It is therefore necessary to develop treatments and methods of effectively treatingMDS and / or AML, and / or other conditions or disorders characterized by dysregulated (e.g.,hyperactive) IRAK (e.g., IRAK 1 and / or 4). Additionally, in doing so, it will be important to determine whether a patient is likely to be responsive to a particular treatment or method of treatment. Certain embodiments of the disclosure can address one or more of these issues.SUMMARY OF THE DISCLOSURE

[0010] In one embodiment, the present disclosure provides a compound of Formula (I)(I), or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: R1 is selected from H, halogen, hydroxy, oxo,, -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7haloalkyl, C1-C7perfluorinated alkyl, C1-C7alkoxy, C1-C7haloalkoxy, or C1- C7 alkyl which is substituted with cycloalkyl; R2is selected from H, halogen, hydroxy, oxo,, -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2- C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7alkyl, C1-C7heteroalkyl, C1-C7haloalkyl, C1-C7perfluorinated alkyl, C1-C7alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7alkyl which is substituted with cycloalkyl; R31is selected from H, halogen, hydroxy, oxo, , -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, - N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7alkyl, C1-C7heteroalkyl, C1-C7haloalkyl, C1-C7perfluorinated alkyl, C1-C7alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7 alkyl which is substituted with cycloalkyl; R3, R4, and R5 are eachindependently selected from H, halogen, hydroxy, oxo, -S(O)2-(C1-C7alkyl), amido, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl,wherein the amido, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (- COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7alkyl, C1-C7haloalkyl, C1-C7perfluorinated alkyl, C1-C7alkoxy, C1-C7haloalkoxy, or C1-C7alkyl which is substituted with cycloalkyl; or R3 and R4 or R4 and R5 bond or fuse to form a heterocyclyl orheteroaryl, each of which is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7heteroalkyl, C1-C7haloalkyl, C1-C7perfluorinated alkyl, C1-C7alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7 alkyl which is substituted with cycloalkyl; R6 isR10, R11, R12, R13, R14are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1- C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ringheteroaryl is optionally substituted with one or more halogen; R15, R16, R17, R18, R19, R20, R21,R22, R23, R24, R25, R26, R27, R28, R29, and R30are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, orfused ring heteroaryl is optionally substituted with one or more halogen; and 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, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. In one embodiment, at least one of (i)-(vi) applies: (i) R1 is -OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or;(iii) one or more of R3, R4, and R5 is -Cl, amido, C2-C7 alkynyl, C1-C7alkyl substitutedwith hydroxy, C1-C7 alkyl substituted with C1-C7 alkoxy, -S(O)2-(C1-C7 alkyl), or 4; (iv) Rand R5 bond or fuse to form an unsubstituted heterocyclyl or an unsubstituted heteroaryl; (v) R6or (vi) R31 is selected from halogen,hydroxy, oxo, -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl,heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, - N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ringheteroaryl, or C1-C7alkyl which is substituted with cycloalkyl.

[0011] In one embodiment, the compound of Formula (I) is a compound of Formula (IIv)or a salt, ester, solvate, optical isomer, geometric isomer, or saltof an isomer thereof; whereinis selected from; R20v is selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, andwherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy; R21v is selected from C1-C6alkyl, C3-C6cycloalkyl, C5-C12spiro-fused cycloalkyl, and C3-C9heterocyclyl, wherein C1-C6alkyl is 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, - OH, and halogen, and C3-C9 heterocyclyl is optionally substituted with one or more substituentsselected from C1-C6 alkyl, -OH, and halogen; R22v, R23v, and R24v are each independently selectedfrom H, CN, amido, halogen, -S(O)2-(C1-C7 alkyl), C1-C6 alkyl, C2-C7 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-C12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from C1-C6 alkoxy, -OH, halogen;and R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb are each independentlyselected 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, atleast one of (i)-(iii) applies: (i) R20v is -OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or; (ii) R21v is or (iii) one or more of R22v, R23v, and R24vis -Cl,amido, C2-C7 alkynyl, C1-C7 alkyl substituted with hydroxy, C1-C7 alkyl substituted with C1-C7 alkoxy, -S(O)2-(C1-C7 alkyl), orIn one embodiment, the compound is a compound ofFormula (IIv) with the provisos that: when R20v is -OCH3 and R21v is unsubstituted C3 cycloalkyl(i) one or more of R22v, R23v, and R24vis selected from amido, unsubstituted oxetane, -S(O)2-(C1-C7 alkyl), C1-C6 alkyl, or C2-C7 alkynyl, wherein C1-C6 alkyl is substituted with one or moresubstituents selected from C1-C6 alkoxy, -OH, halogen, (ii) one or more of R22v, R23v, and R24v is CN and one or more of R22v, R23v, and R24vis halogen, (iii) R22vand R24vare each independently halogen, R23v is H, and one or two of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb is selected from halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms, provided the compound of Formula (IIv) is no , (iv) R22v is Cl, R23v is H, and R24vis H, or (v) R22vis H, R23vis H, and R24vis Cl, or (v) the compound is; when R20v is -OCH3 and R21v is, one or more of R22v, R23v,and R24v is CN and one or more of R22v, R23v, and R24v is halogen; and when R20v is -OCH3 andR21v is unsubstituted oxetane or , one or more of R22v, R23v, and R24v is CN. In oneembodiment, at least one of (i)-(x) applies: (i) R20v is selected from -OCH3, -OCD3, -O(CH2)2OCH3, -O(CH2)2OH, and ; (ii) R21vis selected from unsubstituted C3cycloalky; (iii) R22v is F, R23v isH, and R24v is selected from F, CN, -CH2OH, –C(O)NH2, and –C(O)NHCH3; (iv) R22v is Cl, R23vand R24v are each H; (v) R22v and R23v are each H and R24v is selected from Cl, ethynyl, -CH2OH,-CH2OCH3, -C(O)NH2, -S(O)2CH3, andR25va, R25vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb is H; (vii)each of R25va, R25vb, R27va, R27vb, R28va, R29va, and R29vbis H and R28vbis F; (viii), each of R25va, R27va, R27vb, R28va, R28vb, R29va, and R29vbis H and R25vbis -CH3; (ix), each of R25va, R25vb, R27va, R28va, R28vb, R29va, andR29vb is H and R27vb is F or -CF3; or (x)each of R25va, R25vb,R28va, R28vb, R29va, and R29vbis H and each of R27vaand R27vbare F. In one embodiment, the compound is selected frompharmaceutically acceptable salt of any one thereof.

[0012] In one embodiment, the compound of Formula (I) is a compound of Formula (IIw)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; whereins selected from; R20w is selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, andwherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy; R21w is selected from C1-C6alkyl, C3-C6cycloalkyl, C5-C12spiro-fused cycloalkyl, and C3-C9heterocyclyl, wherein C1-C6alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen; R22w, R23w, and R24w are each independently selected from H, CN,amido, halogen, -S(O)2-(C1-C7alkyl), C1-C6alkyl, C2-C7alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-C12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from C1-C6 alkoxy, -OH, halogen; R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wbare each independently selected from H, halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms; and R31w is selected fromC1-C6alkyl, C1-C6alkoxy, amido, C3-C6cycloalkyl, C3-C9heterocyclyl, -OH, andwherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or moresubstituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy and C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen. In one embodiment, at least one of (i)-(iii) applies: (i) each of R25wa, R25wb, R26wa,R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb is H; (ii) one of R25wa, R25wb, R26wa, R26wb,R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb is selected from halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms; or (iii) R31w is amido or C1-C6 alkyl optionally substituted with one or moresubstituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy. In one embodiment, wherein at least one of (i)-(vi) applies: (i) R20w is -OCH3; (ii) R21w is unsubstituted C3 cycloalkyl;(iii) R22w and R23w are each H and R24w is F; (iv), each of R25wa,R25wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb is H; (v)eachof R25wa, R25wb, R27wa, R27wb, R28wa, R29wa, and R29wb is H and R28wb is F; or (vi) R31w is selectedfrom -C(O)NH2, -CH3, -CH2OH, and. In one embodiment, the compound is selectedpharmaceutically acceptable salt of any one thereof.

[0013] In one embodiment, the compound of Formula (I) is a compound of Formula (IVc)or a salt, ester, solvate, optical isomer, geometric isomer, or saltof an isomer thereof; wherein:is selected from;R40c is selected from C1-C6 alkyl, C1-C6 alkoxy, and -OH, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R41c is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fusedcycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C3-C6 cycloalkyl is optionally substitutedwith one or more substituents selected from C1-C6 alkyl and halogen; R42c, R43c, and R44c areeach independently selected from H and halogen; and R45ca, R45cb, R46ca, R46cb, R47ca, R47cb, R48ca,R48cb, R49ca, and R49cbare each independently selected from H, halogen, -OH, C1-C6alkyl, 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, each of R45ca, R45cb, R46ca, R46cb, R47ca, R47cb, R48ca,R48cb, R49ca, and R49cb is H. In one embodiment, at least one of (i)-(iv) applies: (i) R40c is -OH;(ii) R41c is unsubstituted C3 cycloalkyl; (iii) R42c and R44c are each F and R43c is H; and (iv)wherein each of R45ca, R45cb, R47ca, R47cb, R48ca, R48cb, R49ca,and R49cb is H. In one embodiment, the compound is,or a pharmaceutically acceptable salt thereof.

[0014] In one embodiment, the compound of Formula (I) is a compound of Formula (Vc)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:is selected fromand ;R50c is selected from C1-C6 alkyl, C1-C6alkoxy, -OH, andwherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy; R51c is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C3-C6cycloalkyl is optionally substituted with one or more substituents selected from C1-C6alkyl, -OH, and halogen; R52c is selected from H, CN, amido, halogen, -S(O)2-(C1-C7 alkyl), C1-C6 alkyl, C2-C7 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O- (C6-C12aryl), wherein C1-C6alkyl is optionally substituted with one or more substituents selected from C1-C6alkoxy, -OH, halogen; and R55ca, R55cb, R56ca, R56cb, R57ca, R57cb, R58ca, R58cb, R59ca, and R59cb are each independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, each of R55ca, R55cb, R56ca, R56cb, R57ca, R57cb, R58ca, R58cb, R59ca, and R59cb is H; or one of R55ca, R55cb, R56ca, R56cb, R57ca, R57cb, R58ca, R58cb, R59ca, and R59cb isselected from halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, atleast one of (i)-(vi) applies: (i) R50c is -OCH3; (ii) R51c is unsubstituted C3 cycloalkyl; (iii) R52c isH; (iv), each of R55ca, R55cb, R57ca, R57cb, R58ca, R58cb, R59ca, andR59cb is H; or (v), each of R55ca, R55cb, R57ca, R57cb, R58ca, R59ca, and R59cbis H and R58cbis F. In one embodiment, the compound is selected from:, or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment, the compound of Formula (I) is a compound of Formula (Vd)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:is selected fromR50d is selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, andd C1-C6alkoxy are each optionally substituted with one or moresubstituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy; R51d is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen; R52d is selected from H, CN, amido, halogen, -S(O)2-(C1-C7 alkyl), C1-C6alkyl, C2-C7alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C9heterocyclyl, C6-C12aryl, and -O- (C6-C12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from C1-C6 alkoxy, -OH, halogen; and R55da, R55db, R56da, R56db, R57da, R57db, R58da, R58db, R59da, and R59dbare each independently selected from H, halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, each of R55da, R55db, R56da, R56db, R57da, R57db, R58da, R58db, R59da, and R59db is H or one of R55da, R55db, R56da, R56db, R57da, R57db, R58da, R58db, R59da, and R59dbis selected from halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, at least one of (i)-(vi) applies: (i) R50d is -OCH3; (ii) R51d is unsubstituted C3 cycloalkyl; (iii) R52d isH; (iv)each of R55da, R55db, R57da, R57db, R58da, R58db, R59da, andR59db is H; or (veach of R55da, R55db, R57da, R57db, R58da, R59da, and R59db is H and R58db is F. In one embodiment, the compound is selected from:, or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment, the compound of Formula (I) is an inhibitor of at least one ofIRAK1, IRAK4, and FLT3, or wherein the compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3, or wherein the compound is an inhibitor of IRAK1 and IRAK4, or wherein the compound is an inhibitor of IRAK1, IRAK4, and FLT3. In one embodiment, FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3, optionally wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.

[0017] In another aspect, the present disclosure provides a composition comprising acompound of Formula (I), wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.

[0018] In yet another aspect, the present disclosure provides a method of treating adisease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a composition comprising acompound of Formula (I). In one embodiment, the disease or disorder is responsive to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition. In one embodiment, the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In one embodiment, the compound is administered to the subject in an amount of from about 0.005 mg / kg subject body weight to about 1,000 mg / kg subject body weight. In one embodiment, the disease or disorder is not relapsed / refractory, preferably wherein the disease or disorder is myelodysplastic syndrome(MDS) that is not relapsed / refractory or acute myeloid leukemia (AML) that is notrelapsed / refractory. In one embodiment, the disease or disorder is relapsed / refractory. In oneembodiment, the disease or disorder is: a BCL2 inhibitor relapsed / refractory disease or disorder,preferably a venetoclax relapsed / refractory disease or disorder, a hypomethylating agentrelapsed / refractory disease or disorder, preferably an azacitidine relapsed / refractory disease ordisorder, or a BCL2 inhibitor and a hypomethylating agent relapsed / refractory disease ordisorder, preferably a venetoclax and azacitidine relapsed / refractory disease or disorder. In one embodiment, the disease or disorder comprises a hematopoietic cancer. In one embodiment, thedisease or disorder comprises: (i) at least one cancer selected from: 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, 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, 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 carcinoma, rectal cancer,stomach cancer, and uterine cancer; or (ii) one or more inflammatory diseases or autoimmunedisease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome,Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, or colitis.In one embodiment, the disease or disorder comprises: (i) low-risk myelodysplastic syndrome(MDS), high-risk MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, optionally wherein MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 orSF3B1; or (ii) acute myeloid leukemia (AML) with a splicing factor mutation, AML havingenhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long, optionally wherein AML with a splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 orSF3B1. In one embodiment, the disease or disorder comprises diffuse large B-cell lymphoma (DLBCL), and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL. In one embodiment, themethod further comprises administering to the subject one or more additional therapies selectedfrom: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody-drug conjugate, an mAbs / 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 ERK inhibitor including an ERK2 / MAPK1 or ERK1 / MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase / Leukotriene A4 hydrolase inhibitor, a FLT3 / Axl / ALK inhibitor, a FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT 1, 2, and / or 3 inhibitor, a 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 disease or disorder is responsive to at least one of BCL2 inhibition, BTK inhibition, CDK inhibition, and DNA methyltransferase inhibition; or wherein the disease or disorder is sensitive to anti-inflammatory glucocorticoids. 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, he 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 thereof, theCDK inhibitor is selected from CDK4 / 6 inhibitor palbociclib, CDK7 inhibitor THZ1, and / or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any onethereof, the hypomethylating agent is azacitidine or a pharmaceutically acceptable salt thereof, orthe BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof and thehypomethylating agent is azacitidine or a pharmaceutically acceptable salt thereof. In oneembodiment, the disease or disorder is AML which is not relapsed / refractory and the additional therapy is: a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof,or a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof,or a combination of a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptablesalt thereof and a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptablesalt thereof. In one embodiment, the disease or disorder is MDS which is not relapsed / refractoryand the additional therapy is a hypomethylating agent, preferably azacitidine or apharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is: a BCL2inhibitor resistant disease or disorder, preferably a venetoclax resistant disease or disorder, ahypomethylating agent resistant disease or disorder, preferably an azacitidine resistant disease ordisorder, or a BCL2 inhibitor and a hypomethylating agent resistant disease or disorder,preferably a venetoclax and an azacitidine resistant disease or disorder, or a FLT3 inhibitorresistant disease or disorder. In one embodiment, the disease or disorder is: BCL2 inhibitorresistant acute myeloid leukemia (AML), preferably venetoclax resistant AML, and the additional therapy is a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptablesalt thereof, or BCL2 inhibitor resistant refractory AML, preferably venetoclax resistantrefractory AML, and the additional therapy is a BCL2 inhibitor, preferably venetoclax or apharmaceutically acceptable salt thereof, or BCL2 inhibitor resistant relapsed AML, preferablyvenetoclax resistant relapsed AML, and the additional therapy is a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, the disease ordisorder is: hypomethylating agent resistant acute myeloid leukemia (AML), preferablyazacitidine resistant AML, and the additional therapy is a hypomethylating agent, preferablyazacitidine or a pharmaceutically acceptable salt thereof, or hypomethylating agent resistantrefractory AML, preferably azacitidine resistant refractory AML, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof, orhypomethylating agent resistant relapsed AML, preferably azacitidine resistant relapsed AML,and the additional therapy is a hypomethylating agent, preferably azacitidine or apharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is: BCL-2inhibitor and hypomethylating agent resistant acute myeloid leukemia (AML), preferablyvenetoclax and azacitidine resistant AML, and the additional therapy is the combination of a BCL-2 inhibitor and a hypomethylating agent, preferably a combination of venetoclax or apharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt ofany one thereof, or BCL-2 inhibitor and hypomethylating agent resistant refractory AML,preferably venetoclax and azacitidine resistant refractory AML, and the additional therapy is the combination of a BCL-2 inhibitor and a hypomethylating agent, preferably a combination ofvenetoclax or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceuticallyacceptable salt of any one thereof, or BCL-2 inhibitor and hypomethylating agent resistantrelapsed AML, preferably venetoclax and azacitidine resistant relapsed AML, and the additional therapy is the combination of a BCL-2 inhibitor and a hypomethylating agent, preferably acombination of venetoclax or a pharmaceutically acceptable salt of thereof and azacitidine or apharmaceutically acceptable salt of any one thereof. In one embodiment, the disease or disorderis: hypomethylating agent resistant myelodysplastic syndrome (MDS), preferably azacitidineresistant MDS, and the additional therapy is a hypomethylating agent, preferably azacitidine or apharmaceutically acceptable salt of any one thereof, or hypomethylating agent resistantrefractory MDS, preferably azacitidine resistant refractory MDS, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt of any onethereof, or hypomethylating agent resistant relapsed MDS, preferably azacitidine resistant MDS,and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt of any one thereof. In one embodiment, the disease or disorderis: a BTK inhibitor resistant disease or disorder, optionally an ibrutinib resistant disease ordisorder, sensitive to anti-inflammatory glucocorticoids, optionally a dexamethasone,methylprednisolone, or prednisolone resistant disease or disorder, or a CDK inhibitor resistant disease or disorder, optionally a palbociclib, THZ1, BAY 12511152, or atuveciclib resistantdisease or disorder. In one embodiment, the disease or disorder is: FLT3 inhibitor resistant acutemyeloid leukemia (AML), FLT3 inhibitor resistant refractory AML, or FLT3 inhibitor resistantrelapsed AML. In one embodiment, the compound of Formula (I) or the composition comprisinga compound of Formula (I) and the one or more additional therapies are administered together inone administration or composition. In one embodiment, the compound of Formula (I) or thecomposition comprising a compound of Formula (I) and the one or more additional therapies areadministered separately in more than one administration or more than one composition. In one embodiment, the disease or disorder is alleviated by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject, wherein the disease or disorder is alleviated by inhibiting at least two of IRAK1, IRAK4, and FLT3 in the subject, wherein the disease or disorder is alleviated by inhibiting IRAK1 and IRAK4 in the subject, or wherein the disease or disorder is alleviated by inhibiting IRAK1, IRAK4, and FLT3 in the subject. In one embodiment, FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3, optionally wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3. In one embodiment, the compound is a compound of Formula (IIv), Formula (IIw), Formula (IVc), Formula (Vc), Formula (Vd), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. DETAILED DESCRIPTION OF THE DISCLOSURE

[0019] The following applications are incorporated by reference herein in their entirety,and for all purposes: International Publication No. WO 2018081738, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed October 30, 2017; U.S. Publication No.2021 / 0292843, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed April 4, 2019; International Publication No. WO 2014190163, Combination Therapy for MDS, filed May 22, 2014; U.S. Patent No.9,168,257, Combination Therapy for MDS, issued October 27, 2015; U.S. Patent No.9,504,706, Combination Therapy for MDS, issued November 29, 2016; U.S. Patent No.9,855,273, Combination Therapy for MDS, issued January 2, 2018; International Publication No. WO 2018038988, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 16, 2017; U.S. Patent No.11,254,667, Substituted imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors, issued February 2, 2022; U.S. Publication No.2022 / 0213094, Substituted Imidazo[l,2-a]-pyridines as IRAK 1 / 4 and FLT3 Inhibitors, filed January 4, 2022; U.S. Publication No.2020 / 0199123, Substituted imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors, filed February 28, 2020; U.S. Publication No.2022 / 0235042, Substituted Imidazo[l,2- a]-pyridines as IRAK 1 / 4 and FLT3 Inhibitors, filed January 28, 2022; International PublicationNo. WO 2020252487, Rational therapeutic targeting of oncogenic immune signaling states in myeloid malignancies via the ubiquitin conjugating enzyme UBE2N, filed June 15, 2020; International Publication No. WO 2022026935, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 31, 2021; International Publication No. WO 2022132936, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed December 15, 2021; International Publication No. WO 2022140647, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed December 23, 2021; International Publication No. WO 2023009833, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 29, 2022; International Publication No. WO 2023245123, Multi-CyclicIRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed June 15, 2023; InternationalPublication No. WO 2023250431, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds andUses Thereof, filed June 22, 2023; International Publication No. WO 2024030908, Multi-CyclicIRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed August 1, 2023; andInternational Publication No. WO 2024076614, Multi-Cyclic IRAK and FLT3 InhibitingCompounds and Uses Thereof, filed October 4, 2023.

[0020] While embodiments encompassing the general inventive concepts may takediverse forms, various embodiments will be described herein, with the understanding that thepresent disclosure is to be considered merely exemplary, and the general inventive concepts arenot intended to be limited to the disclosed embodiments.

[0021] Some embodiments of the disclosure include compounds of Formula (I) andFormula (Ia). Other embodiments include compositions (e.g., pharmaceutical compositions)comprising the inventive compound. Still other embodiments of the disclosure includecompositions for treating, for example, certain diseases using the inventive compounds. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating. Further embodiments includemethods for making the inventive compound. Yet further embodiments include methods fordetermining whether a particular patient is likely to be responsive to such treatment with theinventive compounds and compositions.

[0022] Unless otherwise noted, terms are to be understood according to conventionalusage by those of ordinary skill in the relevant art.

[0023] The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0024] Where substituent groups are specified by their conventional chemical formulae,written from left to right, they equally encompass the chemically identical substituents thatwould result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0025] As used herein, in relation to compounds of Formulae (I), (II), (III), etc., the term“attached” signifies a stable covalent bond, certain preferred points of attachment being apparent to those of ordinary skill in the art.

[0026] As used herein (unless otherwise specified), the term “alkyl” means amonovalent, straight or branched hydrocarbon chain, which can be fully saturated, mono- orpolyunsaturated and can include di- and multivalent radicals, having the number of carbon atomsdesignated (i.e., C1-C10means one to ten carbons). For example, the terms “C1-C7alkyl” or “C1-C4 alkyl” refer to straight- or branched-chain saturated hydrocarbon groups having from 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-C7alkyl 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-C4alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl.

[0027] As used herein (unless otherwise specified), the term “alkenyl” means amonovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) double bonds. Double bonds can occur in any stable point along the chain and the carbon-carbondouble bonds can have either the cis or trans configuration. For example, this definition shallinclude 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, l-pentenyl-3-cyclohexenyl, and the like. Similarly, “heteroalkenyl” refers to 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.

[0028] As used herein (unless otherwise specified), the term “alkynyl” means amonovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) triple bonds and that also may optionally include one or more (e.g.1, 2, 3, or 4) double bonds inthe 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.

[0029] As used herein (unless otherwise specified), the term “alkoxy” means any of theabove alkyl, alkenyl, or alkynyl groups which is 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 shown as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy.

[0030] The term “alkylene,” by itself or as part of another substituent, means, unlessotherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, asexemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those 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 eight or fewer carbon atoms.

[0031] As used herein (unless otherwise specified), the term “cycloalkyl” means amonovalent, monocyclic or bicyclic, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered hydrocarbongroup. The rings can be saturated or partially unsaturated. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyls (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 a monocyclic cycloalkyl, the ring isnot aromatic. For a bicyclic cycloalkyl, if one ring is aromatic, then the other is not aromatic.For a bicyclic cycloalkyl, one or both rings can be substituted.

[0032] The term “heteroalkyl,” by itself or in combination with another term, means,unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized, and thenitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N, P, S, and Si can beplaced 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-CH 2, -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 can be consecutive, such as, for example, -CH2-NH-OCH3.

[0033] Similarly, the term “heteroalkylene,” by itself or as part of another substituent,means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, butnot limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction inwhich the formula of the linking group is written. For example, the formula -C(O)2R'- representsboth -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, includethose groups that are attached to the remainder of the molecule through a heteroatom, suchas -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.

[0034] As used herein (unless otherwise specified), the term “halogen” or “halo” meansmonovalent Cl, F, Br, or I. Additionally, terms such as “haloalkyl” are meant 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.

[0035] As used herein (unless otherwise specified), the term “aryl” means a monovalent,monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 member aromatic hydrocarbon group and also means polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linkedcovalently. A fused ring aryl refers to multiple rings fused together wherein 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 an aryl that is bicyclic, one or both rings can be substituted.

[0036] As used herein (unless otherwise specified), the term “heteroaryl” means amonovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon group, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen, oxygen, or sulfur atom, and the monocyclic or bicyclic ring system is aromatic. Heteroaryl groups (or rings) can contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A 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 a bicyclic heteroaryl, if one ring is aryl, then the other is heteroaryl. For a bicyclic heteroaryl, one or both rings can have one or more hetero atoms. For a bicyclic heteroaryl, one or both rings can be substituted.

[0037] An “arylene” and a “heteroarylene,” alone or as part of another substituent, meana divalent radical derived from an aryl and heteroaryl, respectively. Accordingly, the term "aryl"can represent an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl andheterocyclic aromatic groups covalently attached at any ring position capable of forming a stablecovalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g.3-indolyl, 4-imidazolyl). The aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, C1-16alkyl, arylC1-16alkyl, C0-16alkyloxyC0-16alkyl, arylC0-16alkyloxyC0-16alkyl, C0-16alkylthioC0-16alkyl, arylC0-16alkylthioC0-16alkyl, C0- 16alkylaminoC0-16alkyl, arylC0-16alkylaminoC0-16alkyl, di(arylC1-16alkyl)aminoC0-16alkyl, C1- 16alkylcarbonylC0-16alkyl, arylC1-16alkylcarbonylC0-16alkyl, C1-16alkylcarboxyC0-16alkyl, arylC1-16alkylcarboxyC0-16alkyl, C1-16alkylcarbonylaminoC0-16alkyl, arylC1-16alkylcarbonylaminoC0-16alkyl,-C0-16alkylCOOR4, -C0-16alkylCONR5R6wherein R4, R5and R6are independently selected from hydrogen, C1-C11alkyl, arylC0-C11alkyl, or R5 and R6 are taken together with thenitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms withor without one C1-16alkyl, arylC0-C16alkyl, or C0-Cl16alkylaryl substituent. Aryl includes but is not limited to pyrazolyl and triazolyl.

[0038] 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 meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like)including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replacedby, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1- naphthyloxy)propyl, and the like), or a sulfur atom. Accordingly, the terms "arylalkyl" and the like (e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.

[0039] The terms “cycloalkyl” and “heterocycloalkyl”, also referred to as “heterocyclyl”,by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. 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 12membered, hydrocarbon, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen atom, oxygen atom, or sulfur atom, and the monocyclic or bicyclic ring system is not aromatic. Additionally, for heterocycloalkyl, a heteroatom canoccupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkyl include, but are not limited to, 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, pyrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or pyrrolidin- 4-yl), 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 a bicyclic heterocyclyl, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), then the other ring is not aromatic. For a bicyclic heterocyclyl, one or both rings can have one or more hetero atoms. For a bicyclic heterocyclyl, one or both rings can be substituted and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0040] As used herein (unless otherwise specified), the term “hetero atom” means anatom selected from nitrogen atom, oxygen atom, or sulfur atom.

[0041] As used herein (unless otherwise specified), the terms “hydroxy” or “hydroxyl”means a monovalent -OH group.

[0042] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0043] The term “oxo,” as used herein, means an oxygen that is double bonded to acarbon atom.

[0044] The term “alkylsulfonyl,” as used herein, means a moiety having theformula -S(O2)-R', where R' is an alkyl group as defined above. R' can have a specified numberof carbons (e.g., “C1-C4alkylsulfonyl”).

[0045] The term "carbonyloxy" represents a carbonyl group attached through an oxygenbridge.

[0046] In the above definitions, the terms "alkyl" and "alkenyl" can be usedinterchangeably in so far as a stable chemical entity is formed, as would be apparent to those skilled in the art.

[0047] The term “linker” refers to attachment groups interposed between substituents. Insome embodiments, the linker includes amido (-CONH-Rnor -NHCO-Rn), thioamido (-CSNH-Rnor -NHCS-Rn), carboxyl (-CO2-Rnor -OCORn), carbonyl (-CO-Rn), urea (-NHCONH-Rn), thiourea (-NHCSNH-Rn), sulfonamido (-NHSO2-Rnor -SO2NH-Rn), ether (-O-Rn), sulfonyl (-SO2-Rn), sulfoxyl (-SO-Rn), carbamoyl (-NHCO2-Rnor -OCONH-Rn), or amino (-NHRn) linking moieties.

[0048] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”, andso forth) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein.

[0049] As used herein (unless otherwise specified), the term “substituted” (e.g., as insubstituted alkyl) means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from the specified options. The replacement can occur at one or more positions. The term “optionally substituted” means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but is not required to be substituted.

[0050] A “substituent group,” as used herein, means a non-hydrogen substituent groupthat may be, and preferably is, a group 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 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, and (B) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least onesubstituent selected from:(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-C7alkyl, unsubstituted C1-C7heteroalkyl,unsubstituted C1-C7 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, and (ii) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least onesubstituent selected from: (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 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, and (b) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least onesubstituent selected from: -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 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl.

[0051] A “size-limited substituent” or “ size-limited substituent group,” as used herein,means a group, e.g., selected from all of the substituents described above for a “substituentgroup,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20- membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4-8-membered heterocycloalkyl.

[0052] A “lower substituent” or “lower substituent group,” as used herein, means agroup, e.g., selected from all of the substituents described above for a “substituent group,”wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8-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 5-7-membered heterocycloalkyl.

[0053] The term “about” used in the context of a numeric value indicates a range of + / -10% of the numeric value, unless expressly indicated otherwise.

[0054] Some compounds of the disclosure can have one or more chiral centers and canexist in and be isolated in optically active and racemic forms, for any of the one or more chiralcenters. Some compounds can exhibit polymorphism. The compounds of the present disclosure (e.g., Formula I) encompass any optically active, racemate, stereoisomer form, polymorphism, or mixtures thereof. If a chiral center does not provide an indication of its configuration (i.e., R or S) in a chemical structure, it should be considered to represent R, S or a racemate.

[0055] The compounds disclosed herein can contain one or more deuterium atoms. Theone or more deuterium atoms can replace one or more hydrogen atoms on a compound disclosedherein, such as a compound of Formula (I) or Formula (Ia). For example, the one or moredeuterium atoms can replace one or more hydrogen atoms in one or more of variable groups R1,R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 R15, R16, R17, R18, R19, R20, R21, R22, R23,R24, R25, R26, R27, R29, R29, R30, or R31. The one or more deuterium atoms can replace one ormore hydrogen atoms in an optional substituent on one or more of variable groups R1, R2, R3, R4,R5, R6, R7, R8, R9, R10, R11, R12, R13, R14R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, R30, or R31.

[0056] As used herein, the term “sample” encompasses a sample obtained from a subjector patient. The sample can be of any biological tissue or fluid. Such samples include, but are not limited to, sputum, saliva, buccal sample, oral sample, blood, serum, mucus, plasma, urine, bloodcells (e.g., white cells), circulating cells (e.g. stem cells or endothelial cells in the blood), tissue,core or fine needle biopsy samples, cell-containing body fluids, free floating nucleic acids, urine, stool, peritoneal fluid, and pleural fluid, tear fluid, or cells therefrom. Samples can also includesections of tissues such as frozen or fixed sections taken for histological purposes or microdissected cells or extracellular parts thereof. A sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch, excision or by any other surgicalmethod leading to biopsy or resected cellular material. Such a sample can comprise cellsobtained from a subject or patient. In some embodiments, the sample is a body fluid that include, for example, blood fluids, serum, mucus, plasma, lymph, ascitic fluids, gynecological fluids, or urine but not limited to these fluids. In some embodiments, the sample can be a non- invasive sample, such as, for example, a saline swish, a buccal scrape, a buccal swab, and the like.

[0057] As used herein, “blood” can include, for example, plasma, serum, whole blood,blood lysates, and the like.

[0058] As used herein, the term “assessing” includes any form of measurement, andincludes determining if an element is present or not. The terms “determining,” “measuring,” “evaluating,” “assessing,” “analyzing,” and “assaying” can be used interchangeably and can include quantitative and / or qualitative determinations.

[0059] As used herein, the term “monitoring” with reference to a type of cancer refers toa method or process of determining the severity or degree of the type of cancer or stratifying the type of cancer based on risk and / or probability of mortality. In some embodiments, monitoring relates to a method or process of determining the therapeutic efficacy of a treatment being administered to a patient.

[0060] As used herein, “outcome” can refer to an outcome studied. In someembodiments, “outcome” can refer to survival / mortality over a given time horizon. For example, “outcome” can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5years, or 10 years or longer. In some embodiments, an increased risk for a poor outcomeindicates that a therapy has had a poor efficacy, and a reduced risk for a poor outcome indicates that a therapy has had a good efficacy.

[0061] As used herein, the term “high risk clinical trial” refers to one in which the testagent has “more than minimal risk” (as defined by the terminology used by institutional review boards, or IRBs). In some embodiments, a high risk clinical trial is a drug trial.

[0062] As used herein, the term “low risk clinical trial” refers to one in which the testagent has “minimal risk” (as defined by the terminology used by IRBs). In some embodiments, a low risk clinical trial is one that is not a drug trial. In some embodiments, a low risk clinical trialis one that that involves the use of a monitor or clinical practice process. In some embodiments,a low risk clinical trial is an observational clinical trial.

[0063] As used herein, the terms “modulated” or “modulation,” or “regulated” or“regulation” and “differentially regulated” can refer to both up regulation (i.e., activation or stimulation, e.g., by agonizing or potentiating) and down regulation (i.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting), unless otherwise specified or clear from the context of a specific usage.

[0064] As used herein, the term “subject” refers to any suitable (e.g., treatable) memberof the animal kingdom. In the methods, the subject is preferably a mammal. In the methods, thesubject is preferably a human patient. In the methods, the subject may be a mammalian pediatricpatient. In the methods, the pediatric patient is a mammalian (e.g., preferably human) patientunder 18 years of age, while an adult patient is 18 or older.

[0065] As used herein, the term “treating” (and its variations, such as “treatment”“treating,” “treat,” and the like) is, unless stated otherwise, to be considered in its broadestcontext and refers to obtaining a desired pharmacologic and / or physiologic effect. In particular,for example, the term “treating” may not necessarily imply or require that an animal is treateduntil total recovery. Accordingly, “treating” includes amelioration of the symptoms, relief from the symptoms or effects associated with a condition, decrease in severity of a condition, or preventing, preventively ameliorating symptoms, or otherwise reducing the risk of developing aparticular condition. In some aspects, “treating” may not require or include prevention. As usedherein, reference to “treating” an animal includes but is not limited to prophylactic treatment andtherapeutic treatment. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or can be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment,” asused herein, covers any treatment of a disease in a subject, preferably in a mammal (e.g., in ahuman), and may include one or more of: (a) preventing the disease from occurring in a subjectwhich may be predisposed to the disease but has not yet been diagnosed as having it; (b)inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression or elimination of the disease and / or relieving one or more disease symptoms. In particular aspects of the methods, such as conditions or disorders characterized by dysregulated IRAK expression or dysregulated (e.g., hyperactive) IRAK-mediated signaling pathway(s), treatment may be or include reducing such expression or signaling. “Treatment” can also encompass delivery of an agent or administration of a therapy in order to provide for a pharmacologic 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.

[0066] “Therapeutically effective amount” means an amount effective to achieve adesired 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 appropriate to treat an indication. By treating an indication is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life. Such achievement can be measured by any suitable method, such as measurement of tumor size or blood cell count, or any other suitable measurement.

[0067] As used herein, the term “marker” or “biomarker” refers to a biological molecule,such as, for example, a nucleic acid, peptide, protein, hormone, and the like, whose presence orconcentration can be detected and correlated with a known condition, such as a disease state. It can also be used to refer to a differentially expressed gene whose expression pattern can be utilized as part of a predictive, prognostic or diagnostic process in healthy conditions or a disease state, or which, alternatively, can be used in methods for identifying a useful treatment or prevention therapy.

[0068] As used herein, an mRNA “isoform” is an alternative transcript for a specificmRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, shortened, or aberrant mRNA, modified mRNA (e.g. containing any residuemodifications, capping variants, polyadenylation variants, etc.), and the like.

[0069] “Antibody” or “antibody peptide(s)” refer to an intact antibody, or a bindingfragment 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, for example, substantially inhibits adhesion of a receptor to a counterreceptor when an excess of antibody reduces the quantity of receptor bound to counterreceptor by at least about 20%, 40%, 60% or 80%, and more usually greater than about 85% (as measured in an in vitro competitive binding assay).

[0070] Embodiments of the disclosure set forth herein include inventive compounds(e.g., compounds of Formula (I) and Formula (Ia)), such as compounds of Formula (II) andFormula (III)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the disclosure includecompositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using the inventive compounds. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (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 the inventive compounds. Additional embodiments of the disclosure are also discussed herein.Compounds and Compositions, Including Pharmaceutical Compositions

[0071] Some embodiments of the disclosure include compounds having a structureaccording to Formula (Ia):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 (Ia). In some embodiments, the compound is not an ester, not a solvate, and not a prodrug.

[0072] In exemplary embodiments, R1, R2, R3, R4, and R5 of Formula (Ia) areindependently selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which amido, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C2-C6alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (- CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (- SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl,C1-C7alkoxy, C1-C7haloalkoxy, or C1-C7alkyl which is substituted with cycloalkyl.

[0073] In some embodiments, R1 of Formula (Ia) can be H, halogen, hydroxy, oxo, -CN,amido, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which amido, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2,C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7haloalkoxy, or C1-C7alkyl which is substituted with cycloalkyl; R2of Formula (Ia) can be H, halogen, hydroxy, oxo, -CN, amino, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl,C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl,aryl, heteroaryl, or fused ring heteroaryl, which amino, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (- CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (- SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7alkyl, C1-C7heteroalkyl, C1-C7haloalkyl, C1-C7perfluorinated alkyl, C1-C7alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7 alkyl which is substituted with cycloalkyl; R3, R4, and R5of Formula (Ia) can be H, halogen, hydroxy, oxo, -CN, methanoyl (- COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl,C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl.

[0074] R6 of Formula (Ia) can be

[0075] R7, R8, R9, R10, R11, R12, R13, R14 of Formula (Ia) can be H, halogen, hydroxy,oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1- C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fusedring heteroaryl is optionally substituted with one or more halogen; R15, R16, R17, R18, R19, R20,R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 of Formula (Ia) can be H, halogen, hydroxy,oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1- C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen; and m, n, o, p, q, r, s, t, u, v, w, and x can be 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1.

[0076] In some embodiments, R1 of Formula (Ia) is H, halogen, -CONH2, -CONHCH3, -CON(CH3)2, benzyl, C1-C7alkyl, C1-C7alkoxy, or cycloalkyl, which C1-C7alkyl, C1-C7alkoxy, or cycloalkyl is optionally substituted with one or more halogen, hydroxyl, C1-C7 alkyl, or C1-C7 haloalkyl. In some embodiments, R1is H, Cl, -CONH2, -CONHCH3, methoxy, ethoxy, cyclopropyl, or C1-C4alkyl, which methoxy, ethoxy, cyclopropyl, or C1-C4alkyl is optionally substituted with one or more F, -OH, methyl, or CF3. In some embodiments, R1is not H.

[0077] In some embodiments, R2 of Formula (Ia) is H, halogen, hydroxy, O-aryl, amino,C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl, which O-aryl, amino, C1-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl 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, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy,C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R2is H, halogen, hydroxy, O-aryl, amino, C1-C7alkyl, C1-C7alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl which O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 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, C1-C7alkyl, C1-C7haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted withcycloalkyl. In some embodiments, R2is H, Cl, hydroxy, -NHCH3, -N(CH3)2, -OCH3, -OCF3, - OCHF2, -OPh, -CF3, -CHF2, unsubstituted C1-C7alkyl, substituted amino, substituted C1-C7alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl. In some embodiments, R2is not H.

[0078] In some embodiments, R3 of Formula (Ia) is H, halogen, hydroxy, -CN,methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, which C1-C7 alkyl, or C2-C6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl,C1-C7alkoxy, C1-C7haloalkoxy, or C1-C7alkyl which is substituted with cycloalkyl. In some embodiments, R3is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.

[0079] In some embodiments, R4 of Formula (Ia) is H, halogen, hydroxy, -CN,methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, or C1-C7alkoxy, which C1-C7alkyl, or C2-C6alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl,C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R4is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.

[0080] In some embodiments, R5 is of Formula (Ia) H, halogen, hydroxy, -CN,methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, which C1-C7 alkyl, or C2-C6alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH),carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl,C1-C7alkoxy, C1-C7haloalkoxy, or C1-C7alkyl which is substituted with cycloalkyl. In some embodiments, R5is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.

[0081] In some embodiments, R4 of Formula (Ia) is methyl or -CF3, and at least one of R3and R5is H or halogen.

[0082] In some embodiments, there is a chiral center at the R6 attachment carbon ofFormula (Ia). In some embodiments, the chiral center is an R chiral center. In someembodiments, the chiral center is an S chiral center. In certain embodiments, the chiral centercan be represented by the following bonds. Where a chiral center is possible at other positions of the compounds according to Formula (I), as would appreciated by one skilled in the art, the straight bond shown can also be can be

[0083] In some embodiments, R6 of Formula (Ia) is

[0084] In some embodiments, R7, R8, R9, R10, R11, R12, R13, R14 of Formula (Ia) areindependently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (- CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substitutedwith one or more halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl, provided that at least one of R7,R8, R9, R10, R11, R12, R13, and R14is not H.

[0085] In some embodiments, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27,R29, R29, and R30of Formula (Ia) are independently selected from H, halogen, hydroxy, oxo, - CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen, hydroxy, oxo, methanoyl (- COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO- morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl,C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is 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, where q+r+s+t is at least 1, and where u+v+w+x is at least 1.

[0086] In one embodiment, at least one of R7, R8, R9, R10, R11, R12, R13, and R14 ofFormula (Ia) is not H. In another embodiment, each of R7, R8, R9, R10, R11, R12, R13, and R14, if present, is H.

[0087] In one embodiment, at least one of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24,R25, R26, R27, R29, R29, and R30 of Formula (Ia) is not H. In another embodiment, each of R15,R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30, if present, is H.

[0088] In some embodiments, R6 of Formula (Ia) is

[0089] In some embodiments, R6 of Formula (Ia) is

[0090] In one embodiment, the compound is a compound of Formula (I)(I), or a salt, ester, solvate, optical isomer, geometric isomer, salt of anisomer, 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). In some embodiments, the compound is not an ester, not a solvate, and not a prodrug.

[0091] In one embodiment, R1 of Formula (I) is selected from H, halogen,hydroxy, oxo, -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H),C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7heteroalkyl, C1-C7alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl.

[0092] In one embodiment, R1 is -OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or

[0093] In one embodiment, R2 of Formula (I) is selected from H, halogen, hydroxy, oxo,, -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7heteroalkyl, C1-C7alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7 alkyl which is substituted with cycloalkyl.

[0094] In one embodiment, R2 is

[0095] In one embodiment, R31 is selected from H, halogen, hydroxy, oxo,CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO- morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7alkyl, C1-C7heteroalkyl, C1-C7haloalkyl, C1-C7perfluorinated alkyl, C1-C7alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7 alkyl which is substituted with cycloalkyl.

[0096] In one embodiment, R31 is selected from halogen, hydroxy, oxo,amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7heteroalkyl, C1-C7alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, - CONH2, -CONHCH3, -CON(CH3)2, C1-C7alkyl, C1-C7heteroalkyl, C1-C7haloalkyl, C1-C7perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7alkyl which is substituted with cycloalkyl.

[0097] In one embodiment, R3, R4, and R5 of Formula (I) are each independently selectedfrom H, halogen, hydroxy, oxo, -S(O)2-(C1-C7alkyl), amido, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amido, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl,-CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl,C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl.

[0098] In another embodiment, R3 and R4 or R4 and R5 bond or fuse to form aheterocyclyl or heteroaryl, each of which is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, - N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7alkyl,C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7alkyl which is substituted with cycloalkyl.

[0099] In one embodiment, one or more of R3, R4, and R5 is -Cl, amido, C2-C7 alkynyl,C1-C7 alkyl substituted with hydroxy, C1-C7 alkyl substituted with C1-C7 alkoxy, -S(O)2-(C1-C7 alkyl), or . In another embodiment, R4and R5bond or fuse to form an unsubstitutedheterocyclyl or an unsubstituted heteroaryl.

[00100] In one embodiment, R6 of Formula (I) is

[00101] In one embodiment, R6 is

[00102] In one embodiment, R7, R8, R9, R10, R11, R12, R13, R14 of Formula (I) are eachindependently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the methanoyl (- COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen;

[00103] In one embodiment, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27,R29, R29, and R30of Formula (I) are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen.

[00104] In one embodiment, m, n, o, p, q, r, s, t, u, v, w, and x of Formula (I) are eachindependently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1.

[00105] In some embodiments, there is a chiral center at the R6 attachment carbon ofFormula (I). 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 can be represented by the following bondsWhere a chiral center is possible at other positions of the compounds according to Formula (I), as would appreciated by one skilled in the art, the straight bond shown can also be can be

[00106] Some embodiments of the disclosure include compounds having a structureaccording to the following formula:wherein the wavy bond from Y to R6(i.e., ) indicates that, in some instances, there is a chiral center at the R6attachment carbon. In some embodiments, where there is a chiral center at the R6attachment carbon, the wavy bond can indicate an R chiral center, an S chiral center, or a racemate. In certain embodiments,can beor. Where a chiral center is possible at other positions of the compounds according tothe above formula, as would appreciated by one skilled in the art, the straight bond shown can also be can be

[00107] In some embodiments, R6 is , giving a structure ofFormula (II), as follows: wher1 2 3 4 5 7 8 9ein R , R , R , R , R , R , R , R , R10, R11, R12, R13, R14, m, n, o, and p are defined above in Formula (I) or Formula (Ia).

[00108] In some embodiments according to Formula (II), m is 0 or 1, n is 0 or 1, o is 0 or1, and p is 0 or 1.

[0109] In some embodiments, R7, R8, R9, and R10 are H, and at least one of R11, R12, R13,and R14is not H, and / or R11, R12, R13, and R14are H, and at least one of R7, R8, R9, and R10is not H. In particular embodiments, R7, R8, R9, R10, R11, R12, R13, and R14are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2- C7alkenyl, C2-C7alkynyl, C2-C6alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen. In some embodiments, R7, R8, R9, and R10are H, and at least one of R11, R12, R13, and R14is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7alkenyl, C2-C7alkynyl, C2-C6alkoxy, or spiro-fused cycloalkyl is optionallysubstituted with one or more halogen. In some embodiments, R11, R12, R13, and R14 are H, and atleast one of R7, R8, R9, and R10is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C1-C7alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (- CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl isoptionally substituted with one or more halogen. In some embodiments, at least one of R7, R8,R9, and R10is halogen, hydroxyl, C1-C7alkyl, C1-C7haloalkyl, C1-C7alkoxy, or spiro-fusedcycloalkyl. In some embodiments, at least one of R7, R8, R9, and R10 is F, hydroxyl, methyl,methoxy, -CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fusedcyclopentyl. In some embodiments, both of R7 and R8 or both of R9 and R10 are F, or both of R7and R8 or both of R9 and R10 are methyl. In some embodiments, at least one of R11, R12, R13, andR14is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl.In some embodiments, at least one of R11, R12, R13, and R14 is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl. In someembodiments, both of R11 and R12 or both of R13 and R14 are F, or wherein both of R11 and R12 orboth of R13and R14are methyl.

[0110] Further to any embodiment above wherein the compound has the structure ofFormula (II), the compound can have a structure according to any of (IIa)-(IIe), wherein V, W,X, Y, and Z can independently represent any of R7, R8, R9, R10, R11, R12, R13, or R14, and whereinat least one of V, W, X, Y, and Z is not H.

[00111] In an embodiment, the compound of Formula (II) is a compound of Formula (IIf)Formula (IIf), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20f is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O- (C3-C6 cycloalkyl), wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and C3-C6cycloalkyl and -O-(C3-C6cycloalkyl) are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R21f, R22f, and R23f are each independently selected from H and halogen; andR24fa, R24fb, R25fa, R25fb, R26fa, and R26fb 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.

[00112] In an embodiment, one or more of R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb isindependently selected from halogen, -OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6alkoxy. In another embodiment, each of R24fa, R24fb, R25fa, R25fb, R26fa, and R26fbis H.

[00113] In an embodiment, R20f is H. In another embodiment, R20f is not H. In anembodiment, R20f is halogen. In one embodiment, R20f is Cl. In another embodiment, R20f isunsubstituted C1-C6 alkoxy. In one embodiment, R20f is . In another embodiment, R20fis C1-C6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R20f is . In another embodiment, R21g is C1-C6 alkyl substituted with one or more -OH. Inone embodiment, R20f is another embodiment, R20f is C3-C6 cycloalkyl. In oneembodiment, R20fis unsubstituted C3cycloalkyl. In one embodiment, R20fis

[00114] In an embodiment, each of R21f, R22f, and R23f is H. In an embodiment, R21f andR23f are each independently halogen and R22f is H. In one embodiment, R21f and R23f are each F and R22f is H. In an embodiment, R21f and R23f are each H and R22f is halogen. In one embodiment, R21fand R23fare each H and R22fis F.

[00115] In an embodiment, each of R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb is H. In anembodiment, each of R25fa, R25fb, R26fa, and R26fb is H and R24fa and / or R24fb is halogen. In one embodiment, each of R24fb, R25fa, R25fb, R26fa, and R26fbis H and R24fais F. In one embodiment, each of R25fa, R25fb, R26fa, and R26fbis H and each of R24faand R24fbis F. In an embodiment, R25fa, R25fb, R26fa, and R26fb are each H and R24fa and / or R24fb is C1-C6 alkyl. In one embodiment, eachof R25fa, R25fb, R26fa, and R26fbis H and each of R24faand R24fbis -CH3. In one embodiment, each of R24fb, R25fa, R25fb, R26fa, and R26fbis H and R24fais -CH3.

[00116] In an embodiment, the compound of Formula (IIf) has one or more stereocenters.In one embodiment, the compouind of Formula (IIf) comprises a stereocenter where the moietyconnects to the remaining portion of Formula (IIf). In one embodiment, thecompound of Formula (IIf) comprises a stereocenter at one or more of R24fa, R24fb, R25fa, R25fb,R26fa, and / or R26fb. In one embodiment, the compound of Formula (IIf) comprises a stereocenter on R20f.

[00117] In an embodiment, the compound of Formula (II) is a compound of Formula (IIg)formula (IIg) or a salt, ester, solvate, optical isomer,geometric isomer, or salt of an isomer thereof; wherein: R20g is selected from H and C1-C6 alkoxy;R21g is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C6-C12aryl), C3-C9 heterocyclyl, and -NR28gaR28gb, wherein C1-C6 alkyl and C1-C6 alkoxy are eachoptionally substituted with one or more substituents selected from -OH and halogen, C3-C6cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and C3-C9heterocycyl is optionally substituted with one or more substituents selected from C1-C6alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R22g, R23g, and R24g are each independently selected from H and halogen; R25ga, R25gb, R26ga, R26gb, R27ga, and R27gbare each independently selected from H, halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms; andR28ga and R28gb are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl.

[00118] In an embodiment, one or more of R25ga, R25gb, R26ga, R26gb, R27ga, and R27gb isindependently selected from halogen, -OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6alkoxy. In another embodiment, each of R25ga, R25gb, R26ga, R26gb, R27ga, and R27gbis H.

[00119] In an embodiment, R20g is H. In an embodiment, R20g is unsubstituted C1-C6alkoxy. In one embodiment, R20gis selected from -OCH3, -OCH2CH3, and .

[00120] In an embodiment, R21g is halogen. In one embodiment, R21g is Cl. In anembodiment, R21g is unsubstituted C1-C6 alkyl. In one embodiment, R21g is t-butyl. In another embodiment, R21gis C1-C6alkyl substituted with one or more F and / or -OH. In oneembodiment, R21gis selected from -CF3. In another embodiment,R21g is unsubstituted C1-C6 alkoxy. In one embodiment, R21g is -OCH3. In another embodiment, R21gis C1-C6alkoxy substituted with one or more halogen atoms. In another embodiment, R21gis - O-(C6-C12 aryl). In one embodiment, R21g is -O-phenyl. In another embodiment, R21g isunsubstituted C3-C6 cycloalkyl. In one embodiment, R21g is unsubstituted C3 cycloalkyl. In one embodiment, R21g is C3 cycloalkyl substituted with one or more fluorine atoms. In one embodiment, R21gis In another embodiment, R21gis unsubstituted C3-C9heterocyclyl.In one embodiment, R21g is selected from morpholinyl, azetidinyl, piperdinyl, isoxazolyl,pyrazolylwherein G is N or CH, andwherein c is 1 or 2. In anotherembodiment, R21gis C3-C9heterocycyl substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen. In one embodiment, R21gwherein R29g is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6alkyl and C3-C6cycloalkyl are each optionally substituted with one or more halogen and / or -OH. In one embodiment, R21g iswherein R29g is H. Inone embodiment, R21giswherein R29gis unsubstituted C1-C6alkyl. In one embodiment, R21g i wherein R29g is selected from -CH3and isopropyl. In oneembodiment, R21g is wherein R29g is C1-C6 alkyl substituted with one or more -OH and / or F. In one embodiment, R21g is wherein R29g is selected fromand In another embodiment, R21giswherein R29gis selected fromunsubstituted C3 cycloalkyl, azetidinyl, and tetrahydropyranyl. In another embodiment, R21g is, wherein a is 1, 2, or 3, G is N or CH, and each X is independently halogen. In oneembodiment, R21gis selected from In another embodiment,R21g is , wherein b is 0, 1, 2, 3, 4, 5, or 6, c is 1 or 2, and each R220g isindependently C1-C6 alkyl. In one embodiment, R21g is In another embodiment,R21g is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R21g is isoxazolyl monosubstituted with -CH3. In another embodiment, R21g is -NR28gaR28gb wherein R28ga is H andR28gb is selected from -CH3, cyclobutyl, and cyclohexyl. In another embodiment, R21g is - NR28gaR28gb wherein R28ga and R28gb are each independently C1-C6 alkyl. In one embodiment, R21gis -NR28gaR28gbwherein R28gaand R28gbare each -CH3.

[00121] In an embodiment, R22g, R23g, and R24g are each H. In an embodiment, R22g andR24g are each independently halogen and R23g is H. In one embodiment, R22g and R24g are each F and R23gis H. In an embodiment, R22gand R24gare each H and R23gis halogen. In one embodiment, R22gand R24gare each H and R23gis F.

[00122] In an embodiment, each of R25ga, R25gb, R26ga, R26gb, R27ga, and R27gb is H. In anembodiment, each of R26ga, R26gb, R27ga, and R27gb is H and R25ga and / or R25gb is halogen. In one embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gbis H and R25gais F. In one embodiment, each of R26ga, R26gb, R27ga, and R27gb is H and each of R25ga and R25gb is F. In an embodiment, R26ga, R26gb, R27ga, and R27gb are each H and R25ga and / or R25gb is C1-C6 alkyl. In one embodiment,R26ga, R26gb, R27ga, and R27gbare each H and R25gaand R25gbare each -CH3. In one embodiment,each of R25gb, R26ga, R26gb, R27ga, and R27gb is H and R25ga is -CH3. In another embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gb is H and R25ga is selected from substituted C1-C6 alkyl and - OH. In one embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gbis H and R25gais -OH. In one embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gb is H and R25ga is selected from -CF3 and. In another embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gb is H and R25ga is unsubstituted C1-C6 alkoxy. In one embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gb is H and R25gais -OCH3.

[00123] In an embodiment, each of R25ga, R25gb, R26gb, R27ga, and R27gb is H and R26ga isunsubstituted C1-C6 alkyl. In one embodiment, each of R25ga, R25gb, R26gb, R27ga, and R27gb is H and R26gais -CH3.

[00124] In an embodiment, each of R25ga, R25gb, R26ga, and R26gb is H and each of R27ga andR27gb is unsubstituted C1-C6 alkyl. In one embodiment, each of R25ga, R25gb, R26ga, and R26gb is H and each of R27gaand R27gbis -CH3.

[00125] In an embodiment, the compound of Formula (IIg) comprises one or morestereocenters. In one embodiment, the compound of Formula (IIg) comprises a stereocenter on R21g. In one embodiment, the compound of Formula (IIg) comprises a stereocenter where the moietyconnects to the remaining portion of Formula (IIg). In one embodiment, the compound of Formula (IIg) comprises one or more stereocenters at R25ga, R25gb, R26ga, R26gb, R27ga, and / or R27gb.

[00126] In an embodiment, the compound of Formula (II) is a compound of Formula (IIh)Formula (IIh), or a salt, ester, solvate, optical isomer,geometric isomer, or salt of an isomer thereof;wherein: R20h is selected from H and C1-C6 alkoxy;R21his selected from C1-C6alkyl, C3-C6cycloalkyl, and C3-C9heterocyclyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogenand C3-C6 cycloalkyl, and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen; R22ha, R22hb, R23ha, and R23hbare each independently selected from H and C1-C6alkyl, wherein C1-C6alkyl is optionally substituted with one or more halogen atoms; and R24h, R25h, and R26h are each independently selected from H and halogen.

[0127] In an embodiment, R20h is H.

[0128] In an embodiment, R21h is C3-C9 heterocyclyl substituted with one or moresubstituents selected from C1-C6 alkyl, -OH, and halogen. In one embodiment, R21h is pyrazolyl substituted with C1-C6 alkyl and F. In one embodiment, R21h is pyrazolyl substituted with. In one embodiment, R21his

[0129] In an embodiment, one or more of R22ha, R22hb, R23ha, and R23hb is independentlyoptionally substituted C1-C6 alkyl. In another embodiment, each of R22ha, R22hb, R23ha, and R23hb is H. In an embodiment, each of R22ha, R22hbare H and R23haand / or R23hbis C1-C6alkyl. In one embodiment, each of R22ha, R22hb, and R23hais H and R23hbis -CH3. In another embodiment, each of R22ha and R22hb is H and each of R23ha and R23hb is -CH3.

[0130] In an embodiment, R24h, R25h, and R26h are each H. In an embodiment, R24h andR26hare each independently halogen and R25his H. In one embodiment, R24hand R26hare each F and R25h is H. In an embodiment, R24h and R26h are each H and R25h is halogen. In one embodiment, R24h and R26h are each H and R25h is F.

[0131] In an embodiment, the compound of Formula (IIh) comprises one or morestereocenters. In one embodiment, the compound of Formula (IIh) comprises a stereocenter on R21h. In one embodiment, the compound of Formula (IIh) comprises a stereocenter where themoiety connects to the remaining portion of Formula (IIh). In oneembodiment, one or more of R22ha, R22hb, R23ha, and / or R23hb comprises a stereocenter.

[00132] In an embodiment, the compound of Formula (IIh) is

[00133] In an embodiment, the compound of Formula (II) is a compound of Formula (IIi)Formula (IIi), or a salt, ester, solvate, optical isomer, geometricisomer, or salt of an isomer thereof; wherein:is selected from R20i is selected from H,and C1-C6 alkoxy;R21iis selected from C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C9heterocyclyl, 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 oneor more substituents selected from C1-C6alkyl and halogen, and C3-C9heterocycyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9- heterocyclyl, -OH, -C=O, and halogen;R22i, R23i, and R24i are each independently selected from H and halogen; andR25ia, R25ib, R26ia, R26ib, R27ia, R27ib, R28ia, R28ib, R29ia, and R29ib are each independently selected from H, halogen, -OH, or C1-C6alkyl.

[00134] In an embodiment, one or more of R25ia, R25ib, R26ia, R26ib, R27ia, R27ib, R28ia, R28ib,R29ia, and R29ib is independently selected from halogen, -OH, and C1-C6 alkyl. In another embodiment, each of R25ia, R25ib, R26ia, R26ib, R27ia, R27ib, R28ia, R28ib, R29ia, and R29ibis H.

[00135] In an embodiment, R20i is H. In another embodiment, R20i is unsubstituted C1-C6alkoxy. In one embodiment, R20i is -OCH3.

[00136] In an embodiment, R21i is C1-C6 alkyl substituted with one or more F and / or -OH.In one embodiment, R21iis selected from In anotherembodiment, R21iis unsubstituted C3-C6cycloalkyl. In one embodiment, R21iis unsubstituted C3cycloalkyl. In one embodiment, R21i is C3 cycloalkyl substituted with C1-C6 alkyl. In one embodiment, R21iis . In one embodiment, R21iis C3cycloalkyl substituted with one ormore C1-C6 alkyl and one or more fluorine atoms. In one embodiment, R21i is Inanother embodiment, R21iis unsubstituted C3-C9heterocyclyl. In one embodiment, R21iis pyrazolyl. In one embodiment, R21iiswherein J is N or CH. In another embodiment, R21iis C3-C9heterocycyl substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, -C=O, and halogen. In one embodiment, R21i is pyrrolidinyl monosubstituted with -C=O. In one embodiment, R21i isIn one embodiment, R21i iswherein R220i is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogen and / or -OH. In one embodiment, R21i iswherein R220iis H. In one embodiment, R21iis wherein R220iisunsubstituted C1-C6alkyl. In one embodiment, R21iis wherein R220iis -CH3. In one embodiment, R21i is wherein R220i is C1-C6alkyl substituted with one or more -OH and / or F. In one embodiment, R21i is wherein R220iis selected from . In another embodiment, R21i is wherein R220i isunsubstituted C3cycloalkyl.

[00137] In an embodiment, each of R22i, R23i, and R24i is H. In an embodiment, R22i andR24i are each independently halogen and R23i is H. In one embodiment, R22i and R24i are each F and R23iis H. In an embodiment, R22iand R24iare each H and R23iis halogen. In one embodiment, R22iand R24iare each H and R23iis F.

[00138] In an embodiment,, each of R25ia, R25ib, R26ia, R26ib,R27ia, R27ib, R28ia, and R28ibis H. In an embodiment, each of R26ia, R26ib, R27ia, R27ib, R28ia, and R28ib is H and R25ia and / or R25ib is halogen. In one embodiment, each of R26ia, R26ib, R27ia, R27ib, R28ia, and R28ibis H and each of R25iaand R25ibis F. In one embodiment, each of R25ia, R26ia, R26ib, R27ia, R27ib, R28ia, and R28ibis H and R25ibis F.

[00139] In an embodimeneach of R25ia, R25ib, R27ia, R27ib,R28ia, R28ib, R29ia, and R29ib is H. In an embodiment, each of R25ia, R25ib, R27ia, R27ib, R29ia, and R29ib is H and R28ia and / or R28ib is halogen. In one embodiment, each of R25ia, R25ib, R27ia, R27ib, R29ia, and R29ibis H and each of R28iaand R28ibis F. In one embodiment, each of R25ia, R25ib,R27ia, R27ib, R28ia, R29ia, and R29ib is H and R28ib is F. In another embodiment, each of R25ia, R25ib,R28ia, R28ib, R29ia, and R29ib is H and R27ia and / or R27ib is halogen. In one embodiment, each ofR25ia, R25ib, R27ia, R28ia, R28ib, R29ia, and R29ib is H and R27ib is F. In one embodiment, each ofR25ia, R25ib, R27ia, R28ia, R28ib, R29ia, and R29ib is H and each of R27ia and R27ib is F.

[0140] In an embodiment, the compound of Formula (IIi) comprises one or morestereocenters. In one embodiment, the compound of Formula (IIi) comprises a stereocenter on R20i. In one embodiment, the compound of Formula (IIi) comprises a stereocenter on R21i. In one embodiment, the compound of Formula (IIi) comprises a stereocenter where themoiety connects to the remaining portion of Formula (IIi). In one embodiment, one or more of R25ia, R25ib, R26ia, R26ib, R27ia, R27ib, R28ia, R28ib, R29ia, and / or R29ib comprises a stereocenter.

[0141] In an embodiment, the compound of Formula (II) is a compound of Formula (IIj)ormula (IIj), or a salt, ester, solvate, optical isomer, geometricisomer, or salt of an isomer thereof; wherein:R20jis selected from H, and C1-C6alkoxy; R21jis selected from H, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl, wherein C1-C6alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and C3-C6cycloalkyl is optionally substituted with one or more substituents selected from C1-C6alkyl and halogen; and R22j, R23j, and R24j are each independently selected from H and halogen.

[0142] In an embodiment, R20j is H. In another embodiment, R20j is optionallysubstituted C1-C6 alkoxy. In one embodiment, R20j is unsubstituted C1-C6 alkoxy. In one embodiment, R20jis -OCH3.

[00143] In an embodiment, R21j is optionally substituted C3-C6 cycloalkyl. In oneembodiment, R21j is optionally substituted C3 cycloalkyl. In one embodiment, R21j is unsubstituted C3cycloalkyl.

[00144] In an embodiment, R22j, R23j, and R24j are each H. In an embodiment, R22j and R24jare each independently halogen and R23j is H. In one embodiment, R22j and R24j are each F and R23j is H. In an embodiment, R22j and R24j are each H and R23j is halogen. In one embodiment, R22jand R24jare each H and R23jis F.

[00145] In an embodiment,

[00146] In an embodiment, the compound of Formula (IIj) comprises one or morestereocenters. In one embodiment, the compound of Formula (IIj) comprises a stereocenter on R21j. In one embodiment, the compound of Formula (IIj) comprises a stereocenter where themoiety connects to the remaining portion of Formula (IIj).

[00147] In an embodiment, the compound of Formula (Ia) is a compound of Formula (IIk)Formula (IIk), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20k is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O- (C3-C6cycloalkyl), wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl and -O- (C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from C1-C6alkyl and halogen;R21k, R22k, and R23k are each independently selected from H, halogen, C1-C6 alkyl, andC1-C6 alkoxy, wherein C1-C6 alkyl is optionally substituted with one or more halogen; andR24ka, R24kb, R25ka, R25kb, R26ka, and R26kbare 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.

[00148] In one embodiment, one or more of R24ka, R24kb, R25ka, R25kb, R26ka, and R26kb isindependently selected from halogen, -OH, optionally substituted C1-C6alkyl, and optionally substituted C1-C6 alkoxy.

[00149] In one embodiment, at least one of R21k, R22k, and R23k is C1-C6 alkyl. In anotherembodiment, R21k, R22k, and R23kare each H. In one embodiment, R22kis H, R21kand R23kare each independently F or -CH3. In another embodiment, R21k and R22k are each H, R23k is F or - CH3. In another embodiment, R22k and R23k are each H, R21k is F or -CH3. In another embodiment, R21kand R23kare each H, R22kis F or -CH3.

[00150] In one embodiment, R20k is selected from -OCH3 and

[00151] In one embodiment, R24ka, R24kb, R25ka, R25kb, R26ka, and R26kb are each H. Inanother embodiment, R25ka, R25kb, R26ka, and R26kbare each H and R24kaand / or R24kbis F.

[00152] In one embodiment, the compound of Formula (IIk) is selected from:

[00153] In another embodiment, the compound of Formula (Ia) is a compound of Formula(IIm)Formula (IIm), or a salt, ester, solvate, optical isomer,geometric isomer, or salt of an isomer thereof; wherein: R20m is selected from C1-C6 alkyl and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R21m is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C5-C12 spiro- fused cycloalkyl, -O-(C6-C12aryl), C3-C9heterocyclyl, and -NR28maR28mb, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from - OH and halogen, wherein C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6alkyl and halogen, wherein C1-C6alkyl is optionally substituted with one or more -OH, and wherein C3-C9heterocycyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R22m, R23m, and R24m are each independently selected from H, halogen, C1-C6 alkyl, and C1-C6alkoxy, wherein C1-C6alkyl is optionally substituted with one or more halogen; R25ma, R25mb, R26ma, R26mb, R27ma, and R27mbare 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; and R28maand R28mbare each independently selected from H, C1-C6alkyl, and C3-C6cycloalkyl.

[00154] In one embodiment, one or more of R25ma, R25mb, R26ma, R26mb, R27ma, and R27mb isindependently selected from halogen, -OH, optionally substituted C1-C6alkyl, and optionally substituted C1-C6 alkoxy. In another embodiment, R25ma, R25mb, R26ma, R26mb, R27ma, and R27mb areeach H. In another embodiment, R26ma, R26mb, R27ma, and R27mb are each H and R25ma and / or R25mbis F.

[0155] In one embodiment, at least one of R22m, R23m, and R24m is C1-C6 alkyl. In anotherembodiment, at least one of R22m, R23m, and R24m is C1-C6 alkoxy. In another embodiment, R22m, R23m, and R24mare each H. In another embodiment, R23mis H, R22mand R24mare each independently F, -CH3, or -OCH3. In another embodiment, R22m and R23m are each H, R24m is F, - CH3, or -OCH3. In another embodiment, R23m and R24m are each H, R22m is F, -CH3, or -OCH3. In another embodiment, R22mand R24mare each H, and R23mis F, -CH3, or -OCH3.

[00156] In one embodiment, R20m is selected from -OCH3 and

[00157] In one embodiment, R21m is selected from unsubstituted C3-C6 cycloalkyl,

[00158] In one embodiment, the compound of Formula (IIm) is selected from:

[00159] In one embodiment, the compound of Formula (Ia) is a compound of Formula(IIn)Formula (IIn), or a salt, ester, solvate, optical isomer, geometricisomer, or salt of an isomer thereof;wherein:R20n is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O- (C3-C6cycloalkyl), wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl and -O- (C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from C1-C6alkyl and halogen; R21n, R22n, and R23n 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 halogen; andR25na, R25nb, R26na, R26nb, R27na, R27nb, R28na, R28nb, R29na, and R29nb are each independently selected from H, halogen, -OH, or C1-C6alkyl, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms.

[0160] In one embodiment, one or more of R25na, R25nb, R26na, R26nb, R27na, R27nb, R28na,R28nb, R29na, and R29nbis independently selected from halogen, -OH, optionally substituted C1-C6alkyl, and optionally substituted C1-C6 alkoxy.

[0161] In one embodiment, at least one of R21n, R22n, and R23n is C1-C6 alkyl.

[0162] In one embodiment, R20n is selected from -OCH3 and

[0163] In one embodiment, R21n, R22n, and R23n are each H. In another embodiment, R22nis H, R21n and R23n are each independently F or -CH3. In another embodiment, R21n and R22n areeach H, R23n is F or -CH3. In another embodiment, R22n and R23n are each H, R21n is F or -CH3.In another embodiment, R21n and R23n are each H, R22n is F or -CH3.

[0164] In one embodimenteach of R25na, R25nb, R27na, R27nb, R28na, R28nb,R29na, and R29nbis H. In another embodiment, each of R25na, R25nb, R27na, R27nb, R28na, R29na, and R29nb is H and R28nb is F.

[00165] In one embodiment, the compound of Formula (IIn) is selected from:

[00166] In another embodiment, the compound of Formula (Ia) is a compound of Formula(IIp) Formula (IIp), or a salt, ester, solvate, optical isomer, geometricisomer, or salt of an isomer thereof;wherein:R20pis selected from C1-C6alkyl and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R21p is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C5-C12 spiro- fused cycloalkyl, -O-(C6-C12aryl), C3-C9heterocyclyl, and -NR220paR220pb, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6alkyl and halogen, and wherein C3-C9heterocycyl is optionally substituted with one or more substituents selected from C1-C6alkyl, C3-C6-cycloalkyl, C3-C9- heterocyclyl, -OH, and halogen; R22p, R23p, and R24p are each independently selected from H, halogen, C1-C6 alkyl, and C1-C6alkoxy, wherein C1-C6alkyl is optionally substituted with one or more halogen; R25pa, R25pb, R26pa, R26pb, R27pa, R27pb, R28pa, R28pb, R29pa, and R29pbare 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; and R220paand R220pbare each independently selected from H, C1-C6alkyl, and C3-C6cycloalkyl.

[0167] In one embodiment, one or more of R25pa, R25pb, R26pa, R26pb, R27pa, R27pb, R28pa,R28pb, R29pa, and R29pbis independently selected from halogen, -OH, optionally substituted C1-C6alkyl, and optionally substituted C1-C6 alkoxy.

[0168] In one embodiment, at least one of R22p, R23p, and R24p is C1-C6 alkyl. In anotherembodiment, R22p, R23p, and R24piare each H. In one embodiment, R23pis H, R22pand R24pare each independently F, -CH3, or -OCH3. In another embodiment, R22p and R23p are each H, R24p isF, -CH3, or -OCH3. In another embodiment, R23p and R24p are each H, R22p is F, -CH3, or -OCH3.In another embodiment, R22pand R24pare each H, R23pis F, -CH3, or -OCH3.

[0169] In one embodiment, R20p is selected from -OCH3 and

[00170] In one embodiment, R21p is selected unsubstituted C3-C6 cycloalkyl,

[00171] In one embodiment, , each of R25pa, R25pb, R27pa,R27pb, R28pa, R28pb, R29pa, and R29pbis H. In another embodiment,, each of R25pa, R25pb, R27pa, R27pb, R28pa, R29pa, and R29pb is H and R28pb is F.

[00172] In one embodiment, the compound of Formula (IIp) is selected from:

[00173] In one embodiment, the compound of Formula (Ia) is a compound of Formula(IIq)Formula (IIq), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:R20q is C1-C6 alkoxy optionally substituted with one or more substituents selected from - OH and halogen; R21qis C3-C6cycloalkyl optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; and R22q and R23q are each independently halogen.

[00174] In one embodiment,

[0175] In one embodiment, R20q is unsubstituted C1-C6 alkoxy. In one embodiment, R20qis -OCH3.

[00176] In one embodiment, R21q is unsubstituted C3-C6 cycloalkyl. In one embodiment,R21q is unsubstituted C3 cycloalkyl.

[00177] In one embodiment, R22q and R23q are each F.

[0178] In yet another embodiment, the compound of Formula (Ia) is a compound ofFormula (IIr)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20r is C1-C6 alkoxy optionally substituted with one or more substituents selected from - OH and halogen; R21r and R23r are each independently halogen; R22r is H; and R24ra, R24rb, R25ra, R25rb, R26ra, and R26rbare each independently selected from H and halogen, wherein one or more of R24ra, R24rb, R25ra, R25rb, R26ra, and R26rb is halogen.

[0179] In one embodiment, R20r is C1-C6 alkoxy substituted with two halogen atoms. Inone embodiment, R20r is C1-C6 alkoxy substituted with two fluorine atoms. In one embodiment,R20r is C2 alkoxy substituted with two fluorine atoms. In one embodiment, R20r is

[00180] In one embodiment, R21r and R23r are each halogen. In one embodiment, R21r andR23rare each F.

[00181] In one embodiment, R25ra, R25rb, R26ra, R24ra, and R26rb are each H and R24rb ishalogen. In one embodiment, R25ra, R25rb, R26ra, R24ra, and R26rb are each H and R24rb is F.

[00182] In one embodiment, the compound of Formula (IIr) is:or a pharmaceutically acceptable salt thereof.

[00183] In yet another embodiment, the compound of Formula (Ia) is a compound ofFormula (IIs)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20s is selected from C1-C6 alkyl, C1-C6 alkoxy, and -OH, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R21s is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3- C9 heterocyclyl, wherein C1-C6 alkyl are each optionally substituted with one or more substituents selected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted withone or more substituents selected from C1-C6 alkyl and halogen;R22s, R23s, and R24s are each independently selected from H, CN, halogen, C1-C6 alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C6-C12aryl, and -O-(C6-C12aryl), wherein C1-C6alkyl is optionally substituted with one or more halogen; and R25sa, R25sb, R26sa, R26sb, R27sa, and R27sb are each independently selected from H and halogen, wherein one or more of R25sa, R25sb, R26sa, R26sb, R27sa, and R27sbis halogen.

[00184] In one embodiment, R20s is unsubstituted C1-C6 alkoxy. In one embodiment, R20sis -OCH3.

[0185] In one embodiment, when R20s is -OCH3 and R21s is unsubstituted C3 cycloalkyl or, (i) one or more of R22s, R23s, and R24s is CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12aryl, and -O-(C6-C12aryl), (ii) R22sis halogen, R23sis H, and R24sis H, or (iii) R22sis H, R23sis H, and R24sis halogen. In one embodiment, when R20sis -OCH3and R21sis , at least one of R22s, R23s, and R24s is not H. In one embodiment, when R20s is -OCH3,R21s is no

[00186] In one embodiment, R21s is selected from unsubstituted C3-C6 cycloalkyl,. In one embodiment, R21sis C1-C6alkyl substituted with one -OH. In one embodiment, R21sis C3alkyl substituted with one -OH. In one embodiment, R21s is In one embodiment, R21s is C1-C6 alkyl substituted with one -OHand three halogen atoms. In one embodiment, R21sis C3alkyl substituted with one -OH and three fluorine atoms. In one embodiment, R21sis In one embodiment, R21sis C3-C6cycloalkyl substituted with one or more C1-C6 alkyl. In one embodiment, R21s is C4 cycloalkyl substituted with one or more C1-C6 alkyl. In one embodiment, R21s is C4 cycloalkyl substituted with two -CH3. In one embodiment, R21s is

[00187] In one embodiment, R22s, R23s, and R24s are each H. In another embodiment, R23sis H, R22s and R24s are each halogen. In one embodiment, R23s is H, R22s and R24s are each F. In another embodiment, R22s is halogen, R23s and R24s are each H. In one embodiment, R22s is F, R23s and R24sare each H. In another embodiment, R24sis halogen, R22sand R23sare each H. In one embodiment, R24s is F, R22s and R23s are each H.

[0188] In one embodiment, at least one of R22s, R23s, and R24s is selected from CN, C1-C6alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(C6-C12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more halogen. In on embodiment, R23sis H, R22sand R24sare each independently selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl. In another embodiment, R22s is selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl, R23sand R24sare each H. In another embodiment, R24sis selected from -CH3, -OCH3, CN, C3cycloalkyl, phenyl, and -O-phenyl, R22sand R23sare each H.

[00189] In one embodiment, R25sa, R26sa, R26sb, R27sa, and R27sb are each H and R25sb ishalogen. In one embodiment, R25sa, R26sa, R26sb, R27sa, and R27sb are each H and R25sb is F.

[00190] In one embodiment, the compound of Formula (IIs) is selected from:, and a pharmaceutically acceptable salt of any one thereof.

[00191] In one embodiment, the compound of Formula (IIs) is not one of the followingcompounds:or a pharmaceutically acceptable salt thereof.

[00192] In yet another aspect, the compound of Formula (Ia) is a compound of Formulaor a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:R20tis C1-C6alkoxy optionally substituted with one or more substituents selected from - OH and halogen; R21t and R23t are each independently halogen; R22tis H; and R24ta, R24tb, R25ta, R25tb, R26ta, R26tb, R27ta, R27tb, R28ta, R28tb, R29ta, and R29tb are each independently selected from H and halogen.

[0193] In one embodiment,

[0194] In one embodiment, R20t is C1-C6 alkoxy substituted with two halogen atoms. Inone embodiment, R20tis C1-C6alkoxy substituted with two fluorine atoms. In one embodiment, R20t is C2 alkoxy substituted with two fluorine atoms. In one embodiment, R20t is

[0195] In one embodiment, R21t and R23t are each F.

[0196] In one embodimenteach of R25ta, R25tb, R27ta, R27tb, R28ta, R28tb, R29ta, and R29tb is H. In another embodiment,each of R25ta, R25tb, R27ta, R27tb, R28ta, R28tb, and R29tais H and R29tbis halogen. In oneembodiment, each of R25ta, R25tb, R27ta, R27tb, R28ta, R28tb, andR29tais H and R29tbis F.

[00197] In on embodiment, the the compound of Formula (IIt) is selected from:and a pharmaceutically acceptable salt of any one thereof.

[00198] In yet another aspect, the compound of Formula (Ia) is a compound of Formula(IIu)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:R20u is selected from C1-C6 alkyl, C1-C6 alkoxy, and -OH, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R21u is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl are each optionally substituted with one or more substituents selected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted withone or more substituents selected from C1-C6alkyl and halogen; 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), wherein C1-C6 alkyl is optionally substituted with one or more halogen; and R25ua, R25ub, R26ua, R26ub, R27ua, R27ub, R28ua, R28ub, R29ua, and R29ub 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.

[00199] In one embodiment,

[00200] In one embodiment, when R20u is -OCH3 and R21u is unsubstituted C3 cycloalkyl, (i) one or more of R22u, R23u, and R24uis CN, halogen, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C6-C12aryl, and -O-(C6-C12aryl), (ii) R22uis halogen, R23uis H, and R24uis H, or (iii) R22u is H, R23u is H, and R24u is halogen. In one embodiment, when R20u is -OCH3 and R21u , at least one of R22u, R23u, and R24uis not H. In one embodiment, whenR20s is -OCH3, R21s is not

[00201] In one embodiment, R20u is unsubstituted C1-C6 alkoxy. In one embodiment, R20uis -OCH3.

[0202] In one embodiment, R21u is selected from unsubstituted C3-C6 cycloalkyl,In one embodiment, R21u is C1-C6 alkyl substitutedwith one -OH. In one embodiment, R21uis C3alkyl substituted with one -OH. In one embodiment, R21uis In one embodiment, R21uis C1-C6alkyl substituted with one -OHand three halogen atoms. In one embodiment, R21u is C3 alkyl substituted with one -OH and three fluorine atoms. In one embodiment, R21u is In one embodiment, R21u is C3-C6 cycloalkyl substituted with one or more C1-C6alkyl. In one embodiment, R21uis C4cycloalkyl substituted with one or more C1-C6alkyl. In one embodiment, R21uis C4cycloalkyl substituted with two -CH3. In one embodiment, R21uis

[00203] In one embodiment, R22u, R23u, and R24u are each H. In another embodiment, R23uis H, R22uand R24uare each halogen. In one embodiment, R23uis H, R22uand R24uare each F. In another embodiment, R22uis halogen, R23uand R24uare each H. In one embodiment, R22uis F, R23u and R24u are each H. In another embodiment, R24u is halogen, R22u and R23u are each H. In one embodiment, R24u is F, R22u and R23u are each H.

[00204] In one embodiment, at least one of R22u, R23u, and R24u is selected from CN, C1-C6alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(C6-C12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more halogen. In one embodiment, R23u is H, R22u and R24u are each independently selected from -CH3, -OCH3, CN, C3cycloalkyl, phenyl, and -O-phenyl. In another embodiment, R22u is selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O- phenyl, R23u and R24u are each H. In another embodiment, R24u is selected from -CH3, -OCH3, CN, C3cycloalkyl, phenyl, and -O-phenyl, R22uand R23uare each H.

[0205] In one embodiment, each of R25ua, R25ub, R27ua,R27ub, R28ua, R28ub, R29ua, and R29ubis H. In another embodiment,each of R25ua, R25ub, R27ua, R27ub, R28ua, R29ua, and R29ub is H and R28ub is halogen. In one embodiment, , each of R25ua, R25ub, R27ua, R27ub, R28ua, R29ua, and R29ub is H and R28ub is fluorine.

[00206] In one embodiment, the compound of Formula (IIu) is selected from:, and a pharmaceutically acceptable saltof any one thereof.

[00207] In one embodiment, the compound of Formula (IIu) is not one of the followingcompounds:, or a pharmaceutically acceptable salt thereof.

[00208] In one embodiment, the compound of Formula (I) is a compound of Formula(IIv):Formula (IIv), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof;wherein:R20vis selected from C1-C6alkyl, C1-C6alkoxy, -OH, and wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH halogen, and C1-C6 alkoxy;R21v is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6 alkyl, -OH, and halogen; R22v, R23v, and R24v are each independently selected from H, CN, amido, halogen, -S(O)2- (C1-C7alkyl), C1-C6alkyl, C2-C7alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C9heterocyclyl, C6-C12aryl, and -O-(C6-C12aryl), wherein C1-C6alkyl is optionally substituted with one or more substituents selected from C1-C6 alkoxy, -OH, halogen; and R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb are each independently selected from H, halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms.

[00209] In one embodiment, each of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb,R29va, and R29vbis H.

[00210] In one embodiment, one of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb,R29va, and R29vb is selected from halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms.

[00211] In one embodiment, two of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb,R29va, and R29vb is selected from 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

[00212] In one embodiment, R20v is -OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or

[00213] In one embodiment, R21v is

[00214] In one embodiment, one or more of R22v, R23v, and R24v is -Cl, amido, C2-C7alkynyl, C1-C7 alkyl substituted with hydroxy, C1-C7 alkyl substituted with C1-C7 alkoxy, -S(O)2- (C1-C7 alkyl), or

[0215] In one embodiment, when R20v is -OCH3 and R21v is unsubstituted C3 cycloalkyl(i) one or more of R22v, R23v, and R24v is selected from amido, unsubstituted oxetane, --S(O)2-(C1-C7 alkyl), C1-C6 alkyl, or C2-C7 alkynyl, wherein C1-C6 alkyl is substituted with one or moresubstituents selected from C1-C6 alkoxy, -OH, halogen, (ii) one or more of R22v, R23v, and R24v is CN and one or more of R22v, R23v, and R24v is halogen, (iii) R22v and R24v are each independently halogen, R23vis H, and one or two of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vbis selected from halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1- C6 alkoxy are each optionally substituted with one or more halogen atoms, provided the compound of Formula (IIv) is not , (iv) R22vis Cl, R23vis H, and R24vis H, or (v) R22v is H, R23v is H, and R24v is Cl, or (v) the compound is ent, when R20v is -OCH3 and R21v is unsubstituted C3 cycloalkyl,two of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb are F, or one of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb is -CF3.

[0217] In one embodiment, when R20v is -OCH3 and R21v is one or more of R22v,R23v, and R24v is CN and one or more of R22v, R23v, and R24v is halogen.

[00218] In one embodiment, when R20v is -OCH3 and R21v is unsubstituted oxetane or, one or more of R22v, R23v, and R24vis CN.

[00219] In one embodiment, R20v is unsubstituted C1-C6 alkoxy. In one embodiment, R20vis C1-C6 alkoxy substituted with one or more deuterium atoms. In one embodiment, R20v is C1-C6 alkoxy substituted with -OH. In one embodiment, R20vis C1-C6alkoxy substituted with C1-C6alkoxy. In one embodiment, R20v is selected from -OCH3, -OCD3, -O(CH2)2OCH3, -O(CH2)2OH,

[00220] In one embodiment, R21v is unsubstituted C3-C6 cycloalkyl. In one embodiment,R21v is unsubstituted C3 cycloalkyl. In one embodiment, R21v is C3-C6 cycloalkyl substituted withone or more -OH. In one embodiment, R21v is In one embodiment, R21v is C1-C6substituted with one or more halogen and / or -OH. In one embodiment, R21vis C3alkyl substituted with one -OH. In one embodiment, R21v is In one embodiment, R21v is C3alkyl substituted with one -OH and three halogen atoms. In one embodiment, R21v isIn one embodiment, R21v is unsubstituted C3-C9 heterocyclyl. In one embodiment, R21v is In one embodiment, R21v is C3-C9 heterocyclyl substituted with one ormore C1-C6 alkyl. In one embodiment, R21v is

[00221] In one embodiment, R22v is halogen, R23v is H, and R24v is selected from halogen,CN, C1-C6alkyl substituted with one or more -OH, and amido. In one embodiment, R22vis F, R23v is H, and R24v is selected from F, CN, -CH2OH, –C(O)NH2, and –C(O)NHCH3.

[0222] In one embodiment, R22v is halogen, R23v and R24v are each H. In oneembodiment, R22vis Cl, R23vand R24vare each H.

[00223] In one embodiment, R22v and R23v are each H and R24v is selected from halogen,C1-C6 alkyl substituted with one or more -OH, C1-C6 alkyl substituted with one or more C1-C6alkoxy, unsubstituted C2-C7alkynyl, amido, unsubstituted C3-C9heterocyclyl, and -S(O)2-(C1-C7alkyl). In one embodiment, R22v and R23v are each H and R24v is selected from Cl, ethynyl, -CH2OH, -CH2OCH3, -C(O)NH2, -S(O)2CH3, and

[0224] In one embodiment,each of R25va, R25vb, R27va, R27vb, R28va, R28vb, R29va, and R29vbis H.

[00225] In one embodiment,, each of R25va, R25vb, R27va, R27vb, R28va, R29va, and R29vb is H and R28vb is halogen. In one embodiment,, each of R25va, R25vb, R27va, R27vb, R28va, R29va, and R29vb is H and R28vb is F.

[00226] In one embodiment, each of R25va, R27va, R27vb, R28va, R28vb, R29va, and R29vb is H and R25vb is unsubstituted C1-C6 alkyl. In one embodiment, , each of R25va, R27va, R27vb, R28va, R28vb, R29va, and R29vb is H andR25vb is -CH3.

[0227] In one embodiment,, each of R25va, R25vb, R27va, R28va, R28vb, R29va, and R29vb is H and R27vb is halogen or C1-C6 alkyl substituted with one or morehalogen. In one embodiment, each of R25va, R25vb, R27va, R28va,R28vb, R29va, and R29vb is H and R27vb is F or -CF3.

[0228] In one embodiment,each of R25va, R25vb, R28va,R28vb, R29va, and R29vb is H and each of R27va and R27vb are halogen. In one embodiment,each of R25va, R25vb, R28va, R28vb, R29va, and R29vb is H and each of R27vaand R27vbare F.

[00229] In one embodiment, the compound of Formula (IIv) is selected from:, and a pharmaceutically acceptable salt of any one thereof.

[00230] In one embodiment, the compound of Formula (IIv) is not:or a pharmaceutically acceptable saltthereof.

[00231] In one embodiment, the compound of Formula (IIv) is not:or a pharmaceutically acceptable saltthereof.

[00232] In one embodiment, the compound of Formula (IIv) is not:pharmaceutically acceptable salt of any one thereof.

[00233] In one embodiment, the compound of Formula (IIv) is not:,or a pharmaceutically acceptable salt of any one thereof.

[00234] In one embodiment, the compound of Formula (I) is a compound of Formula(IIw)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:R20wis selected from C1-C6alkyl, C1-C6alkoxy, -OH, and wherein C1-C6alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy;R21wis selected from C1-C6alkyl, C3-C6cycloalkyl, C5-C12spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl is optionally substituted with one or more substituentsselected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6 alkyl, -OH, and halogen; R22w, R23w, and R24ware each independently selected from H, CN, amido, halogen, -S(O)2-(C1-C7 alkyl), C1-C6 alkyl, C2-C7 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C9heterocyclyl, C6-C12 aryl, and -O-(C6-C12 aryl), wherein C1-C6 alkyl is optionally substitutedwith one or more substituents selected from C1-C6alkoxy, -OH, halogen; R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wbare 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; and R31wis selected from C1-C6alkyl, C1-C6alkoxy, amido, C3-C6cycloalkyl, C3-C9heterocyclyl, -OH, and , wherein C1-C6 alkyl and C1-C6 alkoxy are each optionallysubstituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6alkoxy and C3-C6cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen.

[0235] In one embodiment, each of R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb,R29wa, and R29wbis H.

[0236] In one embodiment, one of R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb,R29wa, and R29wb is selected from halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms.

[0237] In one embodiment, R31w is amido or C1-C6 alkyl optionally substituted with oneor more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy.

[0238] In one embodiment, R20w is unsubstituted C1-C6 alkoxy. In one embodiment, R20wis -OCH3.

[0239] In one embodiment, R21w is unsubstituted C3-C6 cycloalkyl. In one embodiment,R21wis unsubstituted C3cycloalkyl.

[0240] In one embodiment, R22w and R23w are each H and R24w is halogen. In oneembodiment, R22w and R23w are each H and R24w is F.

[0241] In one embodiment,each of R25wa, R25wb, R27wa,R27wb, R28wa, R28wb, R29wa, and R29wbis H.

[00242] In one embodiment, , each of R25wa, R25wb, R27wa,R27wb, R28wa, R29wa, and R29wb is H and R28wb is halogen. In one embodiment,, each of R25wa, R25wb, R27wa, R27wb, R28wa, R29wa, and R29wb is H and R28wbis F.

[00243] In one embodiment, R31w is amido. In one embodiment, R31w is -C(O)NH2. Inone embodiment, R31w is unsubstituted C1-C6 alkyl. In one embodiment, R31w is -CH3. In one embodiment, R31w is C1-C6 alkyl substituted with one or more -OH. In one embodiment, R31w is-CH2OH or

[00244] In one embodiment, the compound of Formula (IIw) is selected from:pharmaceutically acceptable salt of any one thereof.

[0245] In one embodiment, the compound of Formula (IIr), (IIs), (IIt), (IIu), (IIv), or(IIw) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is aninhibitor of at least one of IRAK1, IRAK4, and FLT3. In one embodiment, the compound of Formula (IIr), (IIs), (IIt), (IIu), (IIv), or (IIw), or a salt, ester, solvate, optical isomer, geometricisomer, or salt of an isomer thereof is an inhibitor of IRAK1 and IRAK4. In one embodiment, the compound of Formula (IIr), (IIs), (IIt), (IIu), (IIv), or (IIw) or a salt, ester, solvate, opticalisomer, geometric isomer, or salt of an isomer thereof is an inhibitor of IRAK1, IRAK4, and FLT3.

[00246] In another aspect, the present disclosure provides a composition comprising acompound of any one of Formula (IIr), (IIs), (IIt), (IIu), (IIv), or (IIw), or a salt, ester, solvate,optical isomer, geometric isomer, or salt of an isomer thereof wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.

[00247] In some embodiments, R6 is , giving a structure ofFormula (III), as follows:wherein R1, R2, R3, R4, R5, R15, R16,17R , R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, R30, q, r, s, t, u, v, w, and x are defined above in Formula (I) or Formula (Ia).

[00248] In some embodiments according to Formula (III), q, r, s, t, u, v, w, and x areindependently 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 0or 1, v is 0 or 1, w is 0 or 1, and x is 0 or 1.

[00249] In some embodiments, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27,R29, R29, and R30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH),carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (- COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen. In some embodiments, one ormore of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are H. Insome embodiments, all of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30are H.

[00250] Further to any embodiment above wherein the compound has the structure ofFormula (III), the compound can have a structure according to any of (IIIa)-(IIIp), as follows:

[00251] In an embodiment, the compound of Formula (III) is a compound of Formula(IIIq) Formula (IIIq), or a salt, ester, solvate, optical isomer,geometric isomer, or salt of an isomer thereof; wherein: R30q is selected from H and C1-C6 alkoxy;R31q is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one ormore substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted withone or more substituents selected from C1-C6 alkyl and halogen, and C3-C9 heterocycyl is optionally substituted with one or more substituents selected from C1-C6alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C12 aryl, -OH, -C=O, and halogen; andR32q, R33q, and R34q are each independently selected from H and halogen.

[00252] In an embodiment, R30q is H.

[0253] In an embodiment, R31q is unsubstituted C3-C9 heterocyclyl. In one embodiment,R31q is pyrazolyl. In one embodiment, R31q is selected fromwherein K is N or CH,wherein d is 1 or 2. In one embodiment, R31q iswhereind is 2. In another embodiment, R31q is C3-C9 heterocycyl substituted with one or moresubstituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C12 aryl, -OH, - C=O, and halogen. In an embodiment, R31q iswherein R35q is selected from H,unsubstituted C1-C6alkyl, unsubstituted C6-C12aryl, and unsubstituted C3-C9heterocyclyl. In one embodiment, R31q iswherein R35q is H. In one embodiment, R31q iswherein R35q is selected from -CH3, isopropyl, phenyl, azetidinyl, andtetrahydropyranyl. In another embodiment, R31q is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R31qis isoxazolyl monosubstituted with -CH3. In one embodiment, R31qis . In another embodiment, R31qis wherein e is 1, 2, or 3, K is N or CH andeach X is independently halogen. In one embodiment, R31q is

[0254] In an embodiment, R32q, R33q, and R34q are each H. In an embodiment, R32q andR34q are each independently halogen and R33q is H. In one embodiment, R32q and R34q are each F and R33qis H. In an embodiment, R32qand R34qare each H and R33qis halogen. In one embodiment, R32q and R34q are each H and R33q is F.

[00255] In an embodiment, the compound of Formula (IIIq) comprises one or morestereocenters.

[00256] In an 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 salt of an isomer thereof.

[00257] In an embodiment, the compound of Formula (III) is a compound of Formula(IIIr)Formula (IIIr), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R30r is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted with oneor more substituents selected from C1-C6 alkyl and halogen, and C3-C9 heterocycyl is optionallysubstituted with one or more substituents selected from C1-C6alkyl, C3-C6-cycloalkyl, C3-C9- heterocyclyl, C6-C12aryl, -OH, -C=O, and halogen; R31r is selected from H and C1-C6 alkoxy; and R32r, R33r, and R34r are each independently selected from H and halogen.

[00258] In an embodiment, R30r is unsubstituted C3-C9 heterocyclyl. In one embodiment,R30ris unsubstituted pyrazolyl. In one embodiment, R30ris selected fromwherein Lis N or CH, wherein f is 1 or 2. In one embodiment, R30ris wherein f is 2. In another embodiment, R30ris C3-C9heterocycyl substituted withone or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C12 aryl, -OH, -C=O, and halogen. In an embodiment, R30r iswherein R35r is selected from H, unsubstituted C1-C6 alkyl, unsubstituted C6-C12 aryl, and unsubstituted C3-C9 heterocyclyl. In an embodiment, R30r is wherein R35ris H. In one embodiment, R30r iswherein R35r is selected from -CH3, isopropyl, phenyl, azetidinyl, andtetrahydropyranyl. In another embodiment, R30ris isoxazolyl substituted with C1-C6alkyl. In one embodiment, R30ris isoxazolyl monosubstituted with -CH3. In one embodiment, R30ris In another embodiment, R30riswherein g is 1, 2, or 3, L is N or CH andeach X is independently halogen. In one embodiment, R30r is

[00259] In an embodiment, R31r is H.

[0260] In an embodiment, R32r, R33r, and R34r are each H. In an embodiment, R32r andR34r are each independently halogen and R33r is H. In one embodiment, R32r and R34r are each F and R33ris H. In an embodiment, R32rand R34rare each H and R33ris halogen. In one embodiment, R32rand R34rare each H and R33ris F.

[00261] In an embodiment, the compound of Formula (IIIr) comprises one or morestereocenters.

[00262] In an embodiment, the compound of Formula (IIIr) is one of compounds 38-44and 62 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.

[0263] In an embodiment, the compound of Formula (III) is a compound of Formula(IIIs)Formula (IIIs), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R30s is selected from H and C1-C6 alkoxy; R31s is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted withone or more substituents selected from C1-C6 alkyl and halogen, and C3-C9 heterocycyl is optionally substituted with one or more substituents selected from C1-C6alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C12aryl, -OH, -C=O, and halogen; and R32s, R33s, and R34s are each independently selected from H and halogen.

[00264] In an embodiment, R30s is H.

[0265] In an embodiment, R31s is unsubstituted C3-C9 heterocyclyl. In one embodiment,R31sis pyrazolyl. In one embodiment, R31sis selected from wherein M is N or CH,wherein h is 1 or 2. In one embodiment, R31s is whereinhis 2. In another embodiment, R31s is C3-C9 heterocycyl substituted with one or moresubstituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C12 aryl, -OH, - C=O, and halogen. In an embodiment, R31siswherein R35sis selected from H, unsubstituted C1-C6 alkyl, unsubstituted C6-C12 aryl, and unsubstituted C3-C9 heterocyclyl. Inone embodiment, R31siswherein R35sis H. In one embodiment, R31siswherein R35s is selected from -CH3, isopropyl, phenyl, azetidinyl, andtetrahydropyranyl. In another embodiment, R31sis isoxazolyl substituted with C1-C6alkyl. In one embodiment, R31s is isoxazolyl monosubstituted with -CH3. In one embodiment, R31s is. In another embodiment, R31s is wherein i is 1, 2, or 3, M is N or CH andeach X is independently halogen. In one embodiment, R31sis

[00266] In an embodiment, R32s, R33s, and R34s are each H. In an embodiment, R32s andR34s are each independently halogen and R33s is H. In one embodiment, R32s and R34s are each F and R33sis H. In an embodiment, R32sand R34sare each H and R33sis halogen. In one embodiment, R32sand R34sare each H and R33sis F.

[00267] In an embodiment, the compound of Formula (IIIs) comprises one or morestereocenters.

[00268] In one embodiment, R6 is giving a structure of Formula(IV), as follows:(IV), wherein R1, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12,R13, R14, m, n, o, and p are defined above in Formula (I).

[0269] In some embodiments according to Formula (IV), m is 0 or 1, n is 0 or 1, o is 0 or1, and p is 0 or 1.

[00270] In some embodiments, R7, R8, R9, and R10 are H, and at least one of R11, R12, R13,and R14is not H, and / or R11, R12, R13, and R14are H, and at least one of R7, R8, R9, and R10is not H. In particular embodiments, R7, R8, R9, R10, R11, R12, R13, and R14are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2- C7alkenyl, C2-C7alkynyl, C2-C6alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen. In some embodiments, R7, R8, R9, and R10are H, and at least one of R11, R12, R13, and R14is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen. In some embodiments, R11, R12, R13, and R14 are H, and atleast one of R7, R8, R9, and R10is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (- CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen. In some embodiments, at least one of R7, R8, R9, and R10 is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, or spiro-fusedcycloalkyl. In some embodiments, at least one of R7, R8, R9, and R10is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl. In some embodiments, both of R7 and R8 or both of R9 and R10 are F, or both of R7and R8or both of R9and R10are methyl. In some embodiments, at least one of R11, R12, R13, and R14is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl. In some embodiments, at least one of R11, R12, R13, and R14is F, hydroxyl, methyl, methoxy, - CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl. In some embodiments, both of R11and R12or both of R13and R14are F, or both of R11and R12or both of R13and R14are methyl.

[00271] In one embodiment, the compound of Formula (IV) is a compound of Formula(IVc)Formula (IVc), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:R40cis selected from C1-C6alkyl, C1-C6alkoxy, and -OH, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R41c is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3- C9heterocyclyl, wherein C1-C6alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6 alkyl and halogen; R42c, R43c, and R44care each independently selected from H and halogen; andR45ca, R45cb, R46ca, R46cb, R47ca, R47cb, R48ca, R48cb, R49ca, and R49cb 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.

[00272] In one embodiment, each of R45ca, R45cb, R46ca, R46cb, R47ca, R47cb, R48ca, R48cb,R49ca, and R49cb is H.

[00273] In one embodiment, R40c is -OH.

[0274] In one embodiment, R41c is unsubstituted C3-C6 cycloalkyl. In one embodiment,R41c is unsubstituted C3 cycloalkyl.

[00275] In one embodiment, R42c and R44c are each halgoen and R43c is H. In oneembodiment, R42c and R44c are each F and R43c is H.

[0276] In one embodiment,In one embodiment, ,wherein each of R45ca, R45cb, R47ca, R47cb, R48ca, R48cb, R49ca,and R49cb is H.

[00277] In one embodiment, the compound of Formula (IV) is:, or a pharmaceutically acceptable salt thereof.

[00278] In one embodiment, R4 and R5 bond or fuse to form a heterocyclyl, giving astructure of Formula (Vc), as follows:or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:R50c is selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, and wherein C1-C6alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selectedfrom deuterium, -OH, halogen, and C1-C6 alkoxy;R51c is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3- C9 heterocyclyl, wherein C1-C6 alkyl is optionally substituted with one or more substituentsselected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6alkyl, -OH, and halogen; R52c is selected from H, CN, amido, halogen, -S(O)2-(C1-C7 alkyl), C1-C6 alkyl, C2-C7alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-C12 aryl),wherein C1-C6alkyl is optionally substituted with one or more substituents selected from C1-C6alkoxy, -OH, halogen; andR55ca, R55cb, R56ca, R56cb, R57ca, R57cb, R58ca, R58cb, R59ca, and R59cb are each independently selected from H, halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms.

[0279] In one embodiment, each of R55ca, R55cb, R56ca, R56cb, R57ca, R57cb, R58ca, R58cb,R59ca, and R59cbis H.

[0280] In one embodiment, one of R55ca, R55cb, R56ca, R56cb, R57ca, R57cb, R58ca, R58cb, R59ca,and R59cb is selected from halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms.

[00281] In one embodiment, R50c is unsubstituted C1-C6 alkoxy. In one embodiment, R50cis -OCH3.

[00282] In one embodiment, R51c is unsubstituted C3-C6 cycloalkyl. In one embodiment,R51cis unsubstituted C3cycloalkyl.

[00283] In one embodiment, R52c is H.

[0284] In one embodiment, , each of R55ca, R55cb, R57ca,R57cb, R58ca, R58cb, R59ca, and R59cb is H.

[00285] In one embodiment, , each of R55ca, R55cb, R57ca,R57cb, R58ca, R59ca, and R59cb is H and R58cb is halogen. In one embodiment,,each of R55ca, R55cb, R57ca, R57cb, R58ca, R59ca, and R59cb is H and R58cbis F.

[0286] In one embodiment, the compound of Formula (Vc) is selected from:pharmaceutically acceptable salt thereof.

[00287] In one embodiment, R4 and R5 bond or fuse to form a heterocyclyl, giving astructure of Formula (Vd), as follows:or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:R50d is selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, and, wherein C1-C6 alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy;R51d is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9heterocyclyl, wherein C1-C6alkyl is optionally substituted with one or more substituentsselected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6 alkyl, -OH, and halogen; R52dis selected from H, CN, amido, halogen, -S(O)2-(C1-C7alkyl), C1-C6alkyl, C2-C7alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-C12 aryl),wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from C1-C6alkoxy, -OH, halogen; andR55da, R55db, R56da, R56db, R57da, R57db, R58da, R58db, R59da, and R59dbare 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.

[0288] In one embodiment, each of R55da, R55db, R56da, R56db, R57da, R57db, R58da, R58db,R59da, and R59db is H.

[0289] In one embodiment, one of R55da, R55db, R56da, R56db, R57da, R57db, R58da, R58db,R59da, and R59dbis selected from halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms.

[0290] In one embodiment, R50d is unsubstituted C1-C alkoxy. In one embodiment, R50dis -OCH3.

[0291] In one embodiment, R51d is unsubstituted C3-C6 cycloalkyl. In one embodiment,R51d is unsubstituted C3 cycloalkyl.

[0292] In one embodiment, R52d is H.

[0293] In one embodiment , each of R55da, R55db, R57da,R57db, R58da, R58db, R59da, and R59dbis H.E

[0294] In one embodiment, is , each of R55da, R55db, R57da,ER57db, R58da, R59da, and R59db is H and R58db is halogen. In one embodiment,is ,each of R55da, R55db, R57da, R57db, R58da, R59da, and R59db is H and R58db is F.

[0295] In one embodiment, the compound of Formula (Vd) is selected from:, , , , , , or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the compounds of Formula (I), or Formula (Ia), such ascompounds of Formula (II), Formula (III), Formula (IV), or Formula (V) are IRAK inhibitors.In one embodiment, the compounds of Formula (I) or Formula (Ia) are IRAK1, IRAK4,IRAK1 / 4, and / or FLT3 inhibitors. In one embodiment, the compounds of Formula (I) or Formula(Ia) are IRAK1 / 4, panFLT3 inhibitors.

[0297] In some embodiments, the compounds of Formula (I) or Formula (Ia), such ascompounds of Formula (II), Formula (III), Formula (IV), or Formula (V) can be any ofCompounds 1-31 or Compounds 1a-38a, as shown in Examples 1-19.

[0298] In some embodiments, the compounds of Formula (I), Formula (Ia), such ascompounds of Formula (II), Formula (III), Formula (IV), or Formula (V) can be in the form ofsalts, optical and geometric isomers, and salts of isomers. In other embodiments, the compounds can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including but not limited to hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some instances, for acidic compounds, salts can include metals, amines, or organic cations (e.g. quaternary ammonium). In yet other embodiments, simple derivatives of the compounds (e.g., ethers, esters, or amides) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, or other suitable means, can be employed.

[0299] In some embodiments, the compounds of the disclosure having a chiral center andcan exist in and be isolated in optically active and racemic forms. In other embodiments,compounds may exhibit polymorphism. Some embodiments of the present disclosure encompassany racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein, including isotopically-labeled and radio-labeled compounds. See e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p.104. Such isomers can be isolated by standard resolution techniques, including e.g., fractional crystallization, chiral chromatography, and the like. See e.g., Eliel, E. L. & Wilen S. H., 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. The preparation of optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.

[0300] In some embodiments, compounds disclosed herein have asymmetric centers andcan occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms as well as mixtures thereof being contemplated for use in the compounds and methods described herein. The compounds contemplated for use in the compounds and methods described herein do not include those that are known in the art to be too unstable to synthesize and / or isolate.

[0301] The compounds disclosed herein can also contain unnatural proportions of atomicisotopes at one or more of the atoms that constitute such compounds. For example, thecompounds can be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the contemplated scope.

[0302] The compounds disclosed herein can contain one or more deuterium atoms. Theone or more deuterium atoms can replace one or more hydrogen atoms on a compound disclosedherein, such as a compound of Formula (I) or Formula (Ia). For example, the one or moredeuterium atoms can replace one or more hydrogen atoms in one or more of variable groups R1,R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14R15, R16, R17, R18, R19, R20, R21, R22, R23,R24, R25, R26, R27, R29, R29, R30, or R31. The one or more deuterium atoms can replace one ormore hydrogen atoms in an optional substituent on one or more of variable groups R1, R2, R3, R4,R5, R6, R7, R8, R9, R10, R11, R12, R13, R14R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, R30, or R31.

[0303] In some embodiments, metabolites of the compounds disclosed herein are usefulfor the methods disclosed herein.

[0304] In some embodiments, compounds contemplated herein may be provided in theform of a prodrug. The term “prodrug” refers to a compound that can be converted into a compound (e.g., a biologically active compound) described herein in vivo. Prodrugs can be useful for a variety of reason known in the art, including e.g., ease of administration due e.g., to enhanced bioavailability in oral administration, and the like. The prodrug can also have improved solubility in pharmaceutical compositions over the biologically active compounds. An example, without limitation, of a prodrug is a compound which is administered as an ester (i.e., the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, 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 hereby incorporated herein by reference for the limited purpose describing procedures and preparation of suitable prodrug derivatives.

[0305] Certain compounds disclosed herein can exist in unsolvated forms as well assolvated forms, including hydrated forms. In general, the solvated forms are equivalent tounsolvated forms and are encompassed within the scope of contemplated compounds. Certaincompounds of the present disclosure can exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.

[0306] In certain embodiments, one or more compounds of the disclosure (e.g., Formula(I) or Formula (Ia) can be part of a composition and can be in an amount (by weight of the totalcomposition) 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 leastabout 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, nomore than about 75%, no more than about 90%, no more than about 95%, no more than about99%, or no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% toabout 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% toabout 90%, or from about 25% to about 75%.In some embodiments, one or more compounds of the disclosure (e.g., Formula (I) or Formula(Ia) can be purified or isolated in an amount (by weight of the total composition) of at least about0.0001%, 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 75%, at least about 90%, at leastabout 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more thanabout 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, fromabout 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% toabout 75%.Combination Therapies

[0307] In one embodiment, the compounds of Formula (I) or Formula (Ia) areadministered with one or more therapeutic agents. Exemplary therapeutic agents include, but are not limited to, a CDK inhibitor, a BCL2 inhibitor, a PTEFb inhibitor, a DNA polymerase inhibitor, a cytidine deaminase inhibitor, a DNA methyltransferase (DNMT) inhibitor, ahypomethylating agent, an immunomodulatory imide, a cereblon modulator, a purine nucleosideantimetabolite, a Type II topoisomerase inhibitor, a DNA intercalator, a hedgehog antagonist, an IDH2 inhibitor, an IDH1 inhibitor, a ribonucleotide reductase inhibitor, an adenosine deaminaseinhibitor, a Mek 1 / 2 inhibitor, an ERK 1 / 2 inhibitor, an AKT inhibitor, a PTPN11 inhibitor, anSHP2 inhibitor, a glucocorticoid steroid, a menin inhibitor, an MDM2 inhibitor, a BTK inhibitor, a mutant / inactivated p53 reactivator, a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a DNA hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2(IDH1 and / or IDH2) inhibitor, an antibody-drug conjugate, an mAbs / immunotherapy, a Plkinhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2 / MAPK1 or ERK1 / MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase / Leukotriene A4 hydrolase inhibitor, a FLT3 / Axl / ALK inhibitor, a FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF- 1R / Kit / PDGFRA / B inhibitor, an AKT 1, 2, and / or 3 inhibitor, a 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.

[0308] In one embodiment, the compound of Formula (I) or Formula (Ia) or thecomposition comprising a compound of Formula (I) or Formula (Ia) is used in combination withat least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, a DNA methyltransferase inhibitor, and a hypomethylating agent. 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 thereof, the CDK inhibitor is selected from CDK4 / 6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and / or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptablesalt of any one thereof, or the DNA methyltransferase inhibitor or hypomethylating agent is azacitidine or a pharmaceutically acceptable salt thereof.

[0309] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor. In oneembodiment, 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 oneembodiment, the therapeutic agent comprises a DNMT inhibitor. In one embodiment, theDNMT inhibitor is zebularine, decitabine, or azacitidine. In one embodiment, the therapeutic agent comprises an immunomodulatory imide (cereblon modulator). In one embodiment, the immunomodulatory imide (cereblon modulator) 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 IItopoisomerase inhibitor / DNA intercalator is vosaroxin. In one embodiment, the therapeuticagent 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 Mek 1 / 2 inhibitor. In one embodiment, the Mek 1 / 2 inhibitor is trametinib. In one embodiment, the therapeutic agent comprises an ERK 1 / 2 inhibitor. In one embodiment, the ERK 1 / 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 aglucocorticoid steroid. In one embodiment, the glucocorticoid steroid is prednisolone. In oneembodiment, 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 navtemadlin (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 mutant / inactivated p53 reactivator. In one embodiment, the mutant / inactivated p53 reactivator is Eprenetapopt (APR-246).

[0310] In one embodiment, the therapeutic agent comprises a CDK inhibitor. The CDKinhibitor can be any CDK inhibitor known to a person of ordinary skill 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.

[0311] In one embodiment, the CDK inhibitor comprises an inhibitor described in one ofthe following patents or patent applications: US 20210332071, US 20210330653, WO 2021214253, WO 2021178595, WO 2021207632, US 8685660, US 20200361906, US 10695346, US 11142507, WO 2021198439, WO 2021201170, US 8153632, US 11013743, US 11135198, US 20210299111, WO 2021190637, WO 2021188855, WO 2021188849, US 20210292299, US 11124836, US 10961527, US 20210284629, US 20210283265, WO 2021183994, WO 2021181233, US 11116755, WO 2021176045, WO 2021177816, WO 2021176049, WO 2021176349, US 20210275522, US 20210275491, US 20210277037, US 11111250, WO 2021142448, WO 2021172359, WO 2021174195, US 20210260209, US 20210261609, US 20210261636, US 20210261546, WO 2021168341, US 11014911, US 9932344, US 8415355, US 11091485, US 11091490, US 20210246422, US 20210246138, US 20210244715, US 11083722, US 11083728, US 20210238226, US 20190142835, WO 2021155006, WO 2021152107, WO 2021155192, US 10294234, US 11077156, WO 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6420345, WO 2002051849, US 6413974, US 6414013, US 6407103, WO 2001083716, US 5672508, US 6291504, WO 2001038532, WO 2001027080, US 6303618, US 6290951, WO 2001055148, WO 2001053293, US 6001868, US 6197804, WO 1999066055, US 6013646, WO 1999043676, 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: Alsfouk, 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, A. B. et al., Future Med. Chem., 2018, 10(11):1369-1388; Sánchez-Martínez, 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, S. R. et al., Pharmacology & Therapeutics, 2017, 173:83-105; Chou, J. et al., Cancer Discovery, 2020, 10:351-370; Galbraith, M. D. et 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.

[0312] In one embodiment, the CDK inhibitor is a CDK9 inhibitor. In one embodiment,the CDK9 inhibitor is Atuveciclib (BAY-1143572) or BAY-1251152 (VIP152). In one embodiment, BAY-1251152 (VIP152) is a selective CDK9 inhibitor while Atuveciclib (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.

[0313] Exemplary CDK inhibitors include, but are not limited to: Compound 21 (PMID27326333) CYC065; YKL-1-116; i-CDK9; JH-VII-49; JH-XI-10-02; SEL120-34A; MM-D37K; PF-06873600; BEY-1007; BEY-1107; birociclib (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;wherein X is N, Y is –C(=O)H, and Ar is X is N, Y is -CH2OH, and Ar is, or X is CH, Y is -CH2OH, and Ar iswherein X is NH or O; wherein X is NH or O;wherein R is H or -CH3;wherein R is -CH3 and X is F, R is H and X is F, or R is -CH3 and X is Cl; wherein R is tetrahydro-pyran-4-yl and R’ is H, R is -CH2CH3and R’ is -OCH3, R is isopropyl and R’ is H, or R is - CH2CH3 and R’ is F;wherein R is t-butyl carboxyl and n is 1 or R is H and n is 2;wherein X is NH or O;wherein R is H and R’ is F, R is F and R’ is F, or R is H and R’ is H;wherein R is -OCH3 and R’ is F, R is F and R’ is SF5, or R is -OCH3 and R’ is -SF5; wherein R is F and R’ is -CH3or R is -SF5and R’ is H;wherein R is -CF3 and R’ is -CH3 or R is H and R’ iscyclopropyl;wherein R is 3-fluoroailin-1yl and R’ is F or R is phenyl and R’ is - CH3;wherein R is H or F and Alkyl is -CH3or -CH2CH3;wherein R is 3-fluorophenyl or morpholin-4yl;wherein R is cyclopropan-1-ol-1-yl, X is Cl, and n is 1 or R is tetrahydrofuran-3yl, X is Cl and n is 1, or R is -CH3, X is F and n is 2, or R is cyclopropane-1-1- yl, X is F and n is 1, or oxatan-3-yl, X is -CH3, and n is 1; wherein R is 1,2-oxazol-3yl or 3,4-difluorobenzen-1yl;wherein R is H, C(=O)NHCH3, -SO2NH2, SO2CH3, or 2,3- dihydroxpropan-1yl;wherein R is H, CH3, 2-aminoethyan-1yl, 3-aminopropan-1yl, or 2,3-dihydroxpropan-1yl;wherein R is H or -CH3;wherein R is H, C(=O)NHCH3, or -SO2CH3;wherein R is 3-fluorobenzyl or 3-fluoropyridin-3yl;wherein Aryl is 4-fluorophenyl, 4-trifluoromethylphenyl, 3- fluorophenyl, 4-methylphenyl, 2-ethylphenyl, or 3-pyridyl and R is H, cyclopropyl, cylcopentyl, or cycloheptyl;wherein R is 2-phenylethan-1yl or (furan-2-yl)methyl;wherein R is H or -C(=O)CH2OH;wherein R is -NHC(=O)CH3 or -NHSO2CH3;wherein R is H or isobutyl;wherein R is H and R’ is -CH3or R is -CN and R’ is H;wherein R is 3,4-dimethyl-1H-pyrazol-4-yl and R’ is -CH3or R is piperazin-1yl and R’ is H;wherein R is 2,6-dichlorophenyl, 2,3,4,5,6-tetrafluorophenyl, or 3- fluorophenyl;wherein R is -CH2NCH3or H;wherein R is -CH2N(CH3)2or H;wherein R is H, -SO2CH3, -CH2C(=O)N(CH3)2, 4-carboxylic acid- cyclobutan-1yl, or (2(hydroxymethy)pyrrolidine-1-yl)-2-one-ethan-1yl, R’ is H or F, and R” is H or -CH2CH3;wherein R1is -OH, R2is H, R3is H, and R4is H (meridianin A), R1is -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 R4is Br (meridianin E); andwherein R is piperidin-3yl, pyrrolodin-3yl, or morpholin-2yl.

[00314] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor and aDNMT inhibitor. In one embodiment, the therapeutic agent comprises venetoclax, or a salt therof, and azacitidine, or a salt thereof.

[00315] In some embodiments, the one or more therapeutic agents can be in the form ofsalts, optical and geometric isomers, and salts of isomers. In other embodiments, the therapeutic agent can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including but not limited to hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some instances, for acidic compounds, salts can include metals, amines, or organic cations (e.g. quaternary ammonium). In yet other embodiments, simple derivatives of the therapeutic agents (e.g., ethers, esters, or amides) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, or other suitable means, can be employed.

[00316] In some embodiments, the therapeutic agent has a chiral center and can exist inand be isolated in optically active and racemic forms. In other embodiments, the therapeuticagent may exhibit polymorphism. Some embodiments of the present disclosure encompass anyracemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein, including isotopically-labeled and radio-labeled compounds. See e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p.104. Such isomers can be isolated by standard resolution techniques, including e.g., fractional crystallization, chiral chromatography, and the like. See e.g., Eliel, E. L. & Wilen S. H., 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. The preparation of optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.

[0317] In some embodiments, the therapeutic agent has asymmetric centers and canoccur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms as well as mixtures thereof being contemplated for use in the compounds and methods described herein. The compounds contemplated for use in the compounds and methods described herein do not include those that are known in the art to be too unstable to synthesize and / or isolate.

[0318] The therapeutic agents disclosed herein can also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute such compounds. For example, thecompounds can be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the contemplated scope.

[0319] In some embodiments, metabolites of the the therapeutic agents disclosed hereinare useful for the methods disclosed herein.

[0320] In some embodiments, the therapeutic agents contemplated herein may beprovided in the form of a prodrug. The term “prodrug” refers to a compound that can be converted into a compound (e.g., a biologically active compound) described herein in vivo. Prodrugs can be useful for a variety of reason known in the art, including e.g., ease of administration due e.g., to enhanced bioavailability in oral administration, and the like. The prodrug can also have improved solubility in pharmaceutical compositions over the biologically active compounds. An example, without limitation, of a prodrug is a compound which is administered as an ester (i.e., the "prodrug") to facilitate transmittal across a cell membranewhere water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, 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 hereby incorporated herein by reference for the limited purpose describing procedures and preparation of suitable prodrug derivatives.

[0321] Certain the therapeutic agent disclosed herein can exist in unsolvated forms aswell as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of contemplated compounds. Certain thetherapeutic agents of the present disclosure can exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein. Pharmaceutical Compositions and Formulations

[0322] In one embodiment, the present disclosure further relates to a compositioncomprising a compound of Formula (I) or Formula (Ia) and a composition comprising atherapeutic agent. Exemplary therapeutic agents are described elsewhere herein. In anotherembodiment, the compound of Formula (I) or Formula (Ia) and the therapeutic agent are co-formulated into a single composition. In one embodiment, the compound of Formula (I) orFormula (Ia) and the therapeutic agent are administered together in one administration orcomposition. In another embodiment, the compound of Formula (I) or Formula (Ia) and thetherapeutic agent are administered separately in more than one administration or more than onecomposition. In one embodiment, the composition comprising the compound of Formula (I) orFormula (Ia) and the composition comprising the therapeutic agent are administered to a subjectat the same time. In another embodiment, the composition comprising the compound of Formula(I) or Formula (Ia) and the composition comprising the therapeutic agent are administered to asubject sequentially. In one embodiment, the composition comprising the compound of Formula(I) or Formula (Ia) and the composition comprising the therapeutic agent are co-administered (oradministered within a defined time period) such that the subject is exposed to both inhibitors over a period of time in which they can act synergistically.

[0323] Some embodiments of the present disclosure include compositions comprisingone or more compounds of the disclosure (e.g., Formula (I) or Formula (Ia)). In oneembodiment, the composition comprising a compound of the 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 compositions that are suitable for administration to animals (e.g., mammals, primates, monkeys, humans, canine, feline, porcine, mice, rabbits, rats, etc.). In some embodiments, there is provided a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient. The compound can be a compound of any of Formulae (I)-(V) as disclosed herein, a compound as set forth in Examples 1-19, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, orderivative thereof. In some embodiments, the compound is set forth in Examples 1-19 herein.

[0324] Further embodiments of the disclosure relate to compositions including acompound as described above. In some embodiments, the amount of the compound can be from about 0.0001% (by weight total composition) to about 99%. In some embodiments, the composition can further include a formulary ingredient, an adjuvant, or a carrier. In some embodiments, the composition can further include a BCL2 inhibitor. In some embodiments, the composition can be used in combination with a second composition including a BCL2 inhibitor. In some embodiments, the BCL2 can be venetoclax, or a salt, isomer, derivative or analog thereof.

[0325] The term “pharmaceutically acceptable salts” is meant to include salts of theactive compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds 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 salt, or a similar salt.When compounds disclosed herein contain relatively basic functionalities, acid addition salts canbe obtained by contacting the neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, 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.

[0326] Compounds disclosed herein can exist as salts, such as with pharmaceuticallyacceptable acids. Accordingly, the compounds contemplated herein include such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0327] The neutral forms of the compounds are preferably regenerated by contacting thesalt 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.

[0328] Pharmaceutically acceptable salts of the compounds above, where a basic oracidic group is present in the structure, are also included within the scope of compounds contemplated herein. When an acidic substituent is present, such as -NHSO3H, -COOH and -P(O)(OH)2, there can be formed the ammonium, sodium, potassium, calcium salt, and the like, for use as the dosage form. Basic groups, such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.

[0329] Also, in the embodiments in which R-COOH is present, pharmaceuticallyacceptable esters can be employed, e. g. , methyl, ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.

[0330] In some instances, the pharmaceutical composition is non-toxic, does not causeside effects, or both. In some embodiments, there may be inherent side effects (e.g., it may harm the patient or may be toxic or harmful to some degree in some patients).

[0331] In some embodiments, one or more compounds of the disclosure (e.g., Formula(I) or Formula (Ia)) can be part of a pharmaceutical composition and can be in an amount of atleast 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 75%, at least about90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, nomore than about 90%, no more than about 95%, no more than about 99%, no more thanabout 99.99%, from about 0.001% to about 99%, from about 0.001% to about 50%, from about0.1% to about 99%, from about 1% to about 95%, from about 10% to about 90%, or from about25% to about 75%. In some embodiments, the pharmaceutical composition can be presented in adosage form which is suitable for the topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, cutaneous, nasal, vaginal, or ocular administration route. In other embodiments, the pharmaceutical composition can be presented in a dosage form which is suitable for parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. The pharmaceutical composition can be in the form of, for example, tablets, capsules, pills, powders granulates, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols or other suitable forms.

[0332] In some embodiments, the compounds disclosed herein can be administered orallyas tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use can contain one or more agents selectedfrom the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. Accordingly, there are also provided pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein.

[0333] In some embodiments, tablets contain the acting ingredient in admixture withnon-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) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

[0334] For preparing pharmaceutical compositions from the compounds disclosed herein,pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substance that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0335] A compound disclosed herein, in the form of a free compound or apharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time.Administration can be intravenously, intraperitoneally, intramuscularly, subcutaneously,intracavity, or transdermally. For in vitro studies the compounds can be added or dissolved in anappropriate biologically acceptable buffer and added to a cell or tissue.

[0336] In powders, the carrier is a finely divided solid in a mixture with the finelydivided active component. In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted in the shape and size desired.

[0337] The powders and tablets preferably contain from 5% to 70% of the activecompound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose,pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0338] For preparing suppositories, a low melting wax, such as a mixture of fatty acidglycerides or cocoa butter, is first melted and the active component is dispersed homogeneouslytherein, as by stirring. The molten homogeneous mixture is then poured into convenient sizedmolds, allowed to cool, and thereby to solidify.

[0339] Liquid form preparations include solutions, suspensions, and emulsions, forexample, water or water / propylene glycol solutions. For parenteral injection, liquid preparationscan be formulated in solution in aqueous polyethylene glycol solution.

[0340] When parenteral application is needed or desired, particularly suitable admixturesfor the compounds disclosed herein are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. This suspension can be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptablevehicles, carriers, and solvents that can be employed are water, Ringer’s solution, and isotonicsodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are convenient unit dosages. The compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical admixtures suitable for use in the pharmaceuticalscompositions and methods disclosed herein include those described, for example, in PHARMACEUTICALSCIENCES(17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of both of which are hereby incorporated by reference.

[0341] In some embodiments, preparations for parenteral administration include sterileaqueous 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 orauxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars,talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers. Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, growth factors and inert gases and the like.

[0342] Preservatives include antimicrobial, anti-oxidants, chelating agents and inertgases. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, inRemington’s Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co. , 1405-1412, 1461-1487 (1975) and The National Formulary XIV., 14th ed. Washington: American PharmaceuticalAssociation (1975), the contents of which are hereby incorporated by reference. The pH and exact concentration of the various components of the pharmaceutical composition are adjustedaccording to routine skills in the art. See e.g., Goodman and Gilman (eds.), 1990, THEPHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).

[0343] Aqueous solutions suitable for oral use can be prepared by dissolving the activecomponent in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension. Such excipients can be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agentswhich can be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate ; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) acondensation product of ethylene oxide with a partial ester derived from fatty acids and hexitolanhydrides, for example polyoxyethylene sorbitan monooleate

[0344] Also included are solid form preparations that are intended to be converted,shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations can contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0345] The pharmaceutical preparation is preferably in unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriate quantities of the activecomponent. The unit dosage form can be a packaged preparation, the package containing discretequantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0346] In some embodiments, the pharmaceutical composition can include one or moreformulary ingredients. A “formulary ingredient” can be any suitable ingredient (e.g., suitable forthe drug(s), for the dosage of the drug(s), for the timing of release of the drugs(s), for the disease,for the disease state, or for the delivery route) including, but not limited to, water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water with chloroform), sugar (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 nonionic surfactants (e.g., polysorbates)), oils (e.g., animal oils, plant oils (e.g., coconut oil or arachis oil), or mineral oils), oil derivatives (e.g., ethyl oleate , glyceryl monostearate, or hydrogenated glycerides), excipients, preservatives (e.g., cysteine, methionine, antioxidants (e.g., vitamins (e.g., A, E, or C), selenium, retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens, (e.g., methyl paraben or propyl paraben)), or combinations thereof.

[0347] In certain embodiments, pharmaceutical compositions can be formulated torelease the active ingredient (e.g., one or more compounds of the disclosure such as Formula (I)or Formula (Ia)-) substantially immediately upon the administration or any substantiallypredetermined time or time after administration. Such formulations can include, for example, controlled release formulations such as various controlled release compositions and coatings.

[0348] Other formulations (e.g., formulations of a pharmaceutical composition) can, incertain embodiments, include those incorporating the drug (or control release formulation) into food, food stuffs, feed, or drink.

[0349] Some compounds can have limited solubility in water and therefore can require asurfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.

[0350] Viscosity greater than that of simple aqueous solutions can be desirable todecrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and / or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.

[0351] The compositions disclosed herein can additionally include components toprovide sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carriersubstrates. These components are discussed in greater detail in U.S. Pat. Nos.4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

[0352] There are provided various pharmaceutical compositions useful for amelioratingcertain diseases and disorders. The pharmaceutical compositions according to one embodiment are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethyleneglycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.Intravenous vehicles include fluid and nutrient replenishers.

[0353] There are provided various pharmaceutical compositions useful for amelioratingcertain diseases and disorders. The pharmaceutical compositions according to one embodiment are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers. Methods of Treating and Preventing Disease

[0354] Further embodiments of the disclosure relate to methods for providing a subjectwith a compound including one or more administrations of one or more compositions including a compound as described above, the compositions may be the same or different if there is more than one administration. In some embodiments, at least one of the one or more compositions further includes a formulary ingredient. In some embodiments, at least one of the one or morecompositions includes a composition including a compound as described above. In some embodiments, at least one of the one or more administrations includes parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In some embodiments, if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. In some embodiments, the compound of at least one of the one or more compositions can be administered to the subject in an amount of from about 0.005 mg / kg subject body weight to about 50 mg / kg subject body weight. In some embodiments, the subject is a mammal, preferably a human, a rodent, or a primate.

[0355] Further embodiments of the disclosure relate to methods for treating a disease ordisorder, where the method includes one or more administrations to a subject of one or more compositions including a compound as described above, where the compositions may be the same or different if there is more than one administration. In some embodiments, the disease or disorder can be responsive 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 includes a formulary ingredient. In some embodiments, at least one of the one or more compositions includes a composition as described above.

[0356] In some embodiments, at least one of the one or more administrations includesparenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In some embodiments, at least one of the one or more administrations includes an oral administration. In some embodiments, if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. In some embodiments, the compound of at least one of the one or more compositions is administered to the subject in an amount of from about 0.005 mg / kg subject body weight to about 50 mg / kg subject body weight. In some embodiments, the subject can be a mammal, preferably a human, a rodent, or a primate. In some embodiments, the subject is in need of the treatment.

[0357] In one embodiment, the disease or disorder is not relapsed / refractory. In anotherembodiment, the disease or disorder is relapsed / refractory. In one embodiment, the disease or disorder is not relapsed / refractory and a compound of Formula (I) or Formula (Ia) disclosedherein are administered to a subject in need thereof as a monotherapy. In one embodiment, thedisease or disorder is not relapsed / refractory and a compound of Formula (I) or Formula (Ia) disclosed herein are administered to a subject in need thereof as a frontline monotherapy. In one embodiment, the disease or disorder is AML or MDS that is not relapsed / refractory and a compound of Formula (I) or Formula (Ia) disclosed herein are administered to a subject in need thereof as a monotherapy. In one embodiment, the disease or disorder is AML or MDS that is not relapsed / refractory and a compound of Formula (I) or Formula (Ia) disclosed herein are administered to a subject in need thereof as a frontline monotherapy.

[0358] In one embodiment, the disease or disorder is a BCL2 inhibitorrelapsed / refractory disease or disorder. In one embodiment, the disease or disorder is a venetoclax relapsed / refractory disease or disorder. In one embodiment, the disease or disorder isa BTK inhibitor relapsed / refractory disease or disorder. In one embodiment, the disease ordisorder is an ibrutinib relapsed / refractory disease or disorder. In one embodiment, the diseaseor disorder is relapsed / refractory to anti-inflammatory glucocorticoids. In one embodiment, thedisease or disorder is a dexamethasone, methylprednisolone, or prednisolone relapsed / refractorydisease or disorder. In one embodiment, the disease or disorder is a CDK inhibitorrelapsed / refractory disease or disorder. In one embodiment, the disease or disorder is apalbociclib, THZ1, BAY 12511152, or atuveciclib relapsed / refractory disease or disorder. Inone embodiment, the disease or disorder is a DNA methyltransferase inhibitor orhypomethylating agent relapsed / refractory disease or disorder. In one embodiment, the diseaseor disorder is an azacitidine relapsed / refractory disease or disorder. In one embodiment, thedisease or disorder is a BCL2 inhibitor and a DNA methyltransferase inhibitor or hypomethylating agent relapsed / refractory disease or disorder. In one embodiment, the disease or disorder is a venetoclax and azacitidine relapsed / refractory disease or disorder.

[0359] In some embodiments, the method is for treating a hematopoietic cancer. In someembodiments, the method is for treating a myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML). In one embodiment, the disease or disorder comprises high-riskmyelodysplastic syndrome (MDS). In one embodiment, the method is for treating high-risk myelodysplastic syndrome (MDS). In one embodiment, the disease or disorder comprises low- risk myelodysplastic syndrome (MDS). In one embodiment, the method is for treating low-risk myelodysplastic syndrome (MDS).

[0360] In one embodiment, the disease or disorder is BCL2 inhibitor resistant acutemyeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax resistant acute myeloid leukemia (AML). In one embodiment, the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML). In one embodiment, the disease or disorder is BCL2 inhibitor and hypomethylating agent resistant acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax and azacitidine resistant acute myeloid leukemia (AML). In one embodiment, the disease or disorder is BCL2 inhibitor and hypomethylating agent resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax and azacitidine resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is BCL2 inhibitor and hypomethylating agent resistant relapsed acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax and azacitidine resistant relapsed acute myeloid leukemia (AML).

[0361] In one embodiment, the disease or disorder is hypomethylating agent resistantmyelodysplastic syndrome (MDS). In one embodiment, the disease or disorder is azacitidine resistant myelodysplastic syndrome (MDS). In one embodiment, the disease or disorder is hypomethylating agent resistant refractory myelodysplastic syndrome (MDS). In one embodiment, the disease or disorder is azacitidine resistant refractory myelodysplastic syndrome (MDS). In one embodiment, the disease or disorder is hypomethylating agent resistant relapsed myelodysplastic syndrome (MDS). In one embodiment, the disease or disorder is azacitidine relapsed myelodysplastic syndrome (MDS).

[0362] In some embodiments, the method is for treating at least one of lymphoma,leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acutelymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, 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 carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatorydiseases or autoimmune disease characterized by overactive IRAK1 and / or IRAK4, orcombinations thereof. In some embodiments, the method is for treating one or moreinflammatory diseases or autoimmune disease selected from chronic inflammation (i.e.,associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations 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 a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or the method is for treating AML having enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or where the AML is not driven by FLT3 mutations but expresses IRAK4-Long. In some embodiments, the method is for treating DLBCL, and the DLBCL includes a L265P MYD88 mutant (ABC) subtype of DLBCL.

[0363] In some embodiments, the method further includes administration of acomposition including a BTK inhibitor. In some embodiments, the BTK inhibitor includes ibrutinib.

[0364] In some embodiments, the subject is susceptible to AML and / or MDS, and / or themethod prevents or ameliorates future AML and / or MDS. In some embodiments, the method occurs after one or more of having myelodysplastic syndrome, having myeloproliferativedisease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer.

[0365] In some embodiments, the method further includes administration of acomposition including a BCL2 inhibitor, or at least one of said compositions including a compound as described above further includes a BCL2 inhibitor. In some embodiments, the compound as described above 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 includes venetoclax, or a salt, isomer, derivative or analog thereof.

[0366] In some embodiments, the method further includes administration of one or moreadditional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor / hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, antibody-drug conjugate, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof. In someembodiments, the DNA methyltransferase inhibitor / hypomethylating agent includes azacytidine,decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproic acid, and / or pracinostat; the purine nucleoside analogue (antimetabolite) includes fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor includes ivosidenib and / or enasidenib; the antibody-drug conjugate includes Anti-CD33 (e.g. Ac225-lintuzumab, vadastuximab, or gemtuzumab- ozogamicin) and / or Anti-CD45 (e.g. I131-apamistamab); the mAbs / Immunotherapy includes Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD123 x 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)); the Plk inhibitor includes volasertib and / or rigosertib; the MEK inhibitor includes trametinib, cobimetinib, selumetinib, pimasertib, and / or refametinib; the CDK9 inhibitor includes alvocidiband / or voruciclib; the CDK8 inhibitor includes SEL120; the retinoic acid receptor agonist includes ATRA (all-trans retinoic acid) and / or SY-1425 (a selective RARα agonist); the TP53 activator includes APR-246 (Eprenetapopt); the smoothened receptor antagonist includes glasdegib; the ERK inhibitor includes an ERK2 / MAPK1 or ERK1 / MAPK3 inhibitor including ulixertinib, SCH772984, ravoxertinib, MK-8353, and / or VTX-11e; the PI3K inhibitor includes fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitor includes bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), everolimus, and / or vistusertib(AZD2014); the glucocorticoid receptor modulator includes an agonist including prednisolone,beclometasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist including mifepristone, miricorilant, and / or onapristone, and / or another binding ligand including vamorolone (VBP15); and / or the EZH2 inhibitor includes tazemetostat.

[0367] In one embodiment, the disease or disorder is AML which is notrelapsed / refractory and the additional therapy is a BCL2 inhibitor. In one embodiment, thedisease or disorder is AML which is not relapsed / refractory and the additional therapy is venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of Formula (I) or Formula (Ia) disclosed herein and the BCL2 inhibitor are administered to a subject as a frontline therapy to treat a disease or disorder which is not relapsed / refractory. In one embodiment, a compound of Formula (I) or Formula (Ia) disclosed herein and the BCL2 inhibitor are administered to a subject as a frontline therapy to treat AML which is not relapsed / refractory.

[0368] In one embodiment, the disease or disorder is a BCL2 inhibitor resistant diseaseor disorder and a compound of Formula (I) or Formula (Ia) is administered to the subject incombination with an additional therapy. In one embodiment, the disease or disorder is avenetoclax resistant disease or disorder and a compound of Formula (I) or Formula (Ia) disclosedherein is administered to the subject in combination with an additional therapy describedelsewhere herein.

[0369] In one embodiment, the disease or disorder is BCL2 inhibitor resistant acutemyeloid leukemia (AML) and the additional therapy is a BCL2 inhibitor. In one embodiment,the disease or disorder is venetoclax resistant acute myeloid leukemia (AML) and the additionaltherapy is venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML) and the additional therapy is a BCL2 inhibitor. In one embodiment, the disease or disorder is venetoclax resistant refractory acute myeloid leukemia (AML) and the additional therapy is venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is BCL2inhibitor resistant relapsed acute myeloid leukemia (AML) and the additional therapy is a BCL2inhibitor. In one embodiment, the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML) and the additional therapy is venetoclax or a pharmaceutically acceptable salt thereof.

[0370] In one embodiment, the disease or disorder is AML which is notrelapsed / refractory and the additional therapy is a hypomethylating agent. In one embodiment,the disease or disorder is AML which is not relapsed / refractory and the additional therapy isazacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, a compound ofFormula (I) or Formula (Ia) disclosed herein and the hypomethylating agent are administered to asubject as a frontline therapy to treat a disease or disorder which is not relapsed / refractory. In one embodiment, a compound of Formula (I) or Formula (Ia) disclosed herein and thehypomethylating agent are administered to a subject as a frontline therapy to treat AML which isnot relapsed / refractory.

[0371] In one embodiment, the disease or disorder is a hypomethylating agent resistantdisease or disorder and a compound of Formula (I) or Formula (Ia) disclosed herein isadministered to the subject in combination with an additional therapy described elsewhereherein. In one embodiment, the disease or disorder is a hypomethylating agent resistant diseaseor disorder, and the additional therapy is a hypomethylating agent. In one embodiment, the disease or disorder is an azacitidine resistant disease or disorder, and the additional therapy is azacitidine or a pharmaceutically acceptable salt thereof.

[0372] In one embodiment, the disease or disorder is hypomethylating agent resistantacute myeloid leukemia (AML) and the additional therapy is a hypomethylating agent. In oneembodiment, the disease or disorder is azacitidine resistant acute myeloid leukemia (AML) andthe additional therapy is azacitidine or a pharmaceutically acceptable salt thereof. In oneembodiment, the disease or disorder is hypomethylating agent resistant refractory acute myeloidleukemia (AML) and the additional therapy is a hypomethylating agent. In one embodiment, thedisease or disorder is azacitidine resistant refractory acute myeloid leukemia (AML) and theadditional therapy is azacitidine or a pharmaceutically acceptable salt thereof. In oneembodiment, the disease or disorder is hypomethylating agent resistant relapsed acute myeloidleukemia (AML) and the additional therapy is a hypomethylating agent. In one embodiment, thedisease or disorder is azacitidine resistant relapsed acute myeloid leukemia (AML) and theadditional therapy is azacitidine or a pharmaceutically acceptable salt thereof.

[0373] In one embodiment, the disease or disorder is AML which is notrelapsed / refractory and the additional therapy is the combination of a BCL2 inhibitor and a hypomethylating agent. In one embodiment, the disease or disorder is AML which is not relapsed / refractory and the additional therapy is the combination of venetoclax or apharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable saltthereof. In one embodiment, a compound of Formula (I) and Formula (Ia) disclosed herein andthe combination of a BCL2 inhibitor and a hypomethylating agent are administered to a subjectas a frontline therapy to treat a disease or disorder which is not relapsed / refractory. In oneembodiment, a compound of Formula (I) and Formula (Ia) disclosed herein and the combinationof a BCL2 inhibitor and a hypomethylating agent are administered to a subject as a frontlinetherapy to treat AML which is not relapsed / refractory.

[0374] In one embodiment, the disease or disorder is a BCL2 inhibitor and ahypomethylating agent resistant disease or disorder and the additional therapy is the combinationof a BCL2 inhibitor and a hypomethylating agent. In one embodiment, the disease or disorder isa venetoclax and azacitidine resistant disease or disorder and the additional therapy is thecombination of venetoclax or a pharmaceutically acceptable salt thereof and azacitidine or apharmaceutically acceptable salt of any one thereof.

[0375] In one embodiment, the disease or disorder is BCL-2 inhibitor andhypomethylating agent resistant acute myeloid leukemia (AML) and the additional therapy is thecombination of a BCL-2 inhibitor and a hypomethylating agent. In one embodiment, the diseaseor disorder is venetoclax and azacitidine resistant acute myeloid leukemia (AML) and theadditional therapy is a combination of venetoclax or a pharmaceutically acceptable salt thereofand azacitidine or a pharmaceutically acceptable salt of any one thereof. In one embodiment, thedisease or disorder is BCL-2 inhibitor and hypomethylating agent resistant refractory acutemyeloid leukemia (AML) and the additional therapy is the combination of a BCL-2 inhibitor anda hypomethylating agent. In one embodiment, the disease or disorder is venetoclax andazacitidine resistant refractory acute myeloid leukemia (AML) and the additional therapy is thecombination of venetoclax or a pharmaceutically acceptable salt thereof and azacitidine or apharmaceutically acceptable salt of any one thereof. In one embodiment, the disease or disorderis BCL-2 inhibitor and hypomethylating agent resistant relapsed acute myeloid leukemia (AML)and the additional therapy is the combination of a BCL-2 inhibitor and a hypomethylating agent.In one embodiment, the disease or disorder is venetoclax and azacitidine resistant relapsed acutemyeloid leukemia (AML) and the additional therapy is the combination of venetoclax or apharmaceutically acceptable salt of thereof and azacitidine or a pharmaceutically acceptable saltof any one thereof.

[0376] In one embodiment, the disease or disorder is MDS which is notrelapsed / refractory and the additional therapy is a hypomethylating agent. In one embodiment, the disease or disorder is MDS which is not relapsed / refractory and the additional therapy is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, a compound ofFormula (I) or Formula (Ia) disclosed herein and the hypomethylating agent are administered to asubject as a frontline therapy to treat a disease or disorder which is not relapsed / refractory. In one embodiment, a compound of Formula (I) or Formula (Ia) disclosed herein and thehypomethylating agent are administered to a subject as a frontline therapy to treat MDS which isnot relapsed / refractory.

[0377] In one embodiment, the disease or disorder is hypomethylating agent resistantmyelodysplastic syndrome (MDS) and the additional therapy is a hypomethylating agent. In oneembodiment, the disease or disorder is azacitidine resistant myelodysplastic syndrome (MDS)and the additional therapy is azacitidine or a pharmaceutically acceptable salt of any one thereof.

[0378] In one embodiment, the disease or disorder is hypomethylating agent resistantrefractory myelodysplastic syndrome (MDS) and the additional therapy is a hypomethylatingagent. In one embodiment, the disease or disorder is azacitidine resistant refractorymyelodysplastic syndrome (MDS) and the additional therapy is azacitidine or a pharmaceuticallyacceptable salt of any one thereof. In one embodiment, the disease or disorder ishypomethylating agent resistant relapsed myelodysplastic syndrome (MDS) and the additionaltherapy is a hypomethylating agent. In one embodiment, the disease or disorder is azacitidineresistant relapsed myelodysplastic syndrome (MDS) and the additional therapy is azacitidine or apharmaceutically acceptable salt of any one thereof.

[0379] Further embodiments of the disclosure relate to compounds as described above,for use in a method for treating a disease or disorder, the method including inhibiting at least one of IRAK and FLT3 by administering one or more compositions including the compound, where the compositions may be the same or different if there is more than one administration. In some embodiments, disease or disorder can be responsive 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 includes a formulary ingredient. In some embodiments, at least one of the one or more compositions includes the composition as described above. In some embodiments, at least one of the one or more administrations includes parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In some embodiments, at least one of the one or more administrations includes an oral administration. In some embodiments, if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.

[0380] In some embodiments, the compound of at least one of the one or morecompositions can be administered to the subject in an amount of from about 0.005 mg / kg subject body weight to about 50 mg / kg subject body weight. In some embodiments, the subject is a mammal, preferably a human, a rodent, or a primate. In some embodiments, the subject is in need of the treatment.

[0381] In some embodiments, the method is for treating a hematopoietic cancer. In someembodiments, 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), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, 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 carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or moreinflammatory diseases or autoimmune disease characterized by overactive IRAK1 and / orIRAK4, or combinations thereof. In some embodiments, the method is for treating one or moreinflammatory diseases or autoimmune disease selected from chronic inflammation (i.e.,associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof. In some embodiments, the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or the method is for treating AML having enhanced IRAK4-Long expression and / or activityrelative to IRAK4-Short, and / or the AML is not driven by FLT3 mutations but expressesIRAK4-Long. In some embodiments, the method is for treating DLBCL, and the DLBCL includes a L265P MYD88 mutant (ABC) subtype of DLBCL.

[0382] In some embodiments, the method further includes administration of acomposition including a BTK inhibitor. In some embodiments, the BTK inhibitor includes ibrutinib.

[0383] In some embodiments, the subject is susceptible to AML and / or MDS, and / or themethod prevents or ameliorates future AML and / or MDS. In some embodiments, the method occurs after one or more of having myelodysplastic syndrome, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer. In some embodiments, method further includes administration of a composition including a BCL2 inhibitor, or at least one of said compositions including the compound of any of claims 1-39 further includes a BCL2 inhibitor. In some embodiments, the compound of any ofclaims 1-39 and the BCL2 inhibitor can be administered together or separately, in one or more administrations of one or more compositions. In some embodiments, the BCL2 inhibitor includes venetoclax, or a salt, isomer, derivative or analog thereof.

[0384] In some embodiments, the method further includes administration of one or moreadditional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor / hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, antibody-drug conjugate, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator,smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoidreceptor modulator, or EZH2 inhibitor, or one or more combinations thereof. In someembodiments, the DNA methyltransferase inhibitor / hypomethylating agent includes azacytidine,decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproic acid, and / or pracinostat; the purine nucleoside analogue (antimetabolite) includes fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor includes ivosidenib and / or enasidenib; the antibody-drug conjugate includes Anti-CD33 (e.g. Ac225-lintuzumab, vadastuximab, or gemtuzumab- ozogamicin) and / or Anti-CD45 (e.g. I131-apamistamab); the mAbs / Immunotherapy includes Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD123 x 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)); the Plk inhibitor includes volasertib and / or rigosertib; the MEK inhibitor includes trametinib, cobimetinib, selumetinib, pimasertib, and / or refametinib; the CDK9 inhibitor includes alvocidib and / or voruciclib; the CDK8 inhibitor includes SEL120; the retinoic acid receptor agonist includes ATRA (all-trans retinoic acid) and / or SY-1425 (a selective RARα agonist); the TP53 activator includes APR-246 (Eprenetapopt); the smoothened receptor antagonist includes glasdegib; the ERK inhibitor includes an ERK2 / MAPK1 or ERK1 / MAPK3 inhibitor including ulixertinib, SCH772984, ravoxertinib, MK-8353, and / or VTX-11e; wherein the PI3K inhibitorincludes fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitor includes bimiralisib (PQR- 309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), everolimus, and / or vistusertib (AZD2014); the glucocorticoid receptor modulator includes an agonist including prednisolone, beclometasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist including mifepristone, miricorilant, and / or onapristone, and / or another binding ligand including vamorolone (VBP15); and / or the EZH2 inhibitor includes tazemetostat.

[0385] In one aspect, the present disclosure relates to a method of treating and / orpreventing a disease or disorder in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of a compound of Formula (I) orFormula (Ia) and a therapeutically effective amount of a CDK inhibitor. In one embodiment, acomposition comprising a therapeutically effective amount of the compound of Formula (I) orFormula (Ia) is administered to the subject. In one embodiment, a composition comprising atherapeutically effective amount of the CDK inhibitor is administered to the subject. In oneembodiment, the compound of Formula (I) or Formula (Ia) treats and / or prevents the disease ordisorder by inhibiting FLT3 (wild type FLT3 and / or mutant FLT3) as well as IRAK4, IRAK1, or both IRAK4 and IRAK1 in the subject in need thereof. In one embodiment, the CDK inhibitor treats and / or prevents the disease or disorder by inhibiting one or more of CKD1, CKD2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13 in the subject in need thereof.

[0386] In addition to their ability to inhibit IRAK, IRAK inhibitors have beendemonstrated to have selectivity for multiple kinases. In some embodiments, compoundsdescribed herein according to Formula (I), or Formula (Ia), such as Compounds 1-31 orCompounds 1-38a as depicted in Examples 1-19, exhibit have inhibitory action against one ormore kinase, such as interleukin-1 receptor-associated kinase (IRAK) and FMS-like tyrosinekinase 3 (FLT3). The inhibitory action against one or more kinase, such as IRAK and FLT3, canallow for treatment and / or prevention of diseases in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans)using a compound of the disclosure (e.g., Formula (I) or Formula (Ia)) including, but not limitedto hematopoietic cancers (e.g., disorders of hematopoietic stem cells in the bone marrow or disorders related to myeloid lineage), MDS, AML, myeloproliferative disease, and diseases (e.g., hematopoietic cancers) related to mutations in IRAK1, IRAK4, and / or FLT3 (e.g., mutations inthe juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 pointmutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation).

[0387] In some embodiments, the compounds of the disclosure can inhibit the activity ofone or more of FLT3, mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3,mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation), IRAK4 (interleukin-1 receptor associated kinase 4), isoforms of IRAK4, mutations of IRAK4, IRAK1 (interleukin-1 receptor associated kinase 1), isoforms of IRAK1, and / or mutations of IRAK1. In someembodiments, the compounds of the disclosure can inhibit the activity of one or both of FLT3and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in thekinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or more of IRAK4, isoformsof IRAK4, mutations of IRAK4, IRAK1, isoforms of IRAK1, or mutations of IRAK1. In someembodiments, the compounds of the disclosure can inhibit the activity of one or both of FLT3and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in thekinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, theFLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or both of IRAK4 and IRAK1, or an isoform or mutation thereof. In some embodiments, the compounds of thedisclosure can inhibit FLT3 in combination with IRAK4, IRAK1, or with IRAK4 and IRAK1.

[0388] In some embodiments, compounds exhibit inhibitory activity against IRAK and / orFLT-3 with activities ^ 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 greater.In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3 with activities between 0.1 nM and 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 againstIRAK and / or FLT-3 with activities ^ 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 a combination of any 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, theinhibitory 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. It is understood that for purposes ofquantification, the terms “activity,” “inhibitory activity,” “biological activity,” “IRAK activity,” “IRAK1 activity,” “IRAK4 activity,” “FLT-3 activity,” and the like in the context of an inhibitory compound disclosed herein can be quantified in a variety of ways known in the art. Unless indicated otherwise, as used herein such terms refer to IC50in the customary sense (i.e., concentration to achieve half-maximal inhibition.

[0389] In some embodiments, hematopoietic cancers that can be treated in an animal(e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents,monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I)or Formula (Ia)) include, but are not limited to hematopoietic cancers and cancers of the myeloid line of blood cells, cancers with an increased risk of occurrence due to other blood disorders, cancers with an increased risk of occurrence due to chemical exposure (e.g., anti-cancer therapies or occupational chemical exposure), cancers with an increased risk of occurrence due to ionizing radiation (e.g., anti-cancer therapies), cancers evolving from myelodysplastic syndromes, cancers evolving from myeloproliferative disease, and cancers of the B cells.

[0390] In some embodiments, hematopoietic cancers that can be treated include, but arenot limited to, MDS, AML, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-celllymphoma (DLBCL) (e.g. ABC DLBCL with MYD88 mutation (e.g., L265P)), follicularlymphoma, or marginal zone lymphoma, or combinations thereof.

[0391] In some embodiments, cancers characterized by dysregulated IRAK expression(IRAK1 and / or IRAK4) and / or IRAK-meidated intracellular signaling, can be treated, and 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 carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof.

[0392] In some embodiments, compounds of the present disclosure can be used to inhibittargets in the context of additional conditions characterized by overactive IRAK1 and / or IRAK4.According to particular aspects of the disclosure, compounds of the present disclosure can beused to inhibit overactive IRAK1 and / or IRAK4 in conditions such as inflammatory diseases andautoimmune disease, wherein said inflammatory diseaess and autoimmune diseases arecharacterized by overactive IRAK1 and / or IRAK4. In some embodiments, inflammatory andautoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-meidated intracellular signaling, can be treated, and include, butare not limited to, chronic inflammation (i.e., associated with viral and bacterial infection),sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, and the like, and combinations thereof.

[0393] In certain embodiments, MDS that can be treated in a subject (e.g., mammals,porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice,rats, and humans) using a compound of the disclosure (e.g., Formula (I) or Formula (Ia)) includebut are not limited to MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, refractory cytopenia with unilineage dysplasia (e.g., refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia withmultilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ringsideroblasts and animals / humans with pathological changes not restricted to red cells such asprominent white cell precursor and platelet precursor (megakaryocyte) dysplasia), refractory anemias with excess blasts I and II, 5q-syndrome, megakaryocyte dysplasia with fibrosis, andrefractory cytopenia of childhood. In some embodiments, MDS that can be treated include, butare not limited to, MDS that is inherited, MDS with an increased risk of occurrence due to an inherited predisposition, MDS with an increased risk of occurrence due to other blood disorders, MDS with an increased risk of occurrence due to chemical exposure, MDS with an increased risk of occurrence due to ionizing radiation, MDS with an increased risk of occurrence due to cancer treatment (e.g., a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5 to 7 years) or DNA topoisomerase inhibitors), MDS evolving from acquired aplastic anemia following immunosuppressive treatment and Fanconi's anemia, MDS with an increased risk due to an mutation in splicing factors, MDS with an increased risk due to a mutation in isocitrate dehydrogenase 1, and MDS with an increased risk due to a mutation in isocitrate dehydrogenase2. Animals that can be treated include but are not limited to mammals, rodents, primates,monkeys (e.g., macaque, rhesus macaque, pig tail macaque), humans, canine, feline, porcine, avian (e.g., chicken), bovine, mice, rabbits, and rats. In the methods, the term “subject” mayrefer to both human and non-human subjects. In some instances, the subject is in need of thetreatment (e.g., by showing signs of disease, e.g. MDS, AML, cancer, autoimmune disease,inflammatory condition, etc., or by having a low blood cell count).

[0394] In some embodiments, MDS that can be treated in a subject (e.g., mammals,porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice,rats, and humans) using a compound of the disclosure (e.g., Formula (I) or Formula (Ia)) include,but are not limited to MDS that can be treated by inhibiting one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAK1 (e.g., using IRAK 1 inhibitors), and / or mutations of IRAK1 (e.g., using inhibitors of IRAK1 mutant). In certain embodiments, MDS that can be treated include, but are not limited to MDSthat can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibitingand IRAK1 (or its mutations), or MDS that can be treated by inhibiting IRAK4 (or its mutations)and IRAK1 (or its mutations). In some embodiments, MDS that can be treated include, but arenot 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 for treating tumors with FLT3 mutations, which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s),e.g., driven by IRAK. In some embodiments, MDS that can be treated is characterized by MDShaving enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / orwherein the MDS is not driven by FLT3 mutations but expresses IRAK4-Long, based on the useof IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent ApplicationNo.16 / 339,692; and Smith, M. A., et al. (2019). “U2AF1 mutations induce oncogenic IRAK4isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5):640-650. DOI: 10.1038 / s41556-019-0314-5, both incorporated by reference herein in theirentirety).

[0395] In some embodiments, AML that can be treated in a subject (e.g., mammals,porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice,rats, and humans) using a compound of the disclosure (e.g., Formula (I) or Formula (Ia)) include,but are not limited to AML that is inherited, AML with an increased risk of occurrence due to an inherited predisposition, AML with one or more recurrent genetic abnormality (e.g., with inversions or translocations, such as MLLT3 / MLL which is a translocation between chromosome9 and 11 (“MLL”) AML with translocation between chromosomes 8 and 21, AML withtranslocation or inversion in chromosome 16, AML with translocation between chromosomes 9 and 11, APL (M3) with translocation between chromosomes 15 and 17, AML with translocation between chromosomes 6 and 9, AML with translocation or inversion in chromosome 3, and the like), AML (megakaryoblastic) with a translocation between chromosomes 1 and 22, AML with myelodysplasia-related changes, AML related to previous chemotherapy or radiation (such as, for example, alkylating agent-related AML, topoisomerase II inhibitor-related AML, and thelike), AML not otherwise categorized (does not fall into above categories - similar to FABclassification; such as, for example, AML minimally differentiated (M0), AML with minimal maturation (M1), AML with maturation (M2), acute myelomonocytic leukemia (M4), acutemonocytic leukemia (M5), acute erythroid leukemia (M6), acute megakaryoblastic leukemia(M7), acute basophilic leukemia, acute panmyelosis with fibrosis, and the like), myeloid sarcoma(also known as granulocytic sarcoma, chloroma or extramedullary myeloblastoma), undifferentiated and biphenotypic acute leukemias (also known as mixed phenotype acute leukemias), AML with an increased risk of occurrence due to other blood disorders, AML with an increased risk of occurrence due to chemical exposure, AML with an increased risk of occurrence due to ionizing radiation, AML evolving from myelodysplastic syndromes, AMLevolving from myeloproliferative disease, AML with an increased risk due to an FLT3 mutation,AML with an increased risk due to an FLT3 mutation in the juxtamembrane region of FLT3,AML with an increased risk due to an FLT3 mutation of an internal tandem duplication in thejuxtamembrane region of FLT3, AML with an increased risk due to an FLT3 mutation in thekinase domain of FLT3, AML with an increased risk due to the FLT3 mutation D835Y, AML with an increased risk due to the FLT3 mutation D835V, AML with an increased risk due to the FLT3 mutation F691L, and AML with an increased risk due to the FLT3 mutation R834Q, andthe like. In some embodiments, AML that can be treated include AML that by inhibiting one ormore of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAK1 (e.g., using IRAK 1 inhibitors), and / or mutations of IRAK1 (e.g., using inhibitors of IRAK1 mutant). In certain embodiments, AML that can be treated include, but are not limited to AML that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAK1 (or its mutations), or AML that can be treated by inhibiting IRAK4 (or its mutations) and IRAK1 (or its mutations). In some embodiments, AML that can be treated include, but are not limited to AML 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 for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due toadaptive resistance mechanism(s), e.g. driven by IRAK. In some embodiments, AML that can betreated is characterized by AML having enhanced IRAK4-Long expression and / or activityrelative to IRAK4-Short, and / or wherein the AML 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, M. A., et al. (2019).“U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways inmyeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038 / s41556-019-0314-5, bothincorporated by reference herein in their entirety).

[0396] In some embodiments, hematopoietic cancers that can be treated in a subject (e.g.,mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys,rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I) orFormula (Ia)) include, but are not limited to hematopoietic cancers (e.g. MDS, AML, DLBCL,and the like, as described previously) that can be treated by inhibiting (e.g., reducing the activity or expression of) one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), isoforms of IRAK4, mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAK1 (e.g., using IRAK 1 inhibitors), isoforms of IRAK1, or mutations of IRAK1 (e.g., using inhibitors of IRAK1 mutants). In certain embodiments, hematopoietic cancers that can be treated include, but are not limited to cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK4 (or its mutations), hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK1 (or its mutations), or hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations), IRAK4 (or its isoforms or mutations), andIRAK1 (or its isoforms or mutations). In some embodiments, hematopoietic cancer that can betreated include, but are not limited to hematopoietic cancer that can be treated by inhibitingFLT3 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 for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due toadaptive resistance mechanism(s), e.g., driven by IRAK. In some embodiments, hematopoieticcancer that can be treated is characterized by hematopoietic cancer having enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein the hematopoietic cancer is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use ofIRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No.16 / 339,692; and Smith, M. A., et al. (2019). “U2AF1 mutations induce oncogenic IRAK4isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5):640-650. DOI: 10.1038 / s41556-019-0314-5, both incorporated by reference herein in theirentirety).

[0397] In some embodiments, cancers that can 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 carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof, 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 for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistancemechanism(s), e.g., driven by IRAK. In some embodiments, cancer that can be treated ischaracterized by cancer having enhanced IRAK4-Long expression and / or activity relative toIRAK4-Short, and / or wherein the cancer 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 describedin U.S. Patent Application No. 16 / 339,692; and Smith, M. A., et al. (2019). “U2AF1 mutationsinduce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloidmalignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038 / s41556-019-0314-5, bothincorporated by reference herein in their entirety).

[0398] In some embodiments, inflammatory and autoimmune diseases characterized bydysregulated (e.g., hyperactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK- meidated intracellular signaling, that can be treated include, but are not limited to, chronicinflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis,systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, and the like, and combinations thereof, 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 for treatinginflammatory and autoimmune diseases with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK. In someembodiments, inflammatory and autoimmune disease that can be treated is characterized byinflammatory and autoimmune disease having enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein the inflammatory and autoimmune disease is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio ofIRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No. 16 / 339,692; and Smith,M. A., et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innateimmune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038 / s41556-019-0314-5, both incorporated by reference herein in their entirety).

[0399] As related to treating MDS (e.g., MDS with a splicing factor mutation, MDS witha mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2), treating can include but is not limited to prophylactic treatment and therapeutic treatment. As such, treatment can include, but is not limited to: preventing 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); reducing the risk 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); ameliorating or relieving symptoms 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); eliciting a bodily response against 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); inhibiting the development or progression 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); inhibiting or preventing the onset of symptoms associated with 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); reducing the severity 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); causing a regression of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation inisocitrate dehydrogenase 2) or one or more of the symptoms associated with MDS (e.g., an increase in blood cell count); causing remission 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); causing remission of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation inisocitrate dehydrogenase 2) by preventing or minimizing FLT3 mutations (e.g., internal tandemduplication mutations or the D835Y mutation); preventing relapse 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); or preventing relapse of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with amutation in isocitrate dehydrogenase 2) in animals / humans that have intrinsic or acquiredresistance to other MDS treatments. In some embodiments, treating does not include prophylactic treatment of MDS (e.g., preventing or ameliorating future MDS).

[0400] As related to treating hematopoietic 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 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), follicularlymphoma, or marginal zone lymphoma, and combinations thereof, and the like), treating can include but is not limited to prophylactic treatment and therapeutic treatment. As such, treatment can include, but is not limited to: 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 lymphoma, orWaldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL),DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinationsthereof, and the like); 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 lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL),DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinationsthereof, and the like); ameliorating or relieving symptoms of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkinlymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-celllymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zonelymphoma, and combinations thereof, and the like); eliciting a bodily response against 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 lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse largeB-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zonelymphoma, and combinations thereof, and the like); inhibiting the development 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 lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma,diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, ormarginal zone lymphoma, and combinations thereof, and the like); 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 lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof,and the like); reducing the severity 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof,and the like); causing a regression 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof,and the like) or one or more of the symptoms associated with cancer (e.g., a decrease in tumor size); causing remission 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 lymphoma, Waldenstrom’s macroglobulinemia, Bcell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicularlymphoma, or marginal zone lymphoma, and combinations thereof, and the like); causingremission of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocyticleukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma,diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, ormarginal zone lymphoma, and combinations thereof, and the like) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or the D835Y mutation); causing remission of acute myeloid leukemia by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or the D835Y mutation); preventing relapse 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-celllymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zonelymphoma, and combinations thereof, and the like); preventing relapse 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-celllymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zonelymphoma, and combinations thereof, and the like) in animals / humans that have intrinsic oracquired resistance to other cancer treatments (e.g., from some FLT3 inhibitors or from MLL);or preventing relapse of acute myeloid leukemia in animals / humans that have intrinsic oracquired resistance to other cancer treatments (e.g., from some FLT3 inhibitors or from MLL). In some embodiments, treating does not include prophylactic treatment of cancer (e.g., preventing or ameliorating future cancer).

[0401] Treatment of a subject can occur using any suitable administration method (suchas those disclosed herein) and using any suitable amount of a compound of the disclosure (e.g.,Formula (I) or Formula (Ia)). In some embodiments, methods of treatment comprise treating ananimal or human for MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation inisocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2). In some embodiments, methods of treatment comprise treating an animal or human for a hematopoieticcancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia(CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof,and the like). Other embodiments include treatment after one or more of having a blooddisorder, having myelodysplastic syndrome, having myeloproliferative disease, an occurrence ofchemical exposure, an exposure to ionizing radiation, or a treatment for a hematopoietic cancer (e.g., with chemotherapy, ionizing radiation, or both). Some embodiments of the disclosure include a method for treating a subject (e.g., an animal such as a human or primate) with acomposition comprising a compound of the disclosure (e.g., Formula (I) or Formula (Ia)) (e.g., apharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration.

[0402] In some embodiments, the method of treatment includes administering to asubject an effective amount of a composition comprising a compound of the disclosure (e.g.,Formula (I) or Formula (Ia)). As used herein, the term “effective amount” refers to a dosage or aseries of dosages sufficient to affect treatment (e.g., to treat MDS such as but not limited to 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); or to treat 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), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, ...

Claims

CLAIMS1. A compound of Formula (I):or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: R1is selected from H, halogen, hydroxy, oxo, -CN, amino, amido, -O-aryl,methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7heteroalkyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, - NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl; R2is selected from H, halogen, hydroxy, oxo, -CN, amino, amido, -O-aryl,methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fusedcycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7alkyl which is substituted with cycloalkyl; R31is selected from H, halogen, hydroxy, oxo, -CN, amino, amido, -O-aryl,methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7heteroalkyl, C1-C7alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7alkoxy, C1-C7haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7alkyl which is substituted with cycloalkyl; R3, R4, and R5are each independently selected from H, halogen, hydroxy, oxo, -S(O)2- (C1-C7alkyl), amido, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2- C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amido, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2- C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, - N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl,pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, - CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7alkyl which is substituted with cycloalkyl; or R3and R4or R4and R5bond or fuse to form a heterocyclyl or heteroaryl, each of which is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO- morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7alkyl which is substituted with cycloalkyl;R7, R8, R9, R10, R11, R12, R13, R14are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl,C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, orfused ring heteroaryl is optionally substituted with one or more deuterium or halogen;R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, and R30are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (- CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the methanoyl (- COH), carboxy (-CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionallysubstituted with one or more deuterium or halogen; andm, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5,where m+n+o+p is at leat 1, q+r+s+t is at least 1, and / or where u+v+w+x is at least 1.

2. The compound of claim 1, wherein at least one of (i)-(vi) applies:(i) R1is -OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or(iii) one or more of R3, R4, and R5 is -Cl, amido, C2-C7 alkynyl, C1-C7 alkyl substitutedwith hydroxy, C1-C7 alkyl substituted with C1-C7 alkoxy, -S(O)2-(C1-C7 alkyl), or(iv) R4 and R5 bond or fuse to form an unsubstituted heterocyclyl or an unsubstitutedheteroaryl;(vi) R31 is selected from halogen, hydroxy, oxo,-CN, amino, amido, -O-aryl,methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7alkyl which is substituted with cycloalkyl.

3. The compound of claim 1 or 2, wherein the compound of Formula (I) is a compound ofFormula (IIv)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:R20vis selected from C1-C6alkyl, C1-C6alkoxy, -OH, and wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy; R21vis selected from C1-C6alkyl, C3-C6cycloalkyl, C5-C12spiro-fused cycloalkyl, and C3-C9heterocyclyl, wherein C1-C6alkyl is optionally substituted with one or more substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6 alkyl, -OH, and halogen, and C3-C9 heterocyclyl is optionallysubstituted with one or more substituents selected from C1-C6alkyl, -OH, and halogen; R22v, R23v, and R24v are each independently selected from H, CN, amido, halogen, -S(O)2- (C1-C7 alkyl), C1-C6 alkyl, C2-C7 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12aryl, and -O-(C6-C12aryl), wherein C1-C6alkyl is optionally substituted with one or more substituents selected from C1-C6alkoxy, -OH, halogen; and R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb are each independently selected from H, halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms.

4. The compound of claim 3, wherein at least one of (i)-(iii) applies:(i) R20vis -OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or(iii) one or more of R22v, R23v, and R24v is -Cl, amido, C2-C7 alkynyl, C1-C7 alkylsubstituted with hydroxy, C1-C7alkyl substituted with C1-C7alkoxy, -S(O)2-(C1-C7alkyl), or5. The compound of claim 3 or 4, with the provisos that:when R20vis -OCH3and R21vis unsubstituted C3cycloalkyl (i) one or more of R22v, R23v, and R24v is selected from amido, unsubstituted oxetane, -S(O)2-(C1-C7 alkyl), C1-C6 alkyl, or C2- C7 alkynyl, wherein C1-C6 alkyl is substituted with one or more substituents selected from C1-C6 alkoxy, -OH, halogen, (ii) one or more of R22v, R23v, and R24vis CN and one or more of R22v, R23v, and R24vis halogen, (iii) R22vand R24vare each independently halogen, R23vis H, and one or two of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb is selected from halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms, provided the compound of Formula (IIv) is not , (iv) R22v is Cl, R23v is H, and R24v is H, or (v) R22v is H, R23vis H, and R24v is Cl, or (v) the compound iswhen R20v is -OCH3 and R21v is one or more of R22v, R23v, and R24vis CN and one or more of R22v, R23v, and R24vis halogen; andwhen R20vis -OCH3and R21vis unsubstituted oxetane orone or more of R22v, R23v, and R24v is CN.

6. The compound of any one of claims 3 to 5, wherein at least one of (i)-(x) applies:(i) R20v is selected from -OCH3, -OCD3, -O(CH2)2OCH3, -O(CH2)2OH, and(ii) R21vis selected from unsubstituted C3cycloalkyl,(iii) R22vis F, R23vis H, and R24vis selected from F, CN, -CH2OH, –C(O)NH2, and – C(O)NHCH3; (iv) R22v is Cl, R23v and R24v are each H; (v) R22vand R23vare each H and R24vis selected from Cl, ethynyl, -CH2OH, -CH2OCH3, - C(O)NH2, -S(O)2CH3, and, each of R25va, R25vb, R27va, R27vb, R28va, R28vb, R29va, and R29vbis H; , each of R25va, R25vb, R27va, R27vb, R28va, R29va, andR29vbis H and R28vbis F;each of R25va, R27va, R27vb, R28va, R28vb, R29va, andR29vbis H and R25vbis -CH3; each of R25va, R25vb, R27va, R28va, R28vb, R29va, andR29vb is H and R27vb is F or -CF3; or , each of R25va, R25vb, R28va, R28vb, R29va, and R29vbisH and each of R27va and R27vb are F.

7. The compound of any one of claims 3 to 6, wherein the compound is selected from:, or a pharmaceutically acceptable salt of any one thereof.

8. The compound of claim 1 or 2, wherein the compound of Formula (I) is a compound ofFormula (IIw)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected fromR20w is selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, and , wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy; R21w is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9heterocyclyl, wherein C1-C6alkyl is optionally substituted with one or more substituentsselected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6 alkyl, -OH, and halogen; R22w, R23w, and R24ware each independently selected from H, CN, amido, halogen, - S(O)2-(C1-C7 alkyl), C1-C6 alkyl, C2-C7 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-C12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from C1-C6alkoxy, -OH, halogen; R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wbare 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; and R31wis selected from C1-C6alkyl, C1-C6alkoxy, amido, C3-C6cycloalkyl, C3-C9heterocyclyl, -OH, and wherein C1-C6 alkyl and C1-C6 alkoxy are each optionallysubstituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6alkoxy and C3-C6cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen.

9. The compound of claim 8, wherein at least one of (i)-(iii) applies:(i) each of R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb is H;(ii) one of R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb is selected from halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms; or (iii) R31w is amido or C1-C6 alkyl optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6alkoxy.

10. The compound of claim 8 or 9, wherein at least one of (i)-(vi) applies:(i) R20wis -OCH3; (ii) R21wis unsubstituted C3cycloalkyl; (iii) R22w and R23w are each H and R24w is F;, each of R25wa, R25wb, R27wa, R27wb, R28wa, R28wb,R29wa, and R29wbis H; ach of R25wa, R25wb, R27wa, R27wb, R28wa, R29wa, and R29wb is H and R28wb is F; or (vi) R31w is selected from -C(O)NH2, -CH3, -CH2OH, and11. The compound of any one of claims 8 to 10, wherein the compound is selected from:pharmaceutically acceptable salt of any one thereof.

12. The compound of claim 1 or 2, wherein the compound of Formula (I) is a compound ofFormula (IVc)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:is selected fromR40cis selected from C1-C6alkyl, C1-C6alkoxy, and -OH, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R41cis selected from C1-C6alkyl, C3-C6cycloalkyl, C5-C12spiro-fused cycloalkyl, and C3- C9heterocyclyl, wherein C1-C6alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6 alkyl and halogen; R42c, R43c, and R44care each independently selected from H and halogen; andR45ca, R45cb, R46ca, R46cb, R47ca, R47cb, R48ca, R48cb, R49ca, and R49cb are each independentlyselected 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.

13. The compound of claim 12, wherein each of R45ca, R45cb, R46ca, R46cb, R47ca, R47cb, R48ca,R48cb, R49ca, and R49cbis H.

14. The compound of claim 12 or 13, wherein at least one of (i)-(iv) applies:(i) R40c is -OH; (ii) R41cis unsubstituted C3cycloalkyl; (iii) R42c and R44c are each F and R43c is H; and wherein each of R45ca, R45cb, R47ca, R47cb, R48ca, R48cb, R49ca, and R49cb is H.

15. The compound of any one of claims 12 to 14, wherein the compound is, or a pharmaceutically acceptablesalt thereof.

16. The compound of claim 1 or 2, wherein the compound of Formula (I) is a compound ofFormula (Vc)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:is selected fromR50c is selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, and wherein C1-C6alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6alkoxy; R51c is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3- C9 heterocyclyl, wherein C1-C6 alkyl is optionally substituted with one or more substituentsselected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6alkyl, -OH, and halogen; R52c is selected from H, CN, amido, halogen, -S(O)2-(C1-C7 alkyl), C1-C6 alkyl, C2-C7 alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C9heterocyclyl, C6-C12aryl, and -O-(C6-C12aryl), wherein C1-C6alkyl is optionally substituted with one or more substituents selected from C1-C6alkoxy, -OH, halogen; and R55ca, R55cb, R56ca, R56cb, R57ca, R57cb, R58ca, R58cb, R59ca, and R59cb are each independently selected from H, halogen, -OH, C1-C6alkyl, and C1-C6alkoxy, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more halogen atoms.

17. The compound of claim 16, wherein:each of R55ca, R55cb, R56ca, R56cb, R57ca, R57cb, R58ca, R58cb, R59ca, and R59cbis H; orone of R55ca, R55cb, R56ca, R56cb, R57ca, R57cb, R58ca, R58cb, R59ca, and R59cb is selected from 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.

18. The compound of claim 16 or 17, wherein at least one of (i)-(vi) applies:(i) R50cis -OCH3; (ii) R51cis unsubstituted C3cycloalkyl; (iii) R52c is H; each of R55ca, R55cb, R57ca, R57cb, R58ca, R58cb, R59ca,and R59cb is H; or , each of R55ca, R55cb, R57ca, R57cb, R58ca, R59ca, andR59cb is H and R58cb is F.

19. The compound of any one of claims 16 to 18, wherein the compound is selected from:, or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 or 2, wherein the compound of Formula (I) is a compound ofFormula (Vd)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:is selected fromR50dis selected from C1-C6alkyl, C1-C6alkoxy, -OH, and, wherein C1-C6alkyl and C1-C6alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy; R51dis selected from C1-C6alkyl, C3-C6cycloalkyl, C5-C12spiro-fused cycloalkyl, and C3-C9heterocyclyl, wherein C1-C6alkyl is optionally substituted with one or more substituentsselected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or moresubstituents selected from C1-C6alkyl, -OH, and halogen; R52dis selected from H, CN, amido, halogen, -S(O)2-(C1-C7alkyl), C1-C6alkyl, C2-C7alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-C12 aryl), wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from C1-C6 alkoxy, -OH, halogen; and R55da, R55db, R56da, R56db, R57da, R57db, R58da, R58db, R59da, and R59dbare 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.

21. The compound of claim 20, wherein:each of R55da, R55db, R56da, R56db, R57da, R57db, R58da, R58db, R59da, and R59db is H; or one of R55da, R55db, R56da, R56db, R57da, R57db, R58da, R58db, R59da, and R59dbis selected from 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.

22. The compound of claim 20 or 21, wherein at least one of (i)-(vi) applies:(i) R50d is -OCH3; (ii) R51d is unsubstituted C3 cycloalkyl; (iii) R52dis H; , each of R55da, R55db, R57da, R57db, R58da, R58db, R59da,and R59dbis H; or , each of R55da, R55db, R57da, R57db, R58da, R59da, andR59db is H and R58db is F.

23. The compound of any one of claims 20 to 22, wherein the compound is selected from:, or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1 to 23, wherein the compound is an inhibitor of atleast one of IRAK1, IRAK4, and FLT3, or wherein the compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3, or wherein the compound is an inhibitor of IRAK1 and IRAK4, or wherein the compound is an inhibitor of IRAK1, IRAK4, and FLT3.

25. The compound of claim 24, wherein FLT3 is selected from WT FLT3, activated FLT3,and mutated FLT3, optionally wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.

26. A composition comprising a compound of any one of claims 1 to 25, wherein thecomposition further comprises a formulary ingredient, an adjuvant, or a carrier.

27. A method of treating a disease or disorder in a subject, the method comprisingadministering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 25 or a composition of claim 26.

28. The method of claim 27, wherein the disease or disorder is responsive to at least one ofinterleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition.

29. The method of claim 27 or 28, wherein the administration comprises parenteraladministration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.

30. The method of any one of claims 27 to 29, wherein the compound is administered to thesubject in an amount of from about 0.005 mg / kg subject body weight to about 1,000 mg / kg subject body weight.

31. The method of any one of claims 27 to 30, wherein the disease or disorder is notrelapsed / refractory, preferably wherein the disease or disorder is myelodysplastic syndrome(MDS) that is not relapsed / refractory or acute myeloid leukemia (AML) that is notrelapsed / refractory.

32. The method of any one of claims 27 to 30, wherein the disease or disorder isrelapsed / refractory.

33. The method of any one of claims 27 to 30, wherein the disease or disorder is:a BCL2 inhibitor relapsed / refractory disease or disorder, preferably a venetoclaxrelapsed / refractory disease or disorder,a hypomethylating agent relapsed / refractory disease or disorder, preferably an azacitidinerelapsed / refractory disease or disorder, ora BCL2 inhibitor and a hypomethylating agent relapsed / refractory disease or disorder,preferably a venetoclax and azacitidine relapsed / refractory disease or disorder.

34. The method of any one of claims 27 to 33, wherein the disease or disorder comprises ahematopoietic cancer.

35. The method of any one of claims 27 to 33, wherein the disease or disorder comprises:(i) at least one cancer selected from: myelodysplastic syndrome (MDS), acute myeloidleukemia (AML), lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin 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, 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 carcinoma, rectal cancer, stomach cancer, and uterine cancer; or (ii) one or more inflammatory diseases 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 sclerosis, Type 1 diabetes mellitus, Crohn’s disease, or colitis.

36. The method of any one of claims 27 to 33, wherein the disease or disorder comprises:(i) low-risk myelodysplastic syndrome (MDS), high-risk MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, optionally wherein MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1; or (ii) acute myeloid leukemia (AML) with a splicing factor mutation, AML having enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long, optionally wherein AML with a splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1.

37. The method of any one of claims 27 to 33, wherein the disease or disorder comprisesdiffuse large B-cell lymphoma (DLBCL), and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL.

38. The method of any one of claims 27 to 37, further comprising administering to thesubject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody- drug conjugate, an mAbs / 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 ERK inhibitor including an ERK2 / MAPK1 or ERK1 / MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, aTopoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase / Leukotriene A4hydrolase inhibitor, a FLT3 / Axl / ALK inhibitor, a FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT 1, 2, and / or 3 inhibitor, a 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.

39. The method of any one of claims 27 to 38, wherein the disease or disorder is responsiveto at least one of BCL2 inhibition, BTK inhibition, CDK inhibition, and DNA methyltransferase inhibition; or wherein the disease or disorder is sensitive to anti-inflammatory glucocorticoids.

40. The method of claim 38 or 39, wherein the additional therapy is at least one of a BCL2inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.

41. The method of any one of claims 38 to 40, 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 a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4 / 6 inhibitor palbociclib, CDK7 inhibitor THZ1, and / or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof, the hypomethylating agent is azacitidine or a pharmaceutically acceptable salt thereof, orthe BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof and thehypomethylating agent is azacitidine or a pharmaceutically acceptable salt thereof.

42. The method of any one of claims 38 to 41, wherein the disease or disorder is AML whichis not relapsed / refractory and the additional therapy is: a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof, or a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof, or a combination of a BCL2 inhibitor, preferably venetoclax or a pharmaceuticallyacceptable salt thereof and a hypomethylating agent, preferably azacitidine or a pharmaceuticallyacceptable salt thereof.

43. The method of any one of claims 38 to 41, wherein the disease or disorder is MDS whichis not relapsed / refractory and the additional therapy is a hypomethylating agent, preferablyazacitidine or a pharmaceutically acceptable salt thereof.

44. The method of any one of claims 38 to 41, wherein the disease or disorder is:a BCL2 inhibitor resistant disease or disorder, preferably a venetoclax resistant disease ordisorder, or ahypomethylating agent resistant disease or disorder, preferably an azacitidine resistantdisease or disorder, ora BCL2 inhibitor and a hypomethylating agent resistant disease or disorder, preferably a venetoclax and an azacitidine resistant disease or disorder, or a FLT3 inhibitor resistant disease or disorder.

45. The method of any one of claims 38 to 41, wherein the disease or disorder is:BCL2 inhibitor resistant acute myeloid leukemia (AML), preferably venetoclax resistantAML, and the additional therapy is a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof, or BCL2 inhibitor resistant refractory AML, preferably venetoclax resistant refractory AML, and the additional therapy is a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof, or BCL2 inhibitor resistant relapsed AML, preferably venetoclax resistant relapsed AML, and the additional therapy is a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof.

46. The method of any one of claims 38 to 41, wherein the disease or disorder is:hypomethylating agent resistant acute myeloid leukemia (AML), preferably azacitidineresistant AML, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof, or hypomethylating agent resistant refractory AML, preferably azacitidine resistantrefractory AML, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof, or hypomethylating agent resistant relapsed AML, preferably azacitidine resistant relapsedAML, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof.

47. The method of any one of claims 38 to 41, wherein the disease or disorder is:BCL-2 inhibitor and hypomethylating agent resistant acute myeloid leukemia (AML),preferably venetoclax and azacitidine resistant AML, and the additional therapy is the combination of a BCL-2 inhibitor and a hypomethylating agent, preferably a combination ofvenetoclax or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceuticallyacceptable salt of any one thereof, or BCL-2 inhibitor and hypomethylating agent resistant refractory AML, preferablyvenetoclax and azacitidine resistant refractory AML, and the additional therapy is the combination of a BCL-2 inhibitor and a hypomethylating agent, preferably a combination ofvenetoclax or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceuticallyacceptable salt of any one thereof, or BCL-2 inhibitor and hypomethylating agent resistant relapsed AML, preferablyvenetoclax and azacitidine resistant relapsed AML, and the additional therapy is the combination of a BCL-2 inhibitor and a hypomethylating agent, preferably a combination of venetoclax or apharmaceutically acceptable salt of thereof and azacitidine or a pharmaceutically acceptable saltof any one thereof.

48. The method of any one of claims 38 to 41, wherein the disease or disorder is:hypomethylating agent resistant myelodysplastic syndrome (MDS), preferably azacitidineresistant MDS, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt of any one thereof, or hypomethylating agent resistant refractory MDS, preferably azacitidine resistantrefractory MDS, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt of any one thereof, or hypomethylating agent resistant relapsed MDS, preferably azacitidine resistant MDS, andthe additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt of any one thereof.

49. The method of any one of claims 38 to 41, wherein the disease or disorder is:a BTK inhibitor resistant disease or disorder, optionally an ibrutinib resistant disease or disorder, sensitive to anti-inflammatory glucocorticoids, optionally a dexamethasone, methylprednisolone, or prednisolone resistant disease or disorder, ora CDK inhibitor resistant disease or disorder, optionally a palbociclib, THZ1, BAY 12511152, or atuveciclib resistant disease or disorder.

50. The method of any one of claims 38 to 41, wherein the disease or disorder is:FLT3 inhibitor resistant acute myeloid leukemia (AML), FLT3 inhibitor resistant refractory AML, or FLT3 inhibitor resistant relapsed AML.

51. The method of claim 38, wherein the compound of any one of claims 1 to 25 or thecomposition of claim 26 and the one or more additional therapies are administered together inone administration or composition.

52. The method of claim 38, wherein the compound of any one of claims 1 to 25 or thecomposition of claim 26 and the one or more additional therapies are administered separately inmore than one administration or more than one composition.

53. The method of any one of claims 27 to 48, wherein the disease or disorder is alleviated by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject, wherein the disease or disorder is alleviated by inhibiting at least two of IRAK1, IRAK4, and FLT3 in the subject, wherein the disease or disorder is alleviated by inhibiting IRAK1 and IRAK4 in the subject, or wherein the disease or disorder is alleviated by inhibiting IRAK1, IRAK4, and FLT3 in the subject.

54. The method of claim 53, wherein FLT3 is selected from WT FLT3, activated FLT3, andmutated FLT3, optionally wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.

55. The method of any one of claims 27 to 54, wherein the compound is a compound ofFormula (IIv), Formula (IIw), Formula (IVc), Formula (Vc), Formula (Vd), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.

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