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

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 which are 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 and Development Agreement with the National Institutes of Health, an Agency of the Department of Health and Human Services. The Government of the United States has certain rights in this invention. BACKGROUND [ 0004 ] Myelodysplastic syndromes (MDS) are malignant, potentially fatal blood diseases that arise from a defective hematopoietic stem / progenitor cell, confer a predisposition to acute myeloid leukemia (AML) (Corey et al., 2007; Nimer, 2008), and often progress to chemotherapy-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 of effective 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 the disease 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 are obstacles which are challenging for identifying and evaluating novel molecular targets for this disease.

[0006] Approximately 30% of MDS patients also develop aggressive AML due to acquisition 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 AML that 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 of proliferation (Melgar et al., 2019). [ 0008 ] In treating MDS and / or AML, there is a need to develop therapies capable of inhibiting 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 to other 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 treating MDS 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) R ' 5 R6 R (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, , O / ii 0H , -CN, amino, amido, -O-aryl, methanoyl (-C0H), 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 (-C0H), 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 (-C0H), 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 Ci-C7 alkyl which is substituted with cycloalkyl; R2 is selected from H, halogen, hydroxy, oxo, ,   0 / n OH ; -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 (-C0H), 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 (-C0H), 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; R31 is selected from H, halogen, t 0 /      11 hydroxy, oxo, OH , -CN, amino, amido, -O-aryl, methanoyl (-C0H), 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 (-C0H), 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 (-C0H), 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; R3, R4, and R5 are each independently selected from H, halogen, hydroxy, oxo, -S(O)2-(Ci-C7 alkyl), amido, -CN, methanoyl (-C0H), 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-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl; or R3 and R4 or R4 and R5 bond or fuse to form a heterocyclyl or heteroaryl, each of which is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-C0H), 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; R6 is '(CR^RW H q(15R16RC)    (CR17R18)r s(19R20RC)    (CR21R22)t m(7R8RC) (CR9R10)n of^R^RCJ^^^CR^R14), HO XO ;23R24RC)    (CR25R26)v w(27R28RC)^n^(CR29R30)x or H0"S^0 ; R7, R8, R9, R10, R11, R12, R13, R14 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-C0H), 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 (-C0H), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, Ci-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen; R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, and R30 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 (-C0H), 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 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 - ,   0 / u+                    y---1 ^0-^0-       |—N  0 OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or OH ; (ii) R2 js ’ \— / OH, or ; (iii) 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-(Ci-C7 alkyl), or O ; (iv) R4 and R5 bond or fuse to form an unsubstituted heterocyclyl or an unsubstituted heteroaryl; (v) R6 is m(7R8RC) (CR9R10)n 0(11R12RC)^n^(CR13R14)! ■°;k HO "O , or q(15R16RCr{CR17R18)r s(19R20RC)    (CR21R22)t u(23R24RC)'^(CR25R26)v „(27R2'RC)^n,(CR29Rm)x ’5k HO '0 ; or (vi) R31 is selected from halogen, , O /     11 hydroxy, oxo, OH , -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 (-C0H), 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 (-C0H), 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.

[0011] In one embodiment, the compound of Formula (I) is a compound of Formula (IIv) ^20v r21v R22v R23v p ^24v or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein is selected from and R25va. R25vb R R29va                                                                  , O R28va          R29vb R27vb R27va • R20v is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and OH , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy; R2ivis selected from Ci- Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from -OH and halogen, C3-Ce cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, -OH, and halogen, and C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, -OH, and halogen; R22V, R23V, and R24Vare each independently selected from H, CN, amido, halogen, -S(O)2-(Ci-C7 alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3- Ce cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -0-(Ce-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen; and R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, at ,   0 /      11 least one of (i)-(iii) applies: (i) R20V is -OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or OH ; (ii) R21V is OH, or O ; or (iii) one or more of R22V, R23V, and R24V is -Cl, amido, C2-C7 alkynyl, C1-C7 alkyl substituted with hydroxy, C1-C7 alkyl substituted with C1-C7 alkoxy, -S(O)2-(Ci-C7 alkyl), or 0     . In one embodiment, the compound is a compound of Formula (IIv) with the provisos that: when R20vis -OCH3 and R21V is unsubstituted C3 cycloalkyl (i) one or more of R22V, R23V, and R24vis selected from amido, unsubstituted oxetane, -S(0)2-(Ci- C7 alkyl), Ci-Ce alkyl, or C2-C7 alkynyl, wherein Ci-Ce alkyl is substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen, (ii) one or more of R22V, R23V, and R24vis CN and one or more of R22V, R23V, and R24vis halogen, (iii) R22V and R24V are 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, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms, provided the compound of Formula (IIv) is not               F           , (iv) R22v is Cl, R23V is H, and R24v is H, or (v) R22V is H, R23V is H, and R24v is Cl, or (v) the compound is OH ; when R2ov is -0CH3 and R21V is I , one or more of R22v, R23 and R24v is CN and one or more of R22v, R23v, and R24v is halogen; and when R2qv is -0CH3 and R2iv is unsubstituted oxetane or I OH , one or more of R22v, R23v, and R24vis CN. In one embodiment, at least one of (i)-(x) applies: (i) R2ov is selected from -0CH3, -0CD3, - O(CH2)2OCH3, -O(CH2)2OH, and 0 ii 0'^0’ OH ; (ii) R2ivis selected from unsubstituted C3 cycloalkyl, A<CF3 lOH OH O 1 H, and R24v is selected from F, CN, -CH2OH, -C(O)NH2, and -C(O)NHCH3; (iv) R22v is Cl, R23v and 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, and O R25va, R25vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb is H; (vii) is each of R25va, R25vb, R27va, R27vb, R28va, R29va, and R29vb is H and R28vb is F; (viii) is , each of R25va, R27va, R27vb, R28va, R28vb, R29va, and R29vb is H and R25vb is - each of R25va, R25vb, R27va, R28va, R28vb, R29va, and R29vb is H and R27vb is F or -CF3; or (x) each Of R25va, R25vb, R28va, R28vb, R29va, and R29vb is H and each of R27va and R27vb are F. In one embodiment, the pharmaceutically 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; wherein: is selected from R25wa v ^25wb R28wb-^U                                    O R28wa jY R29wb R27wb R27wa ; r20w is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and 0H , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy; Rziwis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl, -OH, and halogen; R22W, R23W, and R24w are each independently selected from H, CN, amido, halogen, -S(0)2-(Ci-C? alkyl), C1-C6 alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(Ce-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen; R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms; and Rsiw is selected from ,   0 /      11 Ci-Ce alkyl, Ci-Ce alkoxy, amido, C3-C6 cycloalkyl, C3-C9 heterocyclyl, -OH, and 0H , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy and C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce 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, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms; or (iii) Rsiw is amido or Ci-Ce alkyl optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy. In one embodiment, wherein at least one of (i)-(vi) applies: (i) R20W is -OCH3; (ii) R2i« is unsubstituted C3 cycloalkyl; (iii) R22W and R23W are each H and R24w is F; (iv) is R25wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb is H; (v) of R25wa, R25wb, R27wa, R27wb, R28wa, R29wa, and R29wb is H and R28wb is F; or (vi) R31W is selected pharmaceutically 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 salt of an isomer thereof; wherein: ^4503, ^45cb O A^k.^S-OH R48cb\l JI O / \ K49cb 47cb R47ca . r4Qc js seiectec] frOm Ci-Ce alkyl, Ci-Ce alkoxy, and -OH, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R4icis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl and halogen; R42C, R43c, and R44c are each independently selected from H and halogen; and R^sca, R45cb, R46ca, R46cb, R47ca, R47cb, R48ca, R48cb, R49ca, and R49cb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce 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) R4ocis -OH; (ii) R41C is unsubstituted C3 cycloalkyl; (iii) R42C and R44C are each F and R43C is H; and (iv) R45ca R48cb R48ca js R47cb R45cb 0 ^-OH N x0- R49ca R49cb R47ca wherein each of R45ca, R45cb, R47ca, R47cb, R48ca, R48cb, R49ca, and R49cb is H. In one embodiment, the compound is              F F              , or a pharmaceutically acceptable salt thereof. [ 0014 ] In one embodiment, the compound of Formula (I) is a compound of Formula (Vc) 0                or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: Rbbca. R^5cb R^'^ll^-Rsgca                                         O R58ca jy Rs9cb                                               ^0^0- R57cb R57ca . r50c is seiected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and OH , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy; Rsicis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl, -OH, and halogen; R52C is selected from H, CN, amido, halogen, -S(O)2-(Ci-C7 alkyl), Ci- Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-C12 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen; and Rssca, Rsscb, Rseca, Rsecb, Rs7ca, Rs?cb, Rs&a, Rsscb, Rs9ca, and Rs9cb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, each of Rssca, Rsseb, Rseca, Rsecb, R57ca, Rs7cb, Rssca, Rsscb, R59ca, and R59cb IS H, or one of Rssca, R55cb, R56ca, Rs6cb, R57ca, R57cb, R58ca, R58cb, R59ca, and R59cb IS selected from halogen, -OH, Ci-Ce alkyl, and Ci-Cs alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, at least one of (i)-(vi) applies: (i) Rsoc is -OCH3; (ii) Rsicis unsubstituted C3 cycloalkyl; (iii) R52C is each of R55ca, Rsscb, Rs7ca, R?7cb, Rssca, Rsscb, R?9ca, and R59cb is H; or (v) each of R55ca, R55cb, R?7ca, R57cb, R58ca, R?9ca, and Rs9cb is H and Rsscb is F. In one embodiment, the compound is selected from: [ 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: ^55da \ ^55db R59da R58da |\ R59db R57db Rs7da ; R50d is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and OH wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy; Rs id is selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl, -OH, and halogen; Rs2d is selected from H, CN, amido, halogen, -S(O)2-(Ci-C7 alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce 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 Ci-Ce alkoxy, -OH, halogen; and R55da, Rssdb, Rseda, Rsedb, Rs7da, Rs7db, Rssda, Rssdb, Rs9da, and Rs9db are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, each of Rssda, Rssdb, Rseda, Rsedb, Rs?da, Rs7db, Rssda, Rssdb, Rs9da, and Rs9db is H or one of Rssda, R55db, R56da, R56db, Rs7da, R57db, R58da, RsSdb, R59da, and Rs9db is selected from halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, at least one of (i)-(vi) applies: (i) Rsod is -OCH3; (ii) Rsidis unsubstituted C3 cycloalkyl; (iii) Rs2d is each of R55da, R55db, R57da, R57db, R58da, R58db, R59da, and each of R55da, R55db, R57da, R57db, R?8da, R59da, and R$9db is H and Rssdb is F. In one embodiment, the compound is selected from:

[0016] In one embodiment, the compound of Formula (I) is an inhibitor of at least one of IRAKI, IRAK4, and FLT3, or wherein the compound is an inhibitor of at least two of IRAKI, IRAK4, and FLT3, or wherein the compound is an inhibitor of IRAKI and IRAK4, or wherein the compound is an inhibitor of IRAKI, 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 a compound 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 a disease 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 a compound 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 not relapsed / refractory. In one embodiment, the disease or disorder is relapsed / refractory. In one embodiment, the disease or disorder is: a BCL2 inhibitor relapsed / refractory disease or disorder, preferably a venetoclax relapsed / refractory disease or disorder, a hypomethylating agent relapsed / refractory disease or disorder, preferably an azacitidine relapsed / refractory disease or disorder, or a BCL2 inhibitor and a hypomethylating agent relapsed / refractory disease or disorder, preferably a venetoclax and azacitidine relapsed / refractory disease or disorder. In one embodiment, the disease or disorder comprises a hematopoietic cancer. In one embodiment, the disease 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 autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes 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 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. 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, the method further comprises administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, aDNA 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 / VEGFRl / 2 / 3 / FLT3 / CSF-lR / 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, 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, or the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof and the hypomethylating agent is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, 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 acceptable salt thereof and a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is MDS which is not relapsed / refractory and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is: a BCL2 inhibitor resistant disease or disorder, preferably a venetoclax resistant disease or disorder, a hypomethylating agent resistant disease or disorder, preferably an azacitidine resistant disease or disorder, 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 inhibitor resistant disease or disorder. In one embodiment, the disease or disorder is: BCL2 inhibitor resistant acute myeloid leukemia (AML), preferably venetoclax resistant AML, 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. In one embodiment, the disease or disorder is: hypomethylating agent resistant acute myeloid leukemia (AML), preferably azacitidine resistant 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 resistant refractory 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 relapsed AML, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, 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 of venetoclax or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt of any 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 of venetoclax or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt of any one thereof, or BCL-2 inhibitor and hypomethylating agent resistant relapsed 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 a combination of venetoclax or a pharmaceutically acceptable salt of thereof and azacitidine or a pharmaceutically acceptable salt of any one thereof. In one embodiment, the disease or disorder is: hypomethylating agent resistant myelodysplastic syndrome (MDS), preferably azacitidine resistant 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 resistant refractory 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, 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 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, or a CDK inhibitor resistant disease or disorder, optionally a palbociclib, THZ1, BAY 12511152, or atuveciclib resistant disease or disorder. In one embodiment, the disease or disorder is: FLT3 inhibitor resistant acute myeloid leukemia (AML), FLT3 inhibitor resistant refractory AML, or FLT3 inhibitor resistant relapsed AML. In one embodiment, the compound of Formula (I) or the composition comprising a compound of Formula (I) and the one or more additional therapies are administered together in one administration or composition. In one embodiment, the compound of Formula (I) or the composition comprising a compound of Formula (I) and the one or more additional therapies are administered 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 IRAKI, IRAK4, and FLT3 in the subject, wherein the disease or disorder is alleviated by inhibiting at least two of IRAKI, IRAK4, and FLT3 in the subject, wherein the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject, or wherein the disease or disorder is alleviated by inhibiting IRAKI, 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[l,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[l,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 Publication No. 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-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed June 15, 2023; International Publication No. WO 2023250431, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed June 22, 2023; International Publication No. WO 2024030908, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed August 1, 2023; and International Publication No. WO 2024076614, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed October 4, 2023. [ 0020 ] While embodiments encompassing the general inventive concepts may take diverse forms, various embodiments will be described herein, with the understanding that the present disclosure is to be considered merely exemplary, and the general inventive concepts are not intended to be limited to the disclosed embodiments. [ 0021 ] Some embodiments of the disclosure include compounds of Formula (I) and Formula (la). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the disclosure include 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. Further embodiments include methods for making the inventive compound. Yet further embodiments include methods for determining whether a particular patient is likely to be responsive to such treatment with the inventive compounds and compositions. [0022 ] Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art. [ 0023 ] The abbreviations used herein have their conventional meaning within the chemical 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 that would 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 a monovalent, straight or branched hydrocarbon chain, which can be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). For example, the terms “C1-C7 alkyl” or “Ci-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-C7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, and n-heptyl. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl. [ 0027 ] As used herein (unless otherwise specified), the term “alkenyl” means a monovalent, 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-carbon double bonds can have either the cis or trans configuration. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, 1-pentenyl-3-cyclohex enyl, 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 a monovalent, 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 in the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, 1 -propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0029] As used herein (unless otherwise specified), the term “alkoxy” means any of the above 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, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have 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 a monovalent, monocyclic or bicyclic, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered hydrocarbon group. The rings can be saturated or partially unsaturated. Examples of cycloalkyl groups include, 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 is not 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 the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N, P, S, and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH 2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-0-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CE13, -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, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, 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 in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(0)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(0)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” means monovalent Cl, F, Br, or I. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-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 linked covalently. 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 a monovalent, 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, lH-pyrazol-4-yl, l-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisoxazolyl, lH-pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and lH-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, mean a divalent radical derived from an aryl and heteroaryl, respectively. Accordingly, the term "aryl" can represent an unsubstituted, mono-, di- or tri substituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent 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, Ci-iealkyl, arylCi-iealkyl, Co-iealkyloxyCo-iealkyl, arylCo-iealkyloxyCo-iealkyl, Co-iealkylthioCo-iealkyl, arylCo-iealkylthioCo-iealkyl, Co-lealkylaminoCo-iealkyl, arylCo-iealkylaminoCo-iealkyl, di(arylCi-i6alkyl)aminoCo-i6alkyl, Ci-i6alkylcarbonylCo-i6alkyl, arylCi-i6alkylcarbonylCo-i6alkyl, Ci-i6alkylcarboxyCo-i6alkyl, arylCi-lealkylcarboxyCo-iealkyl, Ci-iealkylcarbonylaminoCo-iealkyl, arylCi-iealkylcarbonylaminoCo-i6alkyl,-Co-i6alkylCOOR4, -Co-iealkylCONRsRe wherein R4, R5 and Re are independently selected from hydrogen, Ci-Cnalkyl, arylCo-Cnalkyl, or R5 and Re are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one Ci-iealkyl, arylCo-Ciealkyl, or Co-Cliealkylaryl 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 replaced by, 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 12 membered, 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 can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkyl include, but are not limited to, l-(l,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-l-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-l-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 an atom 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 Risa substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [ 0043] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [ 0044 ] The term “alkylsulfonyl,” as used herein, means a moiety having the formula -S(O2)-R', where R' is an alkyl group as defined above. R' can have a specified number of carbons (e.g., “C1-C4 alkylsulfonyl”). [ 0045 ] The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge.

[0046] In the above definitions, the terms "alkyl" and "alkenyl" can be used interchangeably 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. In some embodiments, the linker includes amido (-C0NH-Rn or -NHCO-R11), thioamido (-CSNH-R11 or -NHCS-R11), carboxyl (-CO2-R11 or -OCORn), carbonyl (-CO-R11), urea (-NHC0NH-R11), thiourea (-NHCSNH-Rn), sulfonamido (-NHSO2-R11 or -SO2NH-R11), ether (-O-R11), sulfonyl (-SO2-Rn), sulfoxyl (-SO-Rn), carbamoyl (-NHCO2-Rn or -OCONH-R11), or amino (-NHRn) linking moi eties. [ 0048 ] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”, and so 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 in substituted 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 group that may be, and preferably is, a group selected from the following moi eties: (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-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent 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-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: (a) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-C0H), 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-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-C0H), 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-C7 haloalkoxy, 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 “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20membered 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 a group, 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 Ci-Cs alkyl, 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 can exist in and be isolated in optically active and racemic forms, for any of the one or more chiral centers. 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. The one or more deuterium atoms can replace one or more hydrogen atoms on a compound disclosed herein, such as a compound of Formula (I) or Formula (la). For example, the one or more deuterium atoms can replace one or more hydrogen atoms in one or more of variable groups R1, R2, R3, R4, R3, R6, R7, R8, R9, R10, R11, R12, R13, R14 R33, R16, R17, R38, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, R30, or R31. The one or more deuterium atoms can replace one or more hydrogen atoms in an optional substituent on one or more of variable groups R1, R2, R3, R4, R3 R6 R7 R8 R9 R?9     R32 R33 R34 R33 R36 R37 R38 R39 R29 R23 R22 R23 R24 R23 R29 R27, R29, R29, R30, orR33. [ 0056] As used herein, the term “sample” encompasses a sample obtained from a subject or 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, blood cells (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 include sections 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 surgical method leading to biopsy or resected cellular material. Such a sample can comprise cells obtained 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, and includes 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 to a 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 some embodiments, “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, 5 years, or 10 years or longer. In some embodiments, an increased risk for a poor outcome indicates 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 test agent 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 test agent 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 trial is 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) member of the animal kingdom. In the methods, the subject is preferably a mammal. In the methods, the subject is preferably a human patient. In the methods, the subject may be a mammalian pediatric patient. In the methods, the pediatric patient is a mammalian (e.g., preferably human) patient under 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 broadest context 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 treated until 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 a particular condition. In some aspects, “treating” may not require or include prevention. As used herein, reference to “treating” an animal includes but is not limited to prophylactic treatment and therapeutic 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,” as used herein, covers any treatment of a disease in a subject, preferably in a mammal (e.g., in a human), and may include one or more of: (a) preventing the disease from occurring in a subject which 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 a desired and / or beneficial effect. An effective amount can be administered in one or more administrations. In the methods, a therapeutically effective amount is an amount 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 or concentration 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 specific mRNA 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 residue modifications, capping variants, polyadenylation variants, etc.), and the like.

[0069] “Antibody” or “antibody peptide(s)” refer to an intact antibody, or a binding fragment thereof that competes with the intact antibody for specific binding; this definition also encompasses monoclonal and polyclonal antibodies. Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies. An antibody other than a “bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. An antibody, 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 (la)), such as compounds of Formula (II) and Formula (III)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the disclosure include compositions (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 structure according to Formula (la): 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 (la). 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 (la) are independently 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-C7 alkyl, C2-C7 alkenyl, 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 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. [ 0073 ] In some embodiments, R1 of Formula (la) 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-C7 alkyl, C2-C7 alkenyl, 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-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl; R2 of Formula (la) 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 (-C0H), carboxy (- CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CHs)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; R3, R4, and R3 of Formula (la) can be 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, which methanoyl (-C0H), 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 (-C0H), 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 (la) can be [ 0075 ]      R7, R8, R9, R10, R11, R12, R13, R14 of Formula (la) can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, Ci-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-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen; R13, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 of Formula (la) can be H, halogen, hydroxy, oxo, -CN, methanoyl (-C0H), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, Ci-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-C0H), 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 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 (la) is H, halogen, -CONH2, -CONHCH3, -CON(CH3)2, benzyl, C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl, which C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl is optionally substituted with one or more halogen, hydroxyl, C1-C7 alkyl, or C1-C7 haloalkyl. In some embodiments, R1 is H, Cl, -CONH2, -CONHCH3, methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl, which methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl is optionally substituted with one or more F, -OH, methyl, or CF3. In some embodiments, R1 is not H. [ 0077 ] In some embodiments, R2 of Formula (la) is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl, which O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, 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, R2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C1-C7 alkoxy, 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-C7 alkyl, C1-C7 haloalkyl, Ci-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R2 is H, Cl, hydroxy, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -OCHF2, -OPh, -CF3, -CHF2, unsubstituted C1-C7 alkyl, substituted amino, substituted C1-C7 alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl. In some embodiments, R2 is not H. [ 0078 ] In some embodiments, R3 of Formula (la) 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-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R3 is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.

[0079] In some embodiments, R4 of Formula (la) 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-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R4 is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy. [ 0080 ] In some embodiments, R3 is of Formula (la) 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-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R5 is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy. [ 0081 ] In some embodiments, R4 of Formula (la) is methyl or -CF3, and at least one of R3 and R3 is H or halogen. [ 0082 ] In some embodiments, there is a chiral center at the R6 attachment carbon of Formula (la). 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 bonds                   HlllIlH",           or ------->. 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 . "Hlllllll               lllllllllli can be ",           ■,                             , or---------.

[0083] In some embodiments, R6 of Formula (la) i s "T X           eC^RC). XlCR«R^)fl । । 0(”R«Re)„                               (J.R2,R5^ H , or                                           . [ 0084 ] In some embodiments, R7, R8, R9, R10, R11, R12, R13, R14 of Formula (la) are 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, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused 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, provided that at least one of R7, R8, R9, R10, R11, R12, R13, and R14 is not H. [ 0085 ] In some embodiments, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, r29, r29 anj r30 of Formuia (fa) are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C? alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-C0H), 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 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, 0, 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 of Formula (la) 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 R13, R16, R17, R18, R19, R20, R21, R22, R23, R24, R23, r26 r27, r29 r2$>, anj r3o of pormu[a (]a) is not H. In another embodiment, each of R13, 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 (la) is ^{zRsRCf’ '’'(CRWA A ARC) .(Ar13R% H

[0089] In some embodiments, R6 of Formula (la) is „ , J ...... ^•^R^Ru) [ 0090 ] In one embodiment, the compound is a compound of Formula (I) (I), or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. In some embodiments, the compound is a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative of a compound of Formula (I). 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, , O / ii hydroxy, oxo, OH , -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-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 , O /       11 OH .

[0093] In one embodiment, R2 of Formula (I) is selected from H, halogen, hydroxy, oxo, , O / IL OH ; -CN, amino, amido, -O-aryl, methanoyl (-C0H), 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 (-C0H), 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 (-C0H), 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. .          . Fn / 3                   ।

[0094] In one embodiment, R2 is 5  \— / , OH , or O . ,   0 /      11 A0-s-0-

[0095] In one embodiment, R31 is selected from H, halogen, hydroxy, oxo, OH , _ 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-C7 alkyl which is substituted with cycloalkyl.

[0096] In one embodiment, R31 is selected from halogen, hydroxy, oxo, OH ,-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 (-C0H), 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 (-C0H), 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. [ 0097 ] In one embodiment, R3, R4, and R5 of Formula (I) are each independently selected from H, halogen, hydroxy, oxo, -S(O)2-(Ci-C7 alkyl), amido, -CN, methanoyl (-C0H), 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 (-C0H), 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 (-C0H), 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 a heterocyclyl or heteroaryl, each of which is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-C0H), 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.

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

[00100] In one embodiment, R6 of Formula (I) is I                         .ICPFW), fnCR!1RC) ^CR^S ,(0^¾3¾. H ;7r8rc)    (cr9r10' 0(11r12rcknjcr13r14)p HO '0 , or w' (15R16RC)    (CR17R18)r ,(19R20RC)    (CR21R22)t (23R24RC)^'(CR25R26)v ,(27R28RCKn^(CR29R30)x HO XO q(15R16RC)'^(CR17R18)r s(19R20RC)    (CR21R22)t

[00101] In one embodiment, R6 is m(7R8RC) (CR9R10)n 0("R,2RC),n,(CR13Rm)p HO '0        or u(23R24RC)    (CR25R26), ,:27r22rC),n,icr22r30i Si HO '0 'v 'X [00102 ] In one embodiment, R7, R8, R9, R10, R11, R12, R13, R14 of Formula (I) are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-C0H), 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-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 halogen; [00103 ] In one embodiment, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 of 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-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 halogen. [ 00104 ] In one embodiment, m, n, o, p, q, r, s, t, u, v, w, and x of Formula (I) 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. [ 00105 ] In some embodiments, there is a chiral center at the R6 attachment carbon of Formula (1). 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 bonds HllllllllHu,           , or------- 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 ""Hlllll             IIIIIIIIIO              or [ 00106 ] Some embodiments of the disclosure include compounds having a structure according 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 R6 attachment carbon. In some embodiments, where there is a chiral center at the R6 attachment carbon, the wavy bond can indicate an R chiral center, an S chiral center, or a racemate. In certain embodiments, '✓VW can be "^Hll or--------. Where a chiral center is possible at other positions of the compounds according to the above formula, as would appreciated by one skilled in the art, the straight bond shown can alsobecanbe......"HI, IHH""'-, or ol^R^RG)^          ’bp ,               H [ 00107 ] In some embodiments, R is                       , giving a structure of Formula (II), as follows: R10, R11, R12, R13, R14, m, n, o, and p are defined above in Formula (I) or Formula (la). [00108 ] In some embodiments according to Formula (II), m is 0 or 1, n is 0 or 1, o is 0 or 1, and p is 0 or 1. [ 00109 ] In some embodiments, R7, R8, R9, and R10 are H, and at least one of R11, R12, R13, and R14 is not H, and / or R11, R12, R13, and R14 are H, and at least one of R7, R8, R9, and R10 is not H. In particular embodiments, R7, R8, R9, R10, R11, R12, R13, and R14 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, R7, R8, R9, and R10 are H, and at least one of R11, R12, R13, and R14 is 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, R11, R12, R13, and R14 are H, and at least one of R7, R8, R9, and R10 is 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-fused cycloalkyl. 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-fused cyclopentyl. In some embodiments, both of R7 and R8 or both of R9 and R10 are F, or both of R7 and R8 or both of R9 and R10 are methyl. In some embodiments, at least one of R11, R12, R13, and R14 is 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 some embodiments, both of R11 and R12 or both of R13 and R14 are F, or wherein both of R11 and R12 or both of R13 and R14 are methyl.

[00110] Further to any embodiment above wherein the compound has the structure of Formula (II), the compound can have a structure according to any of (Ila)-(IIe), wherein V, W, X, Y, and Z can independently represent any of R7, R8, R9, R10, R11, R12, R13, or R14, and wherein at 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 (Ilf) Formula (Ilf), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20f is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, and -O-(C3-C6 cycloalkyl), wherein C1-C6 alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen; R2if, R22f, and R23f are each independently selected from H and halogen; and R24ra, R24fb, R25fa, R25fb, R26ia, and R26fb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Cg alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. [ 00112 ] In an embodiment, one or more of R24fa, R24fb, R25fa, R2jfb, R26fa, and R26fb is independently selected from halogen, -OH, optionally substituted Ci-Ce alkyl, and optionally substituted Ci-Ce alkoxy. In another embodiment, each of R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb isH.

[00113] In an embodiment, R2of is H. In another embodiment, R2of is not H. In an embodiment, R2of is halogen. In one embodiment, R2of is Cl. In another embodiment, R2of is unsubstituted Ci-Ce alkoxy. In one embodiment, R20f is I . In another embodiment, R20f is Ci-Cg alkoxy substituted with one or more fluorine atoms. In one embodiment, R20f is F . In another embodiment, R2ig is Ci-Cg alkyl substituted with one or more -OH. In VoH one embodiment, R20fis ।     . In another embodiment, R20f is C3-C6 cycloalkyl. In one X / CF3 embodiment, R20f is unsubstituted C3 cycloalkyl. In one embodiment, R20f is . [00114 ] In an embodiment, each of R2H, R22f, and R23f is H. In an embodiment, R2Uand R23f are each independently halogen and R22f is H. In one embodiment, R2if and R23f are each F and R22f is H. In an embodiment, R2if and R23f are each H and R22f is halogen. In one embodiment, R2if and R23f are each H and R22f is F. [ 00115 ] In an embodiment, each of R24fa, R24fb, R25fa, R25&, R26fa, and R26ft is H. In an embodiment, each of R25fa, R25fb, R26fa, and R26fbis H and R24fa and / or R24fb is halogen. In one embodiment, each of R24fb, R25fa, R25fb, R26fa, and R26fb is H and R24fa is F. In one embodiment, each of R25fa, R25fb, R26fa, and R26fb is H and each of R24fa and R24fb is F. In an embodiment, R25fa, R25fb, R26fa, and R26& are each H andR24fa and / or R24fb is Ci-Cg alkyl. In one embodiment, each of R25fa, R25ft, R26fa, and R26fbis H and each of R24fa and R24fb is -CH3. In one embodiment, each of R24fb, R25fa, R25fb, R26fa, and R26ft> is H and R24fa is -CH3.

[00116] In an embodiment, the compound of Formula (Ilf) has one or more stereocenters. In one embodiment, the compouind of Formula (Ilf) comprises a stereocenter where the moiety K24fa xV / x T NH p^R26fb             ...                      . R26fa connects to the remaining portion of Formula (Ilf). In one embodiment, the compound of Formula (Ilf) comprises a stereocenter at one or more of R24fa, R24fb, R25fa, R25fb, R26fa, and / or R26fb. In one embodiment, the compound of Formula (Ilf) comprises a stereocenter on R2of. [ 00117 ] In an embodiment, the compound of Formula (II) is a compound of Formula (Ilg) formula (Ilg) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R2og is selected from H and Ci-Cs alkoxy; R2ig is selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, -O-(C6-Ci2 aryl), C3-C9 heterocyclyl, and -NR28gaR28gb, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen, and C3-C9 heterocycyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, Cs-Cg-heterocyclyl, -OH, and halogen; R22g, R23g, and R24g are each independently selected from H and halogen; R25ga, R25gb, R26ga, R26gb, R27ga, and R27gb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms; and R28ga and R28gbare each independently selected from H, Ci-Ce alkyl, and C3-C6 cycloalkyl. [ 00118 ] In an embodiment, one or more of R2sga, R25gb, R26ga, R26gb, R27ga, and R27gb is independently selected from halogen, -OH, optionally substituted Ci-Ce alkyl, and optionally substituted Ci-Ce alkoxy. In another embodiment, each of R25ga, R2sgb, R26ga, R26gb, R27ga, and R27gb is H.

[00119] In an embodiment, R2og is H. In an embodiment, R2og is unsubstituted Ci-Ce alkoxy. In one embodiment, R2og is selected from -OCH3, -OCH2CH3, and । . [00120 ] In an embodiment, R2ig is halogen. In one embodiment, R2ig is Cl. In an embodiment, R2ig is unsubstituted Ci-Ce alkyl. In one embodiment, R2ig is t-butyl. In another embodiment, R2ig is Ci-Ce alkyl substituted with one or more F and / or -OH. In one V ?Vcr’ embodiment, R2ig is selected from-CF3, I 0H , F , and I 0H . In another embodiment, R2ig is unsubstituted Ci-Ce alkoxy. In one embodiment, R2ig is -OCH3. In another embodiment, R2ig is Ci-Ce alkoxy substituted with one or more halogen atoms. In another embodiment, R2ig is - 0-(Ce-Ci2 aryl). In one embodiment, R2ig is -O-phenyl. In another embodiment, R2ig is unsubstituted C3-C6 cycloalkyl. In one embodiment, R2igis unsubstituted C3 cycloalkyl. In one embodiment, R2ig is C3 cycloalkyl substituted with one or more fluorine atoms. In one X^CF3 embodiment, R2ig is . In another embodiment, R2ig is unsubstituted C3-C9 heterocyclyl. In one embodiment, R2igis selected from morpholinyl, azetidinyl, piperdinyl, isoxazolyl, pyrazolyl, wherein G is N or CH, and wherein c is 1 or 2. In another embodiment, R2igis C3-C9 heterocycyl substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, Cs-Cy-heterocyclyl, -OH, and halogen. In one embodiment, R2ig V’y-I N-. / * R is 299          wherein R29g is selected from H, Ci-Ce alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl and C3-C6 cycloalkyl are each optionally substituted with one 1 / )—? R or more halogen and / or-OH. In one embodiment, R2ig is 299         wherein R29g is H. In R one embodiment, R2ig is 299          wherein R29g is unsubstituted Ci-Ce alkyl. In one N^\ . R embodiment, R2ig is 299         wherein R29g is selected from -CH3 and isopropyl. In one N^=\ s 1 / >—? R embodiment, R2ig is 299          wherein R29g is Ci-Ce alkyl substituted with one or more - OH and / or F. In one embodiment, R2ig is wherein R29g is selected from R ' In another embodiment, R2ig is 299 wherein R29g is selected from unsubstituted C3 cycloalkyl, azetidinyl, and tetrahydropyranyl. In another embodiment, R2ig is , wherein a is 1, 2, or 3, G is N or CH, and each X is independently halogen. In one embodiment, R2ig is selected from (R220g)b      , w R2ig is c N , wherein b is 0, 1, 2, 3, 4, 5, or 6, c is 1 or 2, and each R22og is independently Ci-Ce alkyl. In one embodiment, R2ig is         N . In another embodiment, R2ig is isoxazolyl substituted with Ci-Ce alkyl. In one embodiment, R2ig is isoxazolyl monosubstituted with -CH3. In another embodiment, R2igis -NR28gaR28gb wherein R28ga is H and R28gbis selected from -CH3, cyclobutyl, and cyclohexyl. In another embodiment, R2ig is -NR28gaR28gb wherein R28ga and R28gb are each independently Ci-Ce alkyl. In one embodiment, R2ig is -NR28gaR28gb wherein R28ga and R28gb are each -CH3.

[00121] In an embodiment, R22g, R23g, and R24g are each H. In an embodiment, R22g and R24g are each independently halogen and R23g is H. In one embodiment, R22g and R24g are each F and R23g is H. In an embodiment, R22g and R24g are each H and R23g is halogen. In one embodiment, R22g and R24g are each H and R23g is F. [00122 ] In an embodiment, each of R25ga, R25gb, R26ga, R26gb, R27ga, and R27gb is H. In an embodiment, 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 R27gb is H and R25ga is 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 andR25ga and / or R25gb is Ci-Ce alkyl. In one embodiment, R26ga, R26gb, R27ga, and R27gb are each H and R25ga and R25gb are each -CH3. In one embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gbis H and R25ga is -CH3. In another embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gbis H and R25ga is selected from substituted Ci-Ce alkyl and -OH. In one embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gb is H and R25ga is -OH. In one embodiment, each of R2sgb, R26ga, R26gb, R27ga, and R27gb is H and R2sga is selected from -CF3 ' / yF and F . in another embodiment, each of R2sgb, R26ga, R26gb, R27ga, and R27gb is H and R25gais unsubstituted Ci-Ce alkoxy. In one embodiment, each of R25gb, R26ga, R26gb, R27ga, and R27gb is H and R25ga is -OCH3. [ 00123 ] In an embodiment, each of R25ga, R25gb, R26gb, R27ga, and R27gb is H and R26ga is unsubstituted Ci-Ce alkyl. In one embodiment, each of R25ga, R25gb, R26gb, R27ga, and R27gb is H and R26ga is -CH3. [ 00124 ] In an embodiment, each of R25ga, R25gb, R26ga, and R26gb is H and each of R27ga and R27gb is unsubstituted Ci-Ce alkyl. In one embodiment, each of R25ga, R25gb, R26ga, and R26gb is H and each of R27ga and R27gb is -CH3. [ 00125 ] In an embodiment, the compound of Formula (Ilg) comprises one or more stereocenters. In one embodiment, the compound of Formula (Ilg) comprises a stereocenter on R2ig. In one embodiment, the compound of Formula (Ilg) comprises a stereocenter where the RR2§FjyR2'* moiety r R27gb 27ga connects to the remaining portion of Formula (Ilg). In one embodiment, the compound of Formula (Ilg) 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 (Ilh) Formula (Ilh), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20h is selected from H and Ci-Ce alkoxy; R2111 is selected from Ci-Ce alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C3-C6 cycloalkyl, and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from Ci-Ce alkyl, -OH, and halogen; R22ha, R22hb, R23ha, and R23hb are each independently selected from H and Ci-Ce alkyl, wherein Ci-Ce alkyl is optionally substituted with one or more halogen atoms; and R24h, R2511, and R26h are each independently selected from H and halogen. [ 00127 ] In an embodiment, R20h is H. [ 00128 ] In an embodiment, R2ih is C3-C9 heterocyclyl substituted with one or more substituents selected from Ci-Ce alkyl, -OH, and halogen. In one embodiment, R2ihis pyrazolyl ' / yF substituted with Ci-Ce alkyl and F. In one embodiment, R2111 is pyrazolyl substituted with F . In one embodiment, R2ih is F

[00129] In an embodiment, one or more of R22ha, R22hb, R23ha, and R23hb is independently optionally substituted Ci-Ce alkyl. In another embodiment, each of R22ha, R22hb, R23ha, and R23hb is H. In an embodiment, each of R22ha, R22hb are H and R23ha and / or R23hb is C1-C6 alkyl. In one embodiment, each of R22ha, R22hb, and R23ha is H and R23hb is -CH3. In another embodiment, each of R22ha and R22hb is H and each of R23ha and R23hbis -CH3. [ 00130 ] In an embodiment, R24h, R25h, and R26h are each H. In an embodiment, R2411 and R26h are each independently halogen and R25h is H. In one embodiment, R24h and R26h are 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. [00131 ] In an embodiment, the compound of Formula (Ilh) comprises one or more stereocenters. In one embodiment, the compound of Formula (Ilh) comprises a stereocenter on R2ih. In one embodiment, the compound of Formula (Ilh) comprises a stereocenter where the moiety          R23ha connects to the remaining portion of Formula (Ilh). In one embodiment, one or more of R22ha, R22hb, R23ha, and / or R23hb comprises a stereocenter. [00132 ] In an embodiment, the compound of Formula (Ilh) is H [00133 ] In an embodiment, the compound of Formula (II) is a compound of Formula (Ili) Formula (Ili), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20i is selected from H, and Ci-Ce alkoxy; R2ii is selected from Ci-Ce alkyl, Ci-Ce alkoxy, Ca-Ce cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, Ca-Ce cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen, and C3-C9 heterocycyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, Ca-Ce-cycloalkyl, C3-C9-heterocyclyl, -OH, -C=O, and halogen; R22i, R23i, and R24i are each independently selected from H and halogen; and R25ia, R25ib, R26ia, R26ib, R27ia, R27ib, R28ia, R28ib, R29ia, and R29ib are each independently selected from H, halogen, -OH, or Ci-Ce alkyl. [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 Ci-Ce alkyl. In another embodiment, each of R25ia, R25ib, R26ia, R26ib, R27ia, R27ib, R28ia, R28*, R29ia, and R29ib is H. [00135 ] In an embodiment, R20i is H. In another embodiment, R20i is unsubstituted Ci-Cs alkoxy. In one embodiment, R20i is -OCH3. [ 00136 ] In an embodiment, R2ii is Ci-Ce alkyl substituted with one or more F and / or -OH. In one embodiment, R2ii is selected from I 0H, F , and I OH . In another embodiment, R2ii is unsubstituted C3-C6 cycloalkyl. In one embodiment, R2ii is unsubstituted C3 cycloalkyl. In one embodiment, R2H is C3 cycloalkyl substituted with Ci-Ce alkyl. In one embodiment, R2ii is . In one embodiment, R2ii is C3 cycloalkyl substituted with one or X / CF3 more Ci-Ce alkyl and one or more fluorine atoms. In one embodiment, R2ii is         . In another embodiment, R2H is unsubstituted C3-C9 heterocyclyl. In one embodiment, R2H is pyrazolyl. In one embodiment, R2ii is J N wherein J is N or CH. In another embodiment, R2ii is C3-C9 heterocycyl substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, C3-C9-heterocyclyl, -OH, -C=O, and halogen. In one embodiment, R2H is pyrrolidinyl monosubstituted with -C=O. In one embodiment, R2U is T N-l                             N^\ <> 0 In one embodiment, R2H is ^2201          wherein R220i is selected from H, Ci-Ce alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogen and / or -OH. In one embodiment, R2ii is N^\ <,                                          N^\ s R220i          wherein R220i is H. In one embodiment, R2H is R220i          wherein R220i is unsubstituted Ci-Ce alkyl. In one embodiment, R2ii is R220i wherein R220i is -CH3. In s 1 / )—? R one embodiment, R2ii is 220i          wherein R220i is Ci-Ce alkyl substituted with one or N^\ <, 1 / )—? more-OH and / or F. In one embodiment, R2H is ^220i          wherein R220i is selected from In another embodiment, R2U is R220i wherein R220i is unsubstituted C3 cycloalkyl. [ 00137 ] In an embodiment, each of R22i, R23i, and R24i is H. In an embodiment, R22i and R24i are each independently halogen and R23i is H. In one embodiment, R22i and R24i are each F and R231 is H. In an embodiment, R22i and R24i are each H and R23i is halogen. In one embodiment, R22i and R24i are each H and R23i is F.

[00138] each of R25ia, R25ib, R26ia, R26ib, R27ia, R27ib, R28ia, and R28ib is 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 R28ib is H and each of R25ia and R25ib is F. In one embodiment, each of R25ia, R26ia, R26ib, R27ia, R27ib, R28ia, and R28ib is H and R25ib is F.

[00139] each 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 R29ib is H and each of R28ia and R28ib is F. In one embodiment, each of R25ia, R25ib, R27ia, R27ib, R2?ia, 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 of R25ia, R25ib, R27ia, R28ia, R28ib, R29ia, and R29ib is H and R27ib is F. In one embodiment, each of R25ia, R25ib, R27ia, R28ia, R28ib, R29ia, and R29ib is H and each of R27ia and R27ib is F. [00140 ] In an embodiment, the compound of Formula (Ili) comprises one or more stereocenters. In one embodiment, the compound of Formula (Ili) comprises a stereocenter on R20i. In one embodiment, the compound of Formula (Ili) comprises a stereocenter on R2ii. In ( E J one embodiment, the compound of Formula (Ili) comprises a stereocenter where the moiety connects to the remaining portion of Formula (Ili). In one embodiment, one or more of R25ia, R25ib, R26ia, R26ib, R27ia, R27ib, R28ia, R28ib, R29ia, and / or R29ib comprises a stereocenter.

[00141] In an embodiment, the compound of Formula (II) is a compound of Formula (Ilj) R2ij N ZA H R23j r . 24j Formula (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20j is selected from H, and Ci-Ce alkoxy; R2ij is selected from H, Ci-Ce alkyl, Ci-Ce alkoxy, and Ca-Ce cycloalkyl, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and Ca-Cs cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen; and R22j, R23j, and R24j are each independently selected from H and halogen. [00142 ] In an embodiment, R20j is H. In another embodiment, R20j is optionally substituted Ci-Ce alkoxy. In one embodiment, R20j is unsubstituted Ci-Ce alkoxy. In one embodiment, R20j is -OCH3.

[00143] In an embodiment, R2ij is optionally substituted C3-C6 cycloalkyl. In one embodiment, R2ij is optionally substituted C3 cycloalkyl. In one embodiment, R2ij is unsubstituted C3 cycloalkyl. [00144 ] In an embodiment, R22j, R23j, and R24j are each H. In an embodiment, R22j and R24j are 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, R22j and R24j are each H and R23j is F. ( G )

[00145] In an embodiment, is [0014 6] In an embodiment, the compound of Formula (Ilj) comprises one or more stereocenters. In one embodiment, the compound of Formula (Ilj) comprises a stereocenter on R2ij. In one embodiment, the compound of Formula (Ilj) comprises a stereocenter where the moiety connects to the remaining portion of Formula (Ilj). [00147 ] In an embodiment, the compound of Formula (la) is a compound of Formula (Ilk) Formula (Ilk), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20k is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, and -O-(C3-C6 cycloalkyl), wherein Ci-Ce alkyl and Ci-Ce alkoxy 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 Ci-Ce alkyl and halogen; R2ik, R22k, and R23k are each independently selected from H, halogen, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl is optionally substituted with one or more halogen; and R24ka, R24kb, R25ka, R25kb, R26ka, and R26kb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Cg alkyl and Ci-Ce 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 is independently selected from halogen, -OH, optionally substituted Ci-Ce alkyl, and optionally substituted Ci-Ce alkoxy. [0014 9] In one embodiment, at least one of R2ik, R22k, and R23kis Ci-Ce alkyl. In another embodiment, R2ik, R22k, and R23k are each H. In one embodiment, R22k is H, R2ik and R23k are each independently F or -CH3. In another embodiment, R2ik and R22k are each H, R23k is F or -CH3. In another embodiment, R22kand R23k are each H, R2ik is F or -CH3. In another embodiment, R2ik and R23k are each H, R22k is F or -CH3. [ 00150 ]    In one embodiment, R20k is selected from -OCH3 and F . [ 00151 ]    In one embodiment, R24ka, R24kb, R25ka, R25kb, R26ka, and R26kb are each H. In another embodiment, R25ka, R25kb, R26ka, and R26kb are each H and R24ka and / or R24kb is F. [00152 ] In one embodiment, the compound of Formula (Ilk) is selected from: [00153 ]    In another embodiment, the compound of Formula (la) is a compound of Formula (Ilm) Formula (Ilm), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20m is selected from Ci-Ce alkyl and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R2im is selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C5-C12 spirofused cycloalkyl, -O-(C6-Ci2 aryl), C3-C9 heterocyclyl, and -NR28maR28mb, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen, wherein Ci-Ce alkyl is optionally substituted with one or more -OH, and wherein C3-C9 heterocycyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R22111, R23m, and R24m are each independently selected from H, halogen, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl is optionally substituted with one or more halogen; R25ma, R25mb, R26ma, R26mb, R27ma, and R27mb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms; and R28ma and R28mb are each independently selected from H, Ci-Ce alkyl, and C3-C6 cycloalkyl. [00154 ] In one embodiment, one or more of R25ma, R25mb, R26ma, R26mb, R27ma, and R27mb is independently selected from halogen, -OH, optionally substituted Ci-Ce alkyl, and optionally substituted Ci-Ce alkoxy. In another embodiment, R25ma, R25mb, R26ma, R26mb, R27ma, and R27mb are each H. In another embodiment, R26ma, R26mb, R27ma, and R27mb are each H and R25ma and / or R25mb IS F. [00155 ] In one embodiment, at least one of R22m, R23m, and R24m is Ci-Ce alkyl. In another embodiment, at least one of R22m, R23m, and R24m is Ci-Ce alkoxy. In another embodiment, R22111, R23m, and R24m are each H. In another embodiment, R23m is H, R22m and R24m are 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, R22m and R24m are each H, and R23m is F, -CH3, or -OCH3. [ 00156 ] In one embodiment, R20m is selected from -OCH3 and I . [00157 ] In one embodiment, R2im is selected from unsubstituted C3-C6 cycloalkyl, [ 00158 ] In one embodiment, the compound of Formula (Ilm) is selected from: [ 00159 ] In one embodiment, the compound of Formula (la) is a compound of Formula (Iln) Formula (Iln), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20nis selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, and -O-(C3-C6 cycloalkyl), wherein Ci-Ce alkyl and Ci-Cs alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl and -0-(C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen; R2in, R22n, and R23n are each independently selected from H, halogen, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl is optionally substituted with one or more halogen; and R25na, R25nb, R261M, R26nb, R27na, R27nb, R28na, R28nb, R29na, and R29nb are each independently selected from H, halogen, -OH, or Ci-Ce alkyl, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. [ 00160 ] In One embodiment, One Or more Of R25na, R25nb, R26na, R26nb, R27na, R27nb, R28na, R28nb, R29na, and R29nb is independently selected from halogen, -OH, optionally substituted Ci-Ce alkyl, and optionally substituted Ci-Ce alkoxy. [ 00161 ]    In one embodiment, at least one of R2111, R2211, and R23nis Ci-Ce alkyl. [ 00162 ]    In one embodiment, R2011 is selected from -OCH3 and F [ 00163 ]    In one embodiment, R2in, R22n, and R2311 are each H. In another embodiment, R2211 is H, R2111 and R2311 are each independently F or -CH3. In another embodiment, R2111 and R2211 are each H, R2311 is F or -CH3. In another embodiment, R22n and R23n are each H, R2in is F or -CH3. In another embodiment, R2in and R23n are each H, R22n is F or -CH3.

[00164] In one embodiment, each of R25na, R25nb, R27na, R27nb, R28na, R28nb, R29na, and R29nb IS 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 (Iln) is selected from: [ 00166 ] In another embodiment, the compound of Formula (la) is a compound of Formula (Up) Formula (lip), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20p is selected from Ci-Ce alkyl and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R2iPis selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C5-C12 spirofused cycloalkyl, -O-(C6-Ci2 aryl), C3-C9 heterocyclyl, and -NR220paR220pb, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen, and wherein C3-C9 heterocycyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R22P, R23P, and R24P are each independently selected from H, halogen, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl is optionally substituted with one or more halogen; R25Pa, R25pb, R26Pa, R26Pb, R27Pa, R27Pb, R28Pa, R28Pb, R29Pa, and R29Pb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms; and R22oPa and R22oPb are each independently selected from H, Ci-Ce alkyl, and C3-C6 cycloalkyl. [ 00167 ] In one embodiment, one or more of R25Pa, R25Pb, R26Pa, R26Pb, R27Pa, R27Pb, R28Pa, R28Pb, R29Pa, and R29Pb is independently selected from halogen, -OH, optionally substituted Ci-Ce alkyl, and optionally substituted Ci-Ce alkoxy.

[00168] In one embodiment, at least one of R22P, R23P, and R24Pis Ci-Ce alkyl. In another embodiment, R22P, R23P, and R24P> are each H. In one embodiment, R23P is H, R22P and R24P are each independently F, -CH3, or -OCH3. In another embodiment, R22P and R23P are each H, R24P is F, -CH3, or -OCH3. In another embodiment, R23P and R24P are each H, R22P is F, -CH3, or -OCH3. In another embodiment, R22P and R24P are each H, R23P is F, -CH3, or -OCH3.

[00169] In one embodiment, R2oP is selected from -OCH3 and In one embodiment, R2iPis selected unsubstituted C3-C6 cycloalkyl,

[00170]

[00171] R27Pb, R28Pa, R28Pb, R29Pa, and R29Pb is H. In another embodiment, each Of R25Pa, R25Pb, R27Pa, , each of R25pa, R25Pb, R27Pa, R27pb, R28Pa, R29pa, and R29Pb is H and R28Pb is F. [00172 ] In one embodiment, the compound of Formula (lip) is selected from: HsCO^^n       ^Oy^N      H3C0y^_N F H F Q F < HN^                   HN-^Z                   HN~~_ A%. F A% F F Z\         F Z\          F AY HN-^Z               HN-A                HN-A , , H3COX^\^N        H3CO\^^N        H3C0^^\_N , 0¾.., A-4. F              F ZA          F AZ hn-A             hn-A             hn-A , ,, Yd Z-Z Z-Z dZNH        VANH        V^Z-NH F Z^\            F                 f / ¼ hn-A             hn-A             hn-^Z ■ , , H3C0x^\^-N        H3CCL^\m "ZZ Z'Z Cj^A-NH f         'v==A'NH F / Z          F HN~~Z , HsCOx^^-N        HsCO^^^n       HsCO^^^n Z-Z Z-Z Z-Z F         "z-^A-NH F AY           F ZZ,           F Z~ HN-Z                  HN-^Z                HN-~.

[00173] In one embodiment, the compound of Formula (la) is a compound of Formula (nq) R20q R21 q N               / X R _         V E ) R22q~~-f   \\ V_Z~'N H R 23q          Formula (Ilq), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected from and R2oq is Ci-Ce alkoxy optionally substituted with one or more substituents selected from -OH and halogen; R2iq is C3-C6 cycloalkyl optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen; and R22q and R23q are each independently halogen.

[00174] In one embodiment, is [ 00175 ] In one embodiment, R2oq is unsubstituted Ci-Ce alkoxy. In one embodiment, R2oq is -OCH3. [ 00176 ] In one embodiment, R2iq is unsubstituted C3-C6 cycloalkyl. In one embodiment, R2iq is unsubstituted C3 cycloalkyl.

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

[00178] In yet another embodiment, the compound of Formula (la) is a compound of Formula (Ilr) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20r is Ci-Ce alkoxy optionally substituted with one or more substituents selected from -OH and halogen; R2ir and R23r are each independently halogen; R22ris H; and R24ra, R24rb, R25ra, R25rb, R26ra, and R26rb are each independently selected from H and halogen, wherein one or more of R24ra, R24rb, R25ra, R25rb, R26ra, and R26rb is halogen.

[00179] In one embodiment, R20r is Ci-Ce alkoxy substituted with two halogen atoms. In one embodiment, R20r is Ci-Ce alkoxy substituted with two fluorine atoms. In one embodiment, R20r is C2 alkoxy substituted with two fluorine atoms. In one embodiment, R20r is         F [ 00180 ] In one embodiment, R2ir and R23r are each halogen. In one embodiment, R2ir and R23r are each F. [ 00181 ] In one embodiment, R25ra, R25rb, R26ra, R24ra, and R26rb are each H and R24rb is halogen. In one embodiment, R25ra, R25rb, R26ra, R24ra, and R26rb are each H and R24rb is F. [00182 ] In one embodiment, the compound of Formula (Hr) is: salt thereof. [00183 ] In yet another embodiment, the compound of Formula (la) is a compound of Formula (Ils) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20S is selected from Ci-Ce alkyl, Ci-Ce alkoxy, and -OH, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R2isis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl are each 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 Ci-Ce alkyl and halogen; R22S, R23S, and R24S are each independently selected from H, CN, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(C6-Ci2 aryl), wherein Ci-Ce alkyl 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 R27sb is halogen. [00184 ] In one embodiment, R20S is unsubstituted Ci-Ce alkoxy. In one embodiment, R20S is -OCH3. [00185 ] In one embodiment, when R20sis -OCH3 and R21S is unsubstituted C3 cycloalkyl or OH I , (i) one or more of R22S, R23S, and R24S is CN, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(C6-Ci2 aryl), (ii) R22S is halogen, R23S is H, and R24s is H, or (iii) R22S is H, R23S is H, and R24S is halogen. In one embodiment, when R20S is -OCH3 and R21S is A<CF’ OH I , at least one of R22S, R23s, and R24S is not H. In one embodiment, when R20S is -OCH3, R2is is not In one embodiment, R21S is selected from unsubstituted C3-C6 cycloalkyl,

[00186] . In one embodiment, R21S is C1-C6 alkyl substituted with one -OH. In one embodiment, R21S is C3 alkyl substituted with one -OH. In one OH embodiment, R21S is I . In one embodiment, R21S is Ci-Ce alkyl substituted with one -OH and three halogen atoms. In one embodiment, R21S is C3 alkyl substituted with one -OH and OH three fluorine atoms. In one embodiment, R21S is I In one embodiment, R21S is C3-C6 cycloalkyl substituted with one or more Ci-Ce alkyl. In one embodiment, R21S is C4 cycloalkyl substituted with one or more Ci-Ce 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, R23S is 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 R24S are each H. In another embodiment, R24S is halogen, R22S and R23S are each H. In one embodiment, R24s is F, R22S and R23S are each H. [ 00188 ] In one embodiment, at least one of R22S, R23S, and R24s is selected from CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(Ce-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more halogen. In on embodiment, R23S is H, R22S and R24s are 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, R23S and R24s are each H. In another embodiment, R24s is selected from -CH3, -OCH3, CN, C3 cycloalkyl, phenyl, and -O-phenyl, R22S and R23S are each H.

[00189] In one embodiment, R25sa, R26sa, R26sb, R27sa, and R27sb are each H and R25sb is halogen. In one embodiment, R25sa, R26sa, R26sb, R27sa, and R27sb are each H and R25sb is F. [ 00190 ] In one embodiment, the compound of Formula (Ils) is selected from: and a pharmaceutically acceptable salt of any one thereof. [ 00191 ] In one embodiment, the compound of Formula (Ils) is not one of the following compounds: [ 00192 ]    In yet another aspect, the compound of Formula (la) is a compound of Formula (lit) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R2ot is Ci-Ce alkoxy optionally substituted with one or more substituents selected from -OH and halogen; R2it and R23t are each independently halogen; R22t is H; and R24ta, R24tb, R25ta, R25tb, R26ta, R26tb, R27ta, R27tb, R28ta, R28tb, R29ta, and R29tb are each independently selected from H and halogen. R25tax ^25tb ' / y^NH 028^^5^^^^ ^29ta ^28ta           R29tb _          _                                            IS         R27tb R27ta [ 00194 ] In one embodiment, R2ot is Ci-Ce alkoxy substituted with two halogen atoms. In one embodiment, R2ot is Ci-Ce alkoxy substituted with two fluorine atoms. In one embodiment, R2ot is C2 alkoxy substituted with two fluorine atoms. In one embodiment, R2ot is         F

[00195] In one embodiment, R2H and R23t are each F. R25tax^25tb ' / y^NH ©28tb^>\^Jy ^29ta R28ta           R2gtb .         .                             ,           is R27tb R27ta , each of R25ta, R25tb, R27ta, R25nax^25nb ^y^NH R29na R28na          R29nb _____ ______ _____ ______ ,           is          27nb K27na each of R25ta, R25tb, R27ta, R27tb, R28ta, R28tb, and R29ta is H and R29tbis halogen. In one R29ta is H and R29tb is F. each of R25ta, R25tb, R27ta, R27tb, R28ta, R28tb, and [ 00197 ] In on embodiment, the the compound of Formula (lit) is selected from: [ 00198 ] In yet another aspect, the compound of Formula (la) 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 Ci-Ce alkyl, Ci-Ce alkoxy, and -OH, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R2iuis selected from Ci-Ce 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 with one or more substituents selected from Ci-Ce alkyl and halogen; R22U, R23u, and R24U are each independently selected from H, CN, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -0-(Ce-Ci2 aryl), wherein Ci-Ce 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, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. RjSua.^Sub 'Ar^NH R28ua          R29ub .          _                                            iS R27ub R27ua . [ 00200] In one embodiment, when R20Uis -OCH3 and R21U is unsubstituted C3 cycloalkyl OH or I , (i) one or more of R22U, R23U, and R24U is CN, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-Ce cycloalkyl, C6-C12 aryl, and -O-(Ce-Ci2 aryl), (ii) R22uis halogen, R23U is H, and R24u is H, or (iii) R2211 is H, R23U is H, and R24U is halogen. In one embodiment, when R20U is -OCH3 and R21U CF 6<c 3 \\ is I OH or °   , at least one of R22U, R23U, and R24U is not H. In one embodiment, when R20S is -OCH3, R21S is not F . [ 00201 ] In one embodiment, R20U is unsubstituted Ci-Ce alkoxy. In one embodiment, R20U is -OCH3. In one embodiment, R21U is selected from unsubstituted C3-C6 cycloalkyl,

[00202] In one embodiment, R2iuis Ci-Ce alkyl substituted with one -OH. In one embodiment, R2iuis C3 alkyl substituted with one -OH. In one V embodiment, R21U is I . In one embodiment, R21U is Ci-Ce alkyl substituted with one -OH and three halogen atoms. In one embodiment, R21U is C3 alkyl substituted with one -OH and three fluorine atoms. In one embodiment, R21U is I 0H jn one embodiment, R21U is C3-C6 cycloalkyl substituted with one or more Ci-Ce alkyl. In one embodiment, R21U is C4 cycloalkyl substituted with one or more Ci-Ce alkyl. In one embodiment, R21U is C4 cycloalkyl substituted with two-CH3. In one embodiment, R21U is /      . [ 00203 ] In one embodiment, R22U, R23U, and R24U are each H. In another embodiment, R23U is H, R22U and R24U are each halogen. In one embodiment, R23U is H, R22U and R24U are each F. In another embodiment, R2211 is halogen, R2311 and R2411 are each H. In one embodiment, R2211 is 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 R2211, R2311, and R24uis selected from CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C6-C12 aryl, and -O-(Ce-Ci2 aryl), wherein Ci-Ce 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, C3 cycloalkyl, 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, C3 cycloalkyl, phenyl, and -O-phenyl, R22U and R23U are each H.

[00205] In one embodiment, R27ub, R28ua, R28ub, R29ua, and R29ub is H. each Of R25ua, R25ub, R27ua, In another embodiment, each of R25ua, R25ub, R27ua, R27ub, R28ua, R29ua, and R29ub is H and R28ub is halogen. In one embodiment, is , 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: H3CO^^n        H3COx^^N       H3COx^^N . -A f M       f O       f c HN^                 HN-^Z                HN-, H3CO^m        HaCO^^^N p                                , F \ A F                          F \ X HN~~Z                  HN-^                   HN-~-Z of any one thereof. [ 00207 ] In one embodiment, the compound of Formula (IIu) is not one of the following compounds: , 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: OH R.20v is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH halogen, and Ci-Ce alkoxy; R2ivis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl, -OH, and halogen; R22V, R23V, and R24V are each independently selected from H, CN, amido, halogen, -S(O)2-(C1-C7 alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -0-(Ce-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen; and R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy 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 R29vb is H. [ 00210 ] In one embodiment, one of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb is selected from halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy 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, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce 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 , O /      11 OH i—S   —L    1 s

[00213] In one embodiment, R21V is ’ \— / , OH orO [ 00214 ]    In one embodiment, one or more of R22V, R23V, and R24v 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 O-1 . [00215 ] In one embodiment, when R20vis -OCH3 and R.2iv is unsubstituted C3 cycloalkyl (i) one or more of R22V, R23V, and R24V is selected from amido, unsubstituted oxetane, — S(0)2-(Ci-C7 alkyl), Ci-Ce alkyl, or C2-C7 alkynyl, wherein Ci-Ce alkyl is substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen, (ii) one or more of R22V, R23V, and R24vis CN and one or more of R22V, R23V, and R24vis halogen, (iii) R22V and R24V are each independently halogen, R23v is H, and one or two of R25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vbis selected from halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms, provided the compound of Formula (IIv) is not                F           , (iv) R22V is Cl, R23V is H, and R24V is H, or (v) R22V is H, R23V is H, and R24V is Cl, or (v) the compound is F

[00216] In one embodiment, 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. OH

[00217] In one embodiment, when R20V is -OCH3 and R21V is   I , 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 *<CF’ I 0H , one or more of R22V, R23v, and R24vis CN.

[00219] In one embodiment, R20V is unsubstituted Ci-Cg alkoxy. In one embodiment, R20V is Ci-Ce alkoxy substituted with one or more deuterium atoms. In one embodiment, R20vis Ci-Ce alkoxy substituted with -OH. In one embodiment, R20V is Ci-Ce alkoxy substituted with Ci-Ce alkoxy. In one embodiment, R20V is selected from -OCH3, -OCD3, -O(CH2)2OCH3, -O(CH2)2OH, , O /      11 and OH .

[00220] In one embodiment, R21V is unsubstituted C3-C6 cycloalkyl. In one embodiment, R21V is unsubstituted C3 cycloalkyl. In one embodiment, R2ivis C3-C6 cycloalkyl substituted with one or more -OH. In one embodiment, R21V is OH in One embodiment, R21V is Ci-Ce substituted with one or more halogen and / or -OH. In one embodiment, R21V is C3 alkyl substituted with one-OH. In one embodiment, R21V is I . In one embodiment, R21V is C3 NCF’ OH alkyl substituted with one -OH and three halogen atoms. In one embodiment, R21V is I . In one embodiment, R21V is unsubstituted C3-C9 heterocyclyl. In one embodiment, R21V is l-l / S O or    \— / . In one embodiment, R21V is C3-C9 heterocyclyl substituted with one or more Ci-Ce alkyl. In one embodiment, R21V is [00221 ] In one embodiment, R22V is halogen, R23V is H, and R24v is selected from halogen, CN, Ci-Ce alkyl substituted with one or more -OH, and amido. In one embodiment, R22V is F, R23v is H, and R24v is selected from F, CN, -CH2OH, -C(O)NH2, and -C(O)NHCH3. [00222 ] In one embodiment, R22V is halogen, R23V and R24v are each H. In one embodiment, R22V is Cl, R23V and R24V are each H. [ 00223 ] In one embodiment, R22V and R23V are each H and R24v is selected from halogen, Ci-Ce alkyl substituted with one or more -OH, Ci-Ce alkyl substituted with one or more Ci-Ce alkoxy, unsubstituted C2-C7 alkynyl, amido, unsubstituted C3-C9 heterocyclyl, and -S(0)2-(Ci-C? alkyl). 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 .

[00224] In one embodiment, R27vb, R28va, R28vb, R29va, and R29vb IS H.

[00225] In one embodiment, each of R25va, R25vb, R27va, 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] each of R25va, R27va, R27vb, R28va, R28vb, R29va, and R29vb is H and R25vb is unsubstituted Ci-Ce alkyl. In one embodiment, R25vb is -CH3. each of R25va, R27va, R27vb, R28va, R28vb, R29va, and R29vb is H and [00227 ] In one embodiment, IS , each of R25va, R25vb, R27va, R28va, R28vb, R29va, and R29vb is H and R27vb is halogen or Ci-Ce alkyl substituted with one or more halogen. In one embodiment, is , each of R25va, R25vb, R27va, R28va, R28vb, R29va, and R29vb is H and R27vb is F or -CF3. R25vax ^25vb R29va R28va          R29vb .         .                            ,          is R27vb R27va , 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 R27va and R27vb are F. [0022 9 ] In one embodiment, the compound of Formula (IIv) is selected from: ON CN CN F w°2Wi37Se7 '¥rA Cl F                    CN                           CN MeO^^^N       MeO\^^N ^^-0 f Vt Yn f        Oh       Oh and a pharmaceutically acceptable salt of any one thereof [00230 ] In one embodiment, the compound of Formula (IIv) is not: thereof. F           , or a pharmaceutically acceptable salt [00231 ] In one embodiment, the compound of Formula (IIv) is not: thereof. , or a pharmaceutically acceptable salt [00232 ] 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: , O / u ^0'^'0- Rzow is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and OH ; wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and C1-C6 alkoxy; R2iwis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl, -OH, and halogen; R22W, R23W, and R24w are each independently selected from H, CN, amido, halogen, -S(O)2-(Ci-C7 alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen; R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms; and Rsiw is selected from Ci-Ce alkyl, Ci-Ce alkoxy, amido, C3-C6 cycloalkyl, C3-C9 ,   0 /      11 heterocyclyl, -OH, and OH , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy and C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, -OH, and halogen. [00235 ] In one embodiment, each of R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb is H. [ 00236 ] In one embodiment, one of R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb is selected from halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. [00237 ] In one embodiment, Rsiw is amido or Ci-Cealkyl optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy. [00238 ] In one embodiment, R20W is unsubstituted Ci-Ce alkoxy. In one embodiment, R20W is -OCH3. [ 00239 ] In one embodiment, R21Wis unsubstituted C3-C6 cycloalkyl. In one embodiment, R2iwis unsubstituted C3 cycloalkyl. [00240 ] In one embodiment, R22W and R23W are each H and R24w is halogen. In one embodiment, R22W and R23W are each H and R24w is F.

[00241] In one embodiment, R27wb, R28wa, R28wb, R29wa, and R29wb is H.

[00242] In one embodiment, is each of R25wa, R25wb, R27wa, each of R25wa, R25wb, R27wa, R27wb, R28wa, R29wa, and R29wb is H and R28wb is halogen. In one embodiment, R25waK R25wb R28wb           R29wa R28wa          R29wb 27wb 27wa ? each of R25wa, R25wb, R27wa, R27wb, R28wa, R29wa, and R29wb is H and R28wb is F.

[00243] In one embodiment, Rjiw is amido. In one embodiment, Rsiw is -C(O)NH2. In one embodiment, Rsiw is unsubstituted Ci-Ce alkyl. In one embodiment, Rsiw is -CH3. In one embodiment, Rsiw is Ci-Ce alkyl substituted with one or more -OH. In one embodiment, Rsiw is V -CH2OH or I 0H . [00244 ] In one embodiment, the compound of Formula (IIw) is selected from: pharmaceutically acceptable salt of any one thereof. [ 00245 ] In one embodiment, the compound of Formula (Ilr), (Ils), (lit), (IIu), (IIv), or (IIw) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is an inhibitor of at least one of IRAKI, IRAK4, and FLT3. In one embodiment, the compound of Formula (Ilr), (Ils), (lit), (IIu), (IIv), or (IIw), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is an inhibitor of IRAKI and IRAK4. In one embodiment, the compound of Formula (Ilr), (Ils), (lit), (IIu), (IIv), or (IIw) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is an inhibitor of IRAKI, IRAK4, and FLT3. [0024 6 ] In another aspect, the present disclosure provides a composition comprising a compound of any one of Formula (Ilr), (Ils), (lit), (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. ..-'A q(W6rc)'

[00247] In some embodiments, R6 is            '           , giving a structure of Formula (III), as follows: 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 (la).

[00248] In some embodiments according to Formula (III), q, r, s, t, u, v, w, and x are independently 0, 1, or 2. In some embodiments, q is 0 or 1, r is 0 or 1, s is 0 or 1, t is 0 or 1, u is 0 or 1, v is 0 or 1, w is 0 or 1, and x is 0 or 1. [0024 9 ] 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 or more of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are H. In some embodiments, all of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are H. [ 00250 ] Further to any embodiment above wherein the compound has the structure of Formula (III), the compound can have a structure according to any of (Illa)-(IIIp), as follows: [ 00251 ] In an embodiment, the compound of Formula (III) is a compound of Formula (Illq) Formula (Illq), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: Raoq is selected from H and Ci-Ce alkoxy; R3iq is selected from Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen, and C3-C9 heterocycyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, C3-C9-heterocyclyl, C6-C12 aryl, -OH, -C=O, and halogen; and R32q, R33q, and R34q are each independently selected from H and halogen. [00252 ]    In an embodiment, Rjoq is H. [00253 ]    In an embodiment, Rsiq is unsubstituted C3-C9 heterocyclyl. In one embodiment, Rsiq is pyrazolyl. In one embodiment, Rsiq is selected from wherein K is N or CH, wherein d is 1 or 2. In one embodiment, Rsiq is wherein d is 2. In another embodiment, Rsiq is C3-C9 heterocycyl substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, Cs-Cq-heterocyclyl, C6-C12 aryl, -OH, - * C=O, and halogen. In an embodiment, Rsiq is 35q         wherein R35q is selected from H, unsubstituted Ci-Ce alkyl, unsubstituted C6-C12 aryl, and unsubstituted C3-C9 heterocyclyl. In s 1 / )—? R one embodiment, Rsiq is 35q         wherein R35q is H. In one embodiment, Rsiq is N^\ > R x 35q          wherein Rssq is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. In another embodiment, Rsiq is isoxazolyl substituted with Ci-Ce alkyl. In one embodiment, Rsiq is isoxazolyl monosubstituted with -CH3. In one embodiment, Rsiq is In another embodiment, Rsiqis , wherein e is 1, 2, or 3, K is N or CH and each X is independently halogen. In one embodiment, R3iq is [00254 ] In an embodiment, R32q, R33q, and R^q are each H. In an embodiment, R32q and R34q are each independently halogen and R33q is H. In one embodiment, R32q and R34q are each F and R33q is H. In an embodiment, R32q and R34q are each H and R33q is halogen. In one embodiment, R32q and R34q are each H and R33q is F. [00255 ] In an embodiment, the compound of Formula (Illq) comprises one or more stereocenters. [ 00256 ] In an embodiment, the compound of Formula (Illq) 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 (Ilir) Formula (Ilir), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R30r is selected from Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen, and C3-C9 heterocycyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, C3-C9-heterocyclyl, C6-C12 aryl, -OH, -C=O, and halogen; Rsir is selected from H and Ci-Ce alkoxy; and R32r, R33r, and R34r are each independently selected from H and halogen. [ 00258 ] In an embodiment, Rso, is unsubstituted C3-C9 heterocyclyl. In one embodiment, Raor is unsubstituted pyrazolyl. In one embodiment, Rsor is selected from L N wherein L wherein f is 2. In another embodiment, Kw is C3-C9 heterocycyl substituted with one or more substituents selected from Ci-Ce alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C12 N^\ <, i / )—? aryl, -OH, -C=O, and halogen. In an embodiment, R301- is R35r          wherein R35r is selected from H, unsubstituted Ci-Ce alkyl, unsubstituted Ce-Cn aryl, and unsubstituted C3-C9 «, i    / )—I heterocyclyl. In an embodiment, Rsor is R35r          wherein Rasr is H. In one embodiment, N^\ . Rsor is R35r          wherein R351 is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. In another embodiment, R30r is isoxazolyl substituted with Ci-Ce alkyl. In one embodiment, Rsor is isoxazolyl monosubstituted with -CH3. In one embodiment, Rw is In another embodiment, Rsor is , wherein g is 1, 2, or 3, L is N or CH and each X is independently halogen. In one embodiment, R301 is

[00259] In an embodiment, Rsir is H. [00260 ] In an embodiment, R3213 R33r, and R34r are each H. In an embodiment, Rs2r and R34r are each independently halogen and R33r is H. In one embodiment, R32r and R34r are each F and R33ris H. In an embodiment, R32r and R34r are each H and R33r is halogen. In one embodiment, R321 and R341 are each H and Ri3r is F. [ 00261 ] In an embodiment, the compound of Formula (Ilir) comprises one or more stereocenters. [ 00262 ] In an embodiment, the compound of Formula (Ilir) is one of compounds 38-44 and 62 or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. [00263 ] In an embodiment, the compound of Formula (III) is a compound of Formula (Ills) Formula (Ills), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: Raos is selected from H and Ci-Ce alkoxy; Rais is selected from Ci-Ce alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Cg alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl and halogen, and C3-C9 heterocycyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, C3-C9-heterocyclyl, C6-C12 aryl, -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. [00265 ]    In an embodiment, Rsis is unsubstituted C3-C9 heterocyclyl. In one embodiment, Rais is pyrazolyl. In one embodiment, Rsis is selected from wherein M is N or CH, wherein h is 1 or 2. In one embodiment, R31S is wherein h is 2. In another embodiment, Rsis is C3-C9 heterocycyl substituted with one or more substituents selected from Ci-Ce alkyl, Cs-Ce-cycloalkyl, C3-C9-heterocyclyl, C6-C12 aryl, -OH, - 1 / )—? C=O, and halogen. In an embodiment, R31S is ^35s         wherein R35S is selected from H, unsubstituted Ci-Ce alkyl, unsubstituted C6-C12 aryl, and unsubstituted C3-C9 heterocyclyl. In one embodiment, Rsis is wherein R35S is H. In one embodiment, Rsis is ^35s          wherein R35S is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. In another embodiment, Rsis is isoxazolyl substituted with Ci-Ce alkyl. In one embodiment, Rsis is isoxazolyl monosubstituted with -CH3. In one embodiment, Rsis is In another embodiment, Rsis is , wherein i is 1, 2, or 3, M is N or CH and each X is independently halogen. In one embodiment, Rsis is [ 00266 ] In an embodiment, R32S, R33S, and R34S are each H. In an embodiment, R32S and R34S are each independently halogen and R33S is H. In one embodiment, R32S and R34S are each F and R33S is H. In an embodiment, R32S and R34S are each H and R33S is halogen. In one embodiment, R32S and R34S are each H and R33S is F. [00267 ] In an embodiment, the compound of Formula (Ills) comprises one or more stereocenters. m(7R8RC)^(CR9R10)n o^R^Ck^CR1^14^ . . . . [00268 ] In one embodiment, R6 is HO XO , giving a structure of Formula (IV), as follows: O-S+=O HO         (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).

[00269] In some embodiments according to Formula (IV), m is 0 or 1, n is 0 or 1, o is 0 or 1, 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 R14 is not H, and / or R11, R12, R13, and R14 are H, and at least one of R7, R8, R9, and R10 is not H. In particular embodiments, R7, R8, R9, R10, R11, R12, R13, and R14 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, R7, R8, R9, and R10 are H, and at least one of R11, R12, R13, and R14 is 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, R11, R12, R13, and R14 are H, and at least one of R7, R8, R9, and R10 is 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-fused cycloalkyl. 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-fused cyclopentyl. In some embodiments, both of R7 and R8 or both of R9 and R10 are F, or both of R7 and R8 or both of R9 and R10 are methyl. In some embodiments, at least one of R11, R12, R13, and R14 is 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 some embodiments, both of R11 and R12 or both of R13 and R14 are F, or both of R11 and R12 or both of R13 and R14 are methyl.

[00271] In one embodiment, the compound of Formula (IV) is a compound of Formula (IVc) ^400 R41C N \ p          N ( E ) H ^43c p Formula (IVc), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R40C is selected from Ci-Ce alkyl, Ci-Ce alkoxy, and -OH, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R4icis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 and halogen; R42c, R43c, and R44C are each independently selected from H and halogen; and R45ca, R45cb, R46ca, R46cb, R47ca, R47cb, R48ca, R48cb, R49ca, and R49cb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce 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. [00274 ]    In one embodiment, R41C is unsubstituted C3-C6 cycloalkyl. In one embodiment, R4ic is unsubstituted C3 cycloalkyl. [ 00275 ] In one embodiment, R42C and R44c are each halgoen and R43C is H. In one embodiment, R42C and R44C are each F and R43C is H. R48Cb R47cb R45ca R45cb 0 / 4 S —OH \ O’ R49ca ^4900 ^4703 In one embodiment,

[00276] In one embodiment, and R49cb is H wherein each of R45ca, R45cb, R47ca, R47cb, R48ca, R48cb, R49ca, [ 00277 ] In one embodiment, the compound of Formula (IV) is: F              , or a pharmaceutically acceptable salt thereof. [ 00278 ] In one embodiment, R4 and R5 bond or fuse to form a heterocyclyl, giving a structure of Formula (Vc), as follows: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: Rsoc is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and OH , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy; Rsicis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl, -OH, and halogen; Rs2c is selected from H, CN, amido, halogen, -S(O)2-(Ci-C7 alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(Ce-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen; and Rssca, Rsscb, Rs6ca, Rs6cb, Rs7ca, Rs7cb, Rssca, Rsscb, Rsgca, and Rs9cb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms.

[00279] In one embodiment, each of Rssca, Rsscb, Rseca, Rsecb, R57ca, Rs7cb, Rssca, Rsscb, Rs9ca, and Rs9cb is H. [ 00280 ] In one embodiment, one of Rssca, Rsscb, Rseca, Rsecb, Rs7ca, Rs7cb, Rssca, Rs8cb, Rs9ca, and Rs9cb is selected from halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. [ 00281 ] In one embodiment, Rsoc is unsubstituted Ci-Ce alkoxy. In one embodiment, Rsoc is -OCH3. [ 00282 ] In one embodiment, Rsic is unsubstituted C3-C6 cycloalkyl. In one embodiment, Rsicis unsubstituted C3 cycloalkyl.

[00283] In one embodiment, Rs 2c is H.

[00284] In one embodiment, R57cb, Rs&a, R58cb, R59ca, and Rs9cb is H.

[00285] In one embodiment, each of R55ca, R55cb, R57ca, each of R55ca, Rsscb, Rs7ca, Rs7cb, Rssca, Rs9ca, and Rs9cb is H and Rsscb is halogen. In one embodiment, R R 57cb K57ca , of R55ca, R55cb3 R57ca, R57cb, Rssca, Rs9ca, and Rs9cb is H and Rsscb is F.

[00286] 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 a structure of Formula (Vd), as follows: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: , O / n Rsoa is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and OH , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy; Rsidis selected from Ci-Ce alkyl, Cs-Ce cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl, -OH, and halogen; Rs2d is selected from H, CN, amido, halogen, -S(0)2-(Ci-C? alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(Ce-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen; and R55da, Rssdb, R56da, Rsedb, Rs7da, Rs7db, Rssda, Rssdb, Rs9da, and Rs9db are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. [ 00288 ] In one embodiment, each of Rssda, Rssdb. Rseda, Rsedb, Rs7da, Rs7db, Rssda, Rssdb, R59da, and Rs9db is H. [ 00289 ] In one embodiment, one of Rssda, Rssdb, Rseda, Rs6db, Rs7da, Rs?db, Rssda, Rssdb, Rs9da, and Rs9db is selected from halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms. [00290 ] In one embodiment, Rsod is unsubstituted Ci-C alkoxy. In one embodiment, Rsod is -OCH3 [00291 ] In one embodiment, Rsidis unsubstituted C3-C6 cycloalkyl. In one embodiment, Rsidis unsubstituted C3 cycloalkyl. [ 00292 ] In one embodiment, Rs2d is H. R55da\ ^5db ®R58db>l^-R59da R58da          R59db .         .                            . is R57db R57da , each Of R55da, R55db, R57da, R57db, R58da, R58db, R59da, and Rs9db is H.

[00294] each Of R55da, R55db, R57da, R57db, Rssda, R59da, and R59dbis H and Rssdb is halogen. In one embodiment, R55da. ^db R58da          R59db 57db   57da    , each of R55da, R55db, R57da, Rs7db, R58da, R59da, and R>9db is H and Rs8db is F. [ 00295 ]    In one embodiment, the compound of Formula (Vd) is selected from: pharmaceutically acceptable salt thereof. [ 00296 ] In some embodiments, the compounds of Formula (I), or Formula (la), such as compounds of Formula (II), Formula (III), Formula (IV), or Formula (V) are IRAK inhibitors. In one embodiment, the compounds of Formula (I) or Formula (la) are IRAKI, IRAK4, IRAK1 / 4, and / or FLT3 inhibitors. In one embodiment, the compounds of Formula (I) or Formula (la) are IRAK1 / 4, panFLT3 inhibitors. [00297 ] In some embodiments, the compounds of Formula (I) or Formula (la), such as compounds of Formula (II), Formula (III), Formula (IV), or Formula (V) can be any of Compounds 1-31 or Compounds la-38a, as shown in Examples 1-19. [00298 ] In some embodiments, the compounds of Formula (I), Formula (la), such as compounds of Formula (II), Formula (III), Formula (IV), or Formula (V) can be in the form of salts, 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. [ 00299 ] In some embodiments, the compounds of the disclosure having a chiral center and can exist in and be isolated in optically active and racemic forms. In other embodiments, compounds may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein, including isotopically-labeled and radio-labeled compounds. See e.g., Coding, 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. [ 00300 ] In some embodiments, compounds disclosed herein have asymmetric centers and can 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. [ 00301 ] The compounds disclosed herein can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds 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. [00302 ] The compounds disclosed herein can contain one or more deuterium atoms. The one or more deuterium atoms can replace one or more hydrogen atoms on a compound disclosed herein, such as a compound of Formula (I) or Formula (la). For example, the one or more deuterium atoms can replace one or more hydrogen atoms in one or more of variable groups R1, R2 R3 R4 R3 R6 R7 R8 R9 R^ R^ R^2 R^3 R^4R^3 R^ R^7 R^8 R^9 R29 R2^ R22 R23 R24, R2\ R26, R27, R29, R29, R30, or R31. The one or more deuterium atoms can replace one or more hydrogen atoms in an optional substituent on one or more of variable groups R1, R2, R3, R4, R5 R6 R7 R8 R9 R^ R11 R^2 R^3 R^4R^ R^ R^7 R^8 R^9 R29 R2^ R22 R23 R24 R23 R2$ R27,R29, R29, R30, orR31. [00303 ] In some embodiments, metabolites of the compounds disclosed herein are useful for the methods disclosed herein. [00304 ] In some embodiments, compounds contemplated herein may be provided in the form of a prodrug. The term “prodrug” refers to a compound that can be converted 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. [00305 ] Certain compounds disclosed herein can exist in unsolvated forms as well 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 compounds 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. [ 00306 ] In certain embodiments, one or more compounds of the disclosure (e.g., Formula (I) or Formula (la) can be part of a composition and can be in an amount (by weight of the total composition) of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, or no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. In some embodiments, one or more compounds of the disclosure (e.g., Formula (I) or Formula (la) can be purified or isolated in an amount (by weight of the total composition) of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. Combination Therapies [00307 ] In one embodiment, the compounds of Formula (I) or Formula (la) are administered 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, a hypomethylating agent, an immunomodulatory imide, a cereblon modulator, a purine nucleoside antimetabolite, a Type II topoisomerase inhibitor, a DNA intercalator, a hedgehog antagonist, an IDH2 inhibitor, an IDH1 inhibitor, a ribonucleotide reductase inhibitor, an adenosine deaminase inhibitor, a Mek 1 / 2 inhibitor, an ERK 1 / 2 inhibitor, an AKT inhibitor, a PTPN11 inhibitor, an SHP2 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 Plk 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 / VEGFRl / 2 / 3 / FLT3 / CSF-IR / 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. [ 00308 ] In one embodiment, the compound of Formula (I) or Formula (la) or the composition comprising a compound of Formula (I) or Formula (la) is used in combination with at 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 acceptable salt of any one thereof, or the DNA methyltransferase inhibitor or hypomethylating agent is azacitidine or a pharmaceutically acceptable salt thereof. [ 00309 ] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a salt thereof. In one embodiment, the therapeutic agent comprises a DNA polymerase inhibitor. In one embodiment, the DNA polymerase inhibitor is cytidine. In one embodiment, the therapeutic agent comprises a cytidine deaminase inhibitor. In one embodiment, the cytidine deaminase inhibitor is zebularine. In one embodiment, the therapeutic agent comprises a DNMT inhibitor. In one embodiment, the DNMT inhibitor is zebularine, decitabine, or 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 anti metabolite. In one embodiment, the purine nucleoside antimetabolite is clofarabine. In one embodiment, the therapeutic agent comprises a Type II topoisomerase inhibitor / DNA intercalator. In one embodiment, the Type II topoisomerase inhibitor / DNA intercalator is vosaroxin. In one embodiment, the therapeutic agent comprises a hedgehog antagonist. In one embodiment, the hedgehog antagonist is glasdegib. In one embodiment, the therapeutic agent comprises an LDH1 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 a glucocorticoid steroid. In one embodiment, the glucocorticoid steroid is prednisolone. In one embodiment, the therapeutic agent comprises a menin inhibitor. In one embodiment, the menin inhibitor is SNDX-5613. In one embodiment, the therapeutic agent comprises an MDM2 inhibitor. In one embodiment, the MDM2 inhibitor is 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). [ 00310 ] In one embodiment, the therapeutic agent comprises a CDK inhibitor. The CDK inhibitor 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, CDK 10, CDK11, CDK 12, or CDK 13 inhibitor or a combination thereof. [00311 ] In one embodiment, the CDK inhibitor comprises an inhibitor described in one of the 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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In another embodiment, the CDK inhibitor comprises an inhibitor described in: Alsfouk, A., Journal of Enzyme Inhibition and Medicinal Chemistry, 2021, 36(l):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; Sanchez-Martinez, C. et al., Bioorganic & Medicinal Chemistry Letters, 2019, 29:126637; Di Sante, G. et al., Expert Review of Anticancer Therapy, 2019, 19(7): 569-587; Whittaker, S. R. et al., Pharmacology & Therapeutics, 2017, 173:83-105; Chou, J. etal., 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. [00312 ] 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. [ 00313 ] Exemplary CDK inhibitors include, but are not limited to: Compound 21 (PMID 27326333) CYC065; YKL-1-116; i-CDK9; JH-VII-49; JH-XI-10-02; SEL120-34A; MM-D37K; PF-06873600; BEY-1007; BEY-1107; 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; Dinaciclib (SCH 727965); x NH CDKI-73 (LS-007); .44, flavopiridol (alvocidib); dinaciclib; ,N, ,v N 6 SNS-032 (BMS-3 87032); 1A HN' N q 7 h N NH (RGB286638); H (zortiraciclib, TG02, SB 1317); F (atuveciclib, BAY-1143572); abemaciclib (LY2835219, ribociclib (LEE-011, Kisqali); Palbociclib (PD-0332991, Ibrance); PF-06873600; trilaciclib (G1T28); lerociclib (G1T38); h                SHR- FN- I -■ inditinib (AGM-130);       x""' v "       (+)-BPI- 16350; AT-7519; ox nordihydroguaiaretic acid (NDGA); protaglandin El; candesartan cilexil; N H 20-223 (CP668863); O H roxyl-zhc- 84; abemaciclib; -o W: '-M Cl .4 HN HO N cabozantinib; ® HQ vorinostat; corti statin r ' r N-^'N A; H Cl MSC2530818; CCT251545; CCT251921; ZK-304709; riviciclib (P276-00); R547; N H " N"'       '           AZD5438;         H         AG-024322; LDC3140;                 LDC4297; CMPD14; LDC000067; wogonin; CMPD 93; sorafenib; 'Y senexin A; senexin B; CMPD 20; NH-j NH CMPD 32; OH O Br SEL120; PHA-793887; NH HO IIIM-290; olomoucine; Fascaplysin; hymenialdisine; variolin B; konbu’ acidin 9                    J 11                  Sx HN r a i N 1       JL A JLA L      h -ch3 XXa 5 OH O OH O        OH . 5 H Af\        >T XXX N           wherein X is N, Y is -C(= CH2OH, and Ar is 05n CL xs«kA ® ci         xXys AyNA>  VJ^yN . XX H               HgN"NH 5                                                                            5                                                5 H0\X^ ci^^Xr -0)H, and Ar is             A , X is N, Y is - A , or X is CH, Y is -CH2OH, and Ar is sA                                                          0’ 1 S M A XV1X rs ks Af wherein X is NH or 0; xuu 5 wherein X is NH or 0; 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; R wherein R is tetrahydro-pyran-4-yl and R’ is H, R is -CH2CH3 and R’ is -OCH3, R is isopropyl and R’ is H, or R is - CH2CH3 and R’ is F; ..-x HN" O' wherein R is t-butyl carboxyl and n is 1 or R is H and n is 2; wherein X is NH or O; K P1                   .         .                         .              .                        .                    . wherein R is H and R’ is F, R is F and R’ is F, or R is H and R’ is H; R' wherein R is -OCH3 and R’ is F, R is F and R’ is SF5, or R is -OCH3 and R’ is -SF5; R F wherein R is F and R’ is -CH3 or R is -SF5 and R’ is H; R wherein R is -CF3 and R’ is -CH3 or R is H and R’ is cyclopropyl; / ......\ *.....A..... ..I. X'S , NH; c f Y 'YC H            wherein R is 3-fluoroailin-lyl and R’ is F or R is phenyl and R’ is - CH3; wherein R is H or F and Alkyl is -CH3 or -CH2CH3; wherein R is 3-fluorophenyl or morpholin-4yl; wherein R is cyclopropan-l-ol-l-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 l,2-oxazol-3yl or 3,4-difluorobenzen-lyl; di hydroxpropan-1yl; wherein R is H, C(=0)NHCH3, -SO2NH2, SO2CH3, or 2,3- wherein R is H, CH3, 2-aminoethyan-lyl, 3-aminopropan-lyl, or 2,3 -di hy droxpropan-1 yl; HN wherein R is H or -CH3; F. N- -4-R "N H 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; OH / NH wherein R is 2-phenylethan-lyl or (furan-2-yl)methyl; wherein R is H or -C(=O)CH2OH; wherein R is -NHC(=O)CH3 or -NHSO2CH3; h : y.....Br T \ x NH2 wherein R is H or isobutyl; wherein R is H and R’ is -CH3 or R is -CN and R’ is H; wherein R is 3,4-dimethyl-lH-pyrazol-4-yl and R’ is -CH3 or R is piperazin-lyl and R’ is H; OH O ’               wherein R is 2,6-dichlorophenyl, 2,3,4,5,6-tetrafluorophenyl, or 3- fluorophenyl; HN..... wherein R is -CH2NCH3 or H; wherein R is -CH2N(CH3)2 or H; wherein R is H, -SO2CH3, -CH2C(=O)N(CH3)2, 4-carboxylic acid- cyclobutan-lyl, or (2(hydroxymethy)pyrrolidine-l-yl)-2-one-ethan-lyl, R’ is H or F, and R” is H or -CH2CH3; • N wherein Ri is -OH, R2 is H, R3 is H, and R4 is H (meridianin A), Ri is -OH, R2 is H, R3 is Br, and R4 is H (meridianin B), Ri is H, R2 is Br, R3 is H, and R4 is H (meridianin C), Ri is H, R2 is H, R3 is Br, and R4 is H (meridianin D), or Ri is -OH, R2 is H, R3 is H, and R4 is Br (meridianin E); and HN, ,,0 r R wherein R is piperi din-3yl, pyrrolodin-3yl, or morpholin-2yl. [00314 ] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor and a DNMT 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 of salts, 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 in and be isolated in optically active and racemic forms. In other embodiments, the therapeutic agent may exhibit polymorphism. Some embodiments of the present disclosure encompass any 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. [ 00317 ] In some embodiments, the therapeutic agent has asymmetric centers and can 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. [ 00318 ] The therapeutic agents disclosed herein can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds 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.

[00319] In some embodiments, metabolites of the the therapeutic agents disclosed herein are useful for the methods disclosed herein. [ 00320 ] In some embodiments, the therapeutic agents contemplated herein may be provided 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 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. [00321 ] Certain the therapeutic agent disclosed herein can exist in unsolvated forms as well 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 the therapeutic 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 [00322 ] In one embodiment, the present disclosure further relates to a composition comprising a compound of Formula (I) or Formula (la) and a composition comprising a therapeutic agent. Exemplary therapeutic agents are described elsewhere herein. In another embodiment, the compound of Formula (I) or Formula (la) and the therapeutic agent are coformulated into a single composition. In one embodiment, the compound of Formula (I) or Formula (la) and the therapeutic agent are administered together in one administration or composition. In another embodiment, the compound of Formula (I) or Formula (la) and the therapeutic agent are administered separately in more than one administration or more than one composition. In one embodiment, the composition comprising the compound of Formula (I) or Formula (la) and the composition comprising the therapeutic agent are administered to a subject at the same time. In another embodiment, the composition comprising the compound of Formula (I) or Formula (la) and the composition comprising the therapeutic agent are administered to a subject sequentially. In one embodiment, the composition comprising the compound of Formula (1) or Formula (la) and the composition comprising the therapeutic agent are co-administered (or administered 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. [ 00323 ] Some embodiments of the present disclosure include compositions comprising one or more compounds of the disclosure (e.g., Formula (I) or Formula (la)). In one embodiment, 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, or derivative thereof. In some embodiments, the compound is set forth in Examples 1-19 herein. [00324 ] Further embodiments of the disclosure relate to compositions including a compound 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. [ 00325 ] The term “pharmaceutically acceptable salts” is meant to include salts of the active 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 can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids 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 etal., “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. [00326 ] Compounds disclosed herein can exist as salts, such as with pharmaceutically acceptable 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. [ 00327 ] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. [ 00328 ] Pharmaceutically acceptable salts of the compounds above, where a basic or acidic 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. [00329 ] Also, in the embodiments in which R-COOH is present, pharmaceutically acceptable 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. [00330 ] In some instances, the pharmaceutical composition is non-toxic, does not cause side 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). [00331 ] In some embodiments, one or more compounds of the disclosure (e g., Formula (I) or Formula (la)) can be part of a pharmaceutical composition and can be in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, atleast 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 least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.001% to about 99%, from about 0.001% to about 50%, from about 0.1% to about 99%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. In some embodiments, the pharmaceutical composition can be presented in a dosage 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. [00332 ] In some embodiments, the compounds disclosed herein can be administered orally as 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 selected from 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. [00333 ] In some embodiments, tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate; (2) granulating and disintegrating agents, such as com 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. [00334 ] 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. [00335 ] A compound disclosed herein, in the form of a free compound or a pharmaceutically-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 an appropriate biologically acceptable buffer and added to a cell or tissue. [ 00336 ] In powders, the carrier is a finely divided solid in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. [00337 ] The powders and tablets preferably contain from 5% to 70% of the active compound. 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. [ 00338 ] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[00339] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. [00340 ] When parenteral application is needed or desired, particularly suitable admixtures for 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 acceptable vehicles, carriers, and solvents that can be employed are water, Ringer’s solution, and isotonic sodium 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 pharmaceuticals compositions and methods disclosed herein include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of both of which are hereby incorporated by reference. [00341 ] In some embodiments, preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Frequently used carriers or 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. 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. [ 00342 ] Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington’s Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co. , 1405-1412, 14611487 (1975) and The National Formulary XIV., 14th ed. Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See e.g., Goodman and Gilman (eds.), 1990, The Pharmacological Basis for Therapeutics (7th ed.). [ 00343 ] Aqueous solutions suitable for oral use can be prepared by dissolving the active component 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, me thylcellulose, 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, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which 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) a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate [00344 ] 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. [ 00345 ] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities 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.

[00346] In some embodiments, the pharmaceutical composition can include one or more formulary ingredients. A “formulary ingredient” can be any suitable ingredient (e.g., suitable for the 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.

[00347] In certain embodiments, pharmaceutical compositions can be formulated to release the active ingredient (e.g., one or more compounds of the disclosure such as Formula (I) or Formula (la)-) substantially immediately upon the administration or any substantially predetermined time or time after administration. Such formulations can include, for example, controlled release formulations such as various controlled release compositions and coatings. [0034 8 ] Other formulations (e.g., formulations of a pharmaceutical composition) can, in certain embodiments, include those incorporating the drug (or control release formulation) into food, food stuffs, feed, or drink.

[00349] Some compounds can have limited solubility in water and therefore can require a surfactant 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. [ 00350 ] Viscosity greater than that of simple aqueous solutions can be desirable to decrease 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. [ 00351 ] The compositions disclosed herein can additionally include components to provide sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. 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. [00352 ] There are provided various pharmaceutical compositions useful for ameliorating certain 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. [00353 ] There are provided various pharmaceutical compositions useful for ameliorating certain 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 [00354 ] Further embodiments of the disclosure relate to methods for providing a subject with 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 more compositions 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. [00355 ] Further embodiments of the disclosure relate to methods for treating a disease or disorder, 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. [ 00356 ] 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. 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. [00357 ] In one embodiment, the disease or disorder is not relapsed / refractory. In another embodiment, 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 (la) disclosed herein are administered to a subject in need thereof as a monotherapy. In one embodiment, the disease or disorder is not relapsed / refractory and a compound of Formula (I) or Formula (la) 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 (la) 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 (la) disclosed herein are administered to a subject in need thereof as a frontline monotherapy. [ 00358 ] In one embodiment, the disease or disorder is a BCL2 inhibitor relapsed / 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 is a BTK inhibitor relapsed / refractory disease or disorder. In one embodiment, the disease or disorder is an ibrutinib relapsed / refractory disease or disorder. In one embodiment, the disease or disorder is relapsed / refractory to anti-inflammatory glucocorticoids. In one embodiment, the disease or disorder is a dexamethasone, methylprednisolone, or prednisolone relapsed / refractory disease or disorder. In one embodiment, the disease or disorder is a CDK inhibitor relapsed / refractory disease or disorder. In one embodiment, the disease or disorder is a palbociclib, THZ1, BAY 12511152, or atuveciclib relapsed / refractory disease or disorder. In one embodiment, the disease or disorder is a DNA methyltransferase inhibitor or hypomethylating agent relapsed / refractory disease or disorder. In one embodiment, the disease or disorder is an azacitidine relapsed / refractory disease or disorder. In one embodiment, the disease 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. [ 00359 ] In some embodiments, the method is for treating a hematopoietic cancer. In some embodiments, the method is for treating a myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML). In one embodiment, the disease or disorder comprises high-risk myelodysplastic 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). [00360 ] In one embodiment, the disease or disorder is BCL2 inhibitor resistant acute myeloid 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). [00361 ] In one embodiment, the disease or disorder is hypomethylating agent resistant myelodysplastic 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). [00362 ] 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 more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and / or IRAK4, or combinations thereof. In some embodiments, the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’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. [00363 ] In some embodiments, the method further includes administration of a composition including a BTK inhibitor. In some embodiments, the BTK inhibitor includes ibrutinib. [00364 ] In some embodiments, the subject is susceptible to AML and / or MDS, and / or the method prevents or ameliorates future AML and / or MDS. In some embodiments, the method occurs after one or more of having myelodysplastic syndrome, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer. [00365 ] In some embodiments, the method further includes administration of a composition 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. [ 00366 ] In some embodiments, the method further includes administration of one or more additional 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 some embodiments, 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-PDl / PDLl (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 RARa 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-1 le; 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. [00367 ] In one embodiment, the disease or disorder is AML which is not relap sed / refractory and the additional therapy is a BCL2 inhibitor. In one embodiment, the disease 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 (la) 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 (la) disclosed herein and the BCL2 inhibitor are administered to a subject as a frontline therapy to treat AML which is not rel ap sed / refractory. [00368 ] In one embodiment, the disease or disorder is a BCL2 inhibitor resistant disease or disorder and a compound of Formula (I) or Formula (la) is administered to the subject in combination with an additional therapy. In one embodiment, the disease or disorder is a venetoclax resistant disease or disorder and a compound of Formula (I) or Formula (la) disclosed herein is administered to the subject in combination with an additional therapy described elsewhere herein. [ 00369 ] In one embodiment, the disease or disorder is BCL2 inhibitor resistant acute myeloid 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 additional therapy 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 BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML) and the additional therapy is a BCL2 inhibitor. 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. [00370 ] In one embodiment, the disease or disorder is AML which is not relapsed / 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 is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of Formula (I) or Formula (la) disclosed herein and the hypomethylating agent 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 (la) disclosed herein and the hypomethylating agent are administered to a subject as a frontline therapy to treat AML which is not relapsed / refractory. [00371 ] In one embodiment, the disease or disorder is a hypomethylating agent resistant disease or disorder and a compound of Formula (I) or Formula (la) disclosed herein is administered to the subject in combination with an additional therapy described elsewhere herein. In one embodiment, the disease or disorder is a hypomethylating agent resistant disease or 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. [00372 ] In one embodiment, the disease or disorder is hypomethylating agent resistant acute myeloid leukemia (AML) and the additional therapy is a hypomethylating agent. In one embodiment, the disease or disorder is azacitidine resistant acute myeloid leukemia (AML) and the additional therapy is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is hypomethylating agent resistant refractory acute myeloid leukemia (AML) and the additional therapy is a hypomethylating agent. In one embodiment, the disease or disorder is azacitidine resistant refractory acute myeloid leukemia (AML) and the additional therapy is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is hypomethylating agent resistant relapsed acute myeloid leukemia (AML) and the additional therapy is a hypomethylating agent. In one embodiment, the disease or disorder is azacitidine resistant relapsed acute myeloid leukemia (AML) and the additional therapy is azacitidine or a pharmaceutically acceptable salt thereof. [ 00373 ] In one embodiment, the disease or disorder is AML which is not relapsed / 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 a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of Formula (I) and Formula (la) disclosed herein and the combination of a BCL2 inhibitor and a hypomethylating agent 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) and Formula (la) disclosed herein and the combination of a BCL2 inhibitor and a hypomethylating agent are administered to a subject as a frontline therapy to treat AML which is not relapsed / refractory. [00374 ] In one embodiment, the disease or disorder is a BCL2 inhibitor and a hypomethylating agent resistant disease or disorder and the additional therapy is the combination of a BCL2 inhibitor and a hypomethylating agent. In one embodiment, the disease or disorder is a venetoclax and azacitidine resistant disease or disorder and the additional therapy is the combination of venetoclax or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt of any one thereof. [ 00375 ] In one embodiment, the disease or disorder is BCL-2 inhibitor and hypomethylating agent resistant 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 acute myeloid leukemia (AML) and the additional therapy is a combination of venetoclax or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt of any one thereof. In one embodiment, the disease or disorder is BCL-2 inhibitor and hypomethylating agent resistant refractory 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 refractory acute myeloid leukemia (AML) and the additional therapy is the combination of venetoclax or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt of any one thereof. In one embodiment, the disease or disorder is 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 acute myeloid leukemia (AML) and the additional therapy is the combination of venetoclax or a pharmaceutically acceptable salt of thereof and azacitidine or a pharmaceutically acceptable salt of any one thereof. [00376 ] In one embodiment, the disease or disorder is MDS which is not relapsed / 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 of Formula (I) or Formula (la) disclosed herein and the hypomethylating agent 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 (la) disclosed herein and the hypomethylating agent are administered to a subject as a frontline therapy to treat MDS which is not relapsed / refractory. [ 00377 ] In one embodiment, the disease or disorder is hypomethylating agent resistant myelodysplastic syndrome (MDS) and the additional therapy is a hypomethylating agent. In one embodiment, 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. [ 00378 ] In one embodiment, the disease or disorder is hypomethylating agent resistant refractory myelodysplastic syndrome (MDS) and the additional therapy is a hypomethylating agent. In one embodiment, the disease or disorder is azacitidine resistant refractory myelodysplastic syndrome (MDS) and the additional therapy is azacitidine or a pharmaceutically acceptable salt of any one thereof. In one embodiment, the disease or disorder is hypomethylating agent resistant relapsed myelodysplastic syndrome (MDS) and the additional therapy is a hypomethylating agent. In one embodiment, the disease or disorder is azacitidine resistant relapsed myelodysplastic syndrome (MDS) and the additional therapy is azacitidine or a pharmaceutically acceptable salt of any one thereof. [0037 9 ] 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 fins-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. [ 00380 ] 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. In some embodiments, the subject is in need of the treatment. [ 00381 ] In some embodiments, the method is for treating a hematopoietic cancer. In some embodiments, the method is for treating MDS and / or AML. In some embodiments, the method is for treating at least one of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), 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 inflammatory diseases or autoimmune disease characterized by overactive IRAKI and / or IRAK4, or combinations thereof. In some embodiments, the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’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 activity relative to IRAK4-Short, and / or 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. [00382 ] In some embodiments, the method further includes administration of a composition including a BTK inhibitor. In some embodiments, the BTK inhibitor includes ibrutinib. [00383 ] In some embodiments, the subject is susceptible to AML and / or MDS, and / or the method prevents or ameliorates future AML and / or MDS. In some embodiments, the method occurs after one or more of having 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 of claims 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. [00384 ] In some embodiments, the method further includes administration of one or more additional 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 some embodiments, 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-PDl / PDLl (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 RARa 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-1 le; wherein 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. [00385 ] In one aspect, the present disclosure relates to a method of treating and / or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (la) and a therapeutically effective amount of a CDK inhibitor. In one embodiment, a composition comprising a therapeutically effective amount of the compound of Formula (I) or Formula (la) is administered to the subject. In one embodiment, a composition comprising a therapeutically effective amount of the CDK inhibitor is administered to the subject. In one embodiment, the compound of Formula (I) or Formula (la) treats and / or prevents the disease or disorder by inhibiting FLT3 (wild type FLT3 and / or mutant FLT3) as well as IRAK4, IRAKI, or both IRAK4 and IRAKI 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. [ 00386 ] In addition to their ability to inhibit IRAK, IRAK inhibitors have been demonstrated to have selectivity for multiple kinases. In some embodiments, compounds described herein according to Formula (I), or Formula (la), such as Compounds 1-31 or Compounds 1-3 8a as depicted in Examples 1-19, exhibit have inhibitory action against one or more kinase, such as interleukin-1 receptor-associated kinase (IRAK) and FMS-like tyrosine kinase 3 (FLT3). The inhibitory action against one or more kinase, such as IRAK and FLT3, can allow 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 (la)) including, but not limited to 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 IRAKI, IRAK4, and / or 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). [00387 ] In some embodiments, the compounds of the disclosure can inhibit the activity of one 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, IRAKI (interleukin-1 receptor associated kinase 1), isoforms of IRAKI, and / or mutations of IRAKI. In some embodiments, the compounds of the disclosure can inhibit the activity of one or both of FLT3 and 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) and optionally inhibits one or more of IRAK4, isoforms of IRAK4, mutations of IRAK4, IRAKI, isoforms of IRAKI, or mutations of IRAKI. In some embodiments, the compounds of the disclosure can inhibit the activity of one or both of FLT3 and 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) and optionally inhibits one or both of IRAK4 and IRAKI, or an isoform or mutation thereof. In some embodiments, the compounds of the disclosure can inhibit FLT3 in combination with IRAK4, IRAKI, or with IRAK4 and IRAKI. [ 00388 ] In some embodiments, compounds exhibit inhibitory activity against IRAK and / or FLT-3 with activities > 1 pM, 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 against IRAK and / or FLT-3 with activities <0.1 pM, 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, 10100 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, 101000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM. In some embodiments, the inhibitory activity is in the range of about 1-10 nM, 10-100 nM, 0.1-1 pM, 1-10 pM, 10-100 pM, 100-200 pM, 200-500 pM, or even 500-1000 pM. It is understood that for purposes of quantification, the terms “activity,” “inhibitory activity,” “biological activity,” “IRAK activity,” “IRAKI 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 IC50 in the customary sense (i.e., concentration to achieve half-maximal inhibition. [ 00389 ] 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 (la)) 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. [00390 ] In some embodiments, hematopoietic cancers that can be treated include, but are not 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-cell lymphoma (DLBCL) (e.g. ABC DLBCL with MYD88 mutation (e.g., L265P)), follicular lymphoma, or marginal zone lymphoma, or combinations thereof. [ 00391 ] In some embodiments, cancers characterized by dysregulated IRAK expression (IRAKI 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. [00392 ] In some embodiments, compounds of the present disclosure can be used to inhibit targets in the context of additional conditions characterized by overactive IRAKI and / or IRAK4. According to particular aspects of the disclosure, compounds of the present disclosure can be used to inhibit overactive IRAKI and / or IRAK4 in conditions such as inflammatory diseases and autoimmune disease, wherein said inflammatory diseaess and autoimmune diseases are characterized by overactive IRAKI and / or IRAK4. In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAKI and / or IRAK4) and / or IRAK-meidated intracellular signaling, can be treated, and include, but are 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, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, and the like, and combinations thereof. [00393 ] 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 (la)) include but 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 with multilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ring sideroblasts and animals / humans with pathological changes not restricted to red cells such as prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia), refractory anemias with excess blasts I and II, 5q-syndrome, megakaryocyte dysplasia with fibrosis, and refractory cytopenia of childhood. In some embodiments, MDS that can be treated include, but are 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 dehydrogenase 2. 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” may refer to both human and non-human subjects. In some instances, the subject is in need of the treatment (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). [00394 ] 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 (la)) 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), IRAKI (e.g., using IRAK 1 inhibitors), and / or mutations of IRAKI (e.g., using inhibitors of IRAKI mutant). In certain embodiments, MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAKI (or its mutations), or MDS that can be treated by inhibiting IRAK4 (or its mutations) and IRAKI (or its mutations). In some embodiments, MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI 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 MDS having enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein the MDS 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 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). [00395 ] 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 (1) or Formula (la)) 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 chromosome 9 and 11 (“MLL”) AML with translocation between chromosomes 8 and 21, AML with translocation 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 the like), AML not otherwise categorized (does not fall into above categories - similar to FAB classification; such as, for example, AML minimally differentiated (M0), AML with minimal maturation (Ml), AML with maturation (M2), acute myelomonocytic leukemia (M4), acute monocytic 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, AML evolving 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 the juxtamembrane region of FLT3, AML with an increased risk due to an FLT3 mutation in the kinase 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, and the like. In some embodiments, AML that can be treated include AML that by inhibiting one or more ofFLT3 (e.g., using FLT3 inhibitors), mutations ofFLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAKI (e.g., using IRAK 1 inhibitors), and / or mutations of IRAKI (e.g., using inhibitors of IRAKI 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 IRAKI (or its mutations), or AML that can be treated by inhibiting IRAK4 (or its mutations) and IRAKI (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, IRAKI, or both IRAK4 and IRAKI. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI 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, AML that can be treated is characterized by 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, 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 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). [ 00396 ] 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) or Formula (la)) 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), IRAKI (e.g., using IRAK 1 inhibitors), isoforms of IRAKI, or mutations of IRAKI (e.g., using inhibitors of IRAKI 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 IRAKI (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), and IRAKI (or its isoforms or mutations). In some embodiments, hematopoietic cancer that can be treated include, but are not limited to hematopoietic cancer that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI 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, hematopoietic cancer 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 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 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). [ 00397 ] 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, IRAKI, or both IRAK4 and IRAKI. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI 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, cancer that can be treated is characterized by cancer having enhanced IRAK4-Long expression and / or activity relative to IRAK4-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 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 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). [00398 ] In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAKI and / or IRAK4) and / or IRAK-meidated intracellular signaling, that can be treated include, but are 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, Sjogren’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, IRAKI, or both IRAK4 and IRAKI. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating inflammatory 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 some embodiments, inflammatory and autoimmune disease that can be treated is characterized by inflammatory 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 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 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). [ 00399 ] As related to treating 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), 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 in isocitrate dehydrogenase 2) or one or more of the symptoms associated with MDS (eg., 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 mutat...

Claims

1. A compound of Formula (I):or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein:,   0 / iiR1 is selected from H, halogen, hydroxy, oxo, OH , -CN, amino, amido, -O-aryl, methanoyl (-C0H), 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 (-C0H), 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 (-C0H), 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;,   0 /      11R2 is selected from H, halogen, hydroxy, oxo, OH , -CN, amino, amido, -O-aryl, methanoyl (-C0H), 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 (-C0H), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, 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 (-C0H), 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;, O Ao-S-o-R31 is selected from H, halogen, hydroxy, oxo, OH , -CN, amino, amido, -O-aryl, methanoyl (-C0H), 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 (-C0H), 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 (-C0H), 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;R3, R4, and R5 are each independently selected from H, halogen, hydroxy, oxo, -S(O)2-(C1-C7 alkyl), amido, -CN, methanoyl (-C0H), 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 (-C0H), 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 (-C0H), 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(CHa)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; orR3 and R4 or R4 and R5 bond or fuse to form a heterocyclyl or heteroaryl, each of which is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, methanoyl (-C0H), 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;R6 is7R8RC) (cr9r10(6^¾3¾' Y0(1,Rl2RC),N,(CR'3R,4)pHO "Oorq(15R16RC) s(19R20RC) u(23R24RC)Ycr17r18)(CR21R22)t(CR25R26)vw(27r28rc)^n^(cr29r30)x■°i,HO XOR7, R8, R9, R10, R11, R12, R13, R14 are each independently selected from H, halogen,hydroxy, oxo, -CN, methanoyl (-C0H), 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 (-C0H), 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 deuterium or halogen;R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, and R30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-C0H), 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-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 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:,   0 /     11(i) R1 is -OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or OH(iii) one or more of R3, R4, and R? is -Cl, amido, C2-C7 alkynyl, C1-C7 alkyl substitutedwith hydroxy, C1-C7 alkyl substituted with C1-C7 alkoxy, -S(O)2-(Ci-C7 alkyl), or(iv) R4 and R5 bond or fuse to form an unsubstituted heterocyclyl or an unsubstituted heteroaryl;(v) R6 ism(7R8RC) (CR9R10)n 0(11R12RCkNJCR13R14)pHO '0, orq(15R16RC) (CR17R18)r s(19R20RC) (CR21R22)t U(23R24RC)^'(CR25R26)V w(27R28RC)^n^(CR29R30)xHO^O,   0 / ii(vi) R31 is selected from halogen, hydroxy, oxo, OH , -CN, amino, amido, -O-aryl, methanoyl (-C0H), 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 (-C0H), 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 (-C0H), 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.

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:, O / iiR.20v is selected from Ci-Ce alkyl, C1-C6 alkoxy, -OH, and OH , wherein C1-C6 alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy;R2ivis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl 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 Ci-Ce alkyl, -OH, and halogen, and C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, -OH, and halogen;R22V, R23V, and R24V are each independently selected from H, CN, amido, halogen, -S(0)2-(C1-C7 alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -0-(Ce-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen; andR25va, R25vb, R26va, R26vb, R27va, R27vb, R28va, R28vb, R29va, and R29vb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms.

4. The compound of claim 3, wherein at least one of (i)-(iii) applies:,   0 /      11(i) R2ov is -OH, -OCD3, -O(CH2)2OH, -O(CH2)2OCH3, or OH(ii) R2iv is, or O ; or(iii) one or more of R22V, R23V, and R24V is -Cl, amido, C2-C7 alkynyl, C1-C7 alkyl substituted with hydroxy, C1-C7 alkyl substituted with C1-C7 alkoxy, -S(O)2-(Ci-C7 alkyl), or5. The compound of claim 3 or 4, with the provisos that:when R20vis -OCH3 and R21V is unsubstituted C3 cycloalkyl (i) one or more of R22V, R23V, and R24vis selected from amido, unsubstituted oxetane, -S(O)2-(Ci-C7 alkyl), Ci-Ce alkyl, or C2-C7 alkynyl, wherein Ci-Ce alkyl is substituted with one or more substituents selected from Ci-Ce 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) R22V and R24v are 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, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Cg alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms, provided the compound of Formula (IIv)is H, and R24V is Cl, or (v) the compound is               F           ;when R20V is -OCH3 and R21V is I , one or more of R22V, R23v, and R24v is CN and one or more of R22V, R23V, and R24vis halogen; andVF’when R20V is-OCH3 and R21V is unsubstituted oxetane or I OH , one or more of R22R23V, and R24V is CN.

6. The compound of any one of claims 3 to 5, wherein at least one of (i)-(x) applies:(i) R2ov is selected from -OCH3, -OCD3, -O(CH2)2OCH3, -O(CH2)2OH, and0 II 0-^0-OH(ii) R2ivis selected from unsubstituted C3 cycloalkyl,*<CF-^OHOH1rY rS I-n 0O—1 , o—1 5 and    \— / ;(iii) R22V is F, R23V is H, and R24v is selected from F, CN, -CH2OH, -C(0)NH2, and -C(0)NHCH3;(iv) R22V is Cl, R23V and 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, and 0(vi) and R29vb is H;(vii)isis, each of R25va, R25vb, R27va, R27vb, R28va, R28vb, R29’, each of R25va, R25vb, R27va, R27vb, R28va, R29va, andR29vb is H and R28vb is F;, each of R25va, R27va, R27vb, R28va, R28vb, R29va, andR29vb is H and R25vb is -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 R29vb isH 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:

8. The compound of claim 1 or 2, wherein 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:, O / uR20W is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and 0H , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy;R2iwis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce alkyl is optionally substituted with one or more substituentsselected from -OH and halogen and C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, -OH, and halogen;R22W, R23W, and R24w are each independently selected from H, CN, amido, halogen, -S(O)2-(Ci-C7 alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen;R25wa, R25wb, R26wa, R26wb, R27wa, R27wb, R28wa, R28wb, R29wa, and R29wb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms; andRsiw is selected from Ci-Ce alkyl, Ci-Ce alkoxy, amido, C3-C6 cycloalkyl, C3-C9 ,   0 /      11heterocyclyl, -OH, and OH , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy and C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from Ci-Ce alkyl, -OH, and halogen.

9. The compound of claim 8, wherein at least one of (i)-(iii) applies:(1) 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, Ci-Ce alkyl, and Ci-Cs alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms; or(iii) R31W is amido or Ci-Ce alkyl optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy.

10. The compound of claim 8 or 9, wherein at least one of (i)-(vi) applies:(i) R20W is -OCH3;(ii) R2iwis unsubstituted C3 cycloalkyl;(iii) R22W and R23W are each H and R24w is F;each of R25wa, R25wb, R27wa, R27wb5 R28wa, R28wb,R29wa, and R29wb is H;each Of R25wa, R25wb, R27wa, R27wb, R28wa, R29wa, andR29wb is H and R28wb is F; or(vi) Rsiw is selected from -C(0)NH2, -CH3, -CH2OH, and I 0Hpharmaceutically acceptable salt of any one thereof.

12. The compound of claim 1 or 2, wherein the compound of Formula (I) is a compound of Formula (IVc)or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:R40c is selected from Ci-Ce alkyl, Ci-Ce alkoxy, and -OH, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen;R4icis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl and halogen;R42C, R43c, and R44c are each independently selected from H and halogen; andR45ca, R45cb, R46ca, R46cb, R47ca, R47cb, R48ca, R48cb, R49ca, and R49cb are CHCh independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce 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 R49cb is H.14.The compound of claim 12 or 13, wherein at least one of (i)-(iv) applies:(i) R4ocis -OH;(ii) R41C is unsubstituted C3 cycloalkyl;(iii) R42C and R44c are each F and R43C is H; and(iv)R48cbR48caR47cb^4503R45cb0 H S —OH0'R49caR49cb R47cawherein 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 issalt thereof.

16. The compound of claim 1 or 2, wherein 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:Rsoc is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and OH , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy;Rsicis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl, -OH, and halogen;Rs2c is selected from H, CN, amido, halogen, -S(O)2-(Ci-C7 alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(Ce-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Ce alkoxy, -OH, halogen; andRssca, Rsscb, Rs6ca, Rs6cb, Rs7ca, Rs7cb, Rssca, Rsscb, Rsgca, and Rs9cb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms.

17. The compound of claim 16, wherein:each of Rs5ca, Rs5cb, R56ca, R56cb, R?7ca, R57cb, R58ca, R58cb, R59ca, and R?9cb IS H, Orone of R55ca, Rsscb, Rseca, Rs6cb, Rs7Ca, Rs7cb, Rssca, Rs&b, Rs9ca, and Rs9cb is selected from halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce 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) R50c is -0CH3;(ii) Rsic is unsubstituted C3 cycloalkyl;(iii) R52C is H;each of R55ca, R55cb, R?7ca, Rj7cb, RjSea, Rs8cb, R59ca,and Rs9cb is H; orRgScax. R55CbR58ca          R59cbR57cb R57ca , each of R55ca, R55cb, R57ca, R57cb, RjSca, R59ca,andRs9cb is H and Rsscb is F.

19. The compound of any one of claims 16 to 18, wherein the compound is selected from:

20. The compound of claim 1 or 2, wherein 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:, O / iiR5od is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -OH, and 0H , wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more substituents selected from deuterium, -OH, halogen, and Ci-Ce alkoxy;Rsidis selected from Ci-Ce alkyl, C3-C6 cycloalkyl, C5-C12 spiro-fused cycloalkyl, and C3-C9 heterocyclyl, wherein Ci-Ce 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 Ci-Ce alkyl, -OH, and halogen;Rs2d is selected from H, CN, amido, halogen, -S(0)2-(Ci-C? alkyl), Ci-Ce alkyl, C2-C7 alkynyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C12 aryl, and -O-(C6-Ci2 aryl), wherein Ci-Ce alkyl is optionally substituted with one or more substituents selected from Ci-Cg alkoxy, -OH, halogen; andRssda, R55db, R56da, Rsedb, Rs7da, Rs7db, Rssda, Rssdb, Rs9da, and Rsgdb are each independently selected from H, halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Ce alkyl and Ci-Ce alkoxy are each optionally substituted with one or more halogen atoms.

21. The compound of claim 20, wherein:each of R55da, RiSdb, R56da, R56db, R?7da, Rs7db, R>8da, R58db, R59da, and Rsbdb is H; Orone of Rssda, Rssdb, Rseda, Rsedb, Rs7da, Rs7db, Rssda, Rssdb, Rs9da, and Rs9db is selected from halogen, -OH, Ci-Ce alkyl, and Ci-Ce alkoxy, wherein Ci-Cg alkyl and Ci-Ce 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) Rsod is -OCH3;(ii) Rsidis unsubstituted C3 cycloalkyl;(iii) R52d is H;R55dax^55db©R^^^L^-RsGda R58da          Rs9db, ,          is R57db Rs7da , each of Rs5da, R55db, R?7da, R57db, R58da, Rssdb, R?9da,and Rs9db is H; or, each of R?5da, R55db, R57da, R57db, R58da, Rs9da, andR59db is H and Rssdb 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 at least one of IRAKI, IRAK4, and FLT3, or wherein the compound is an inhibitor of at least two of IRAKI, IRAK4, and FLT3, or wherein the compound is an inhibitor of IRAKI and IRAK4, or wherein the compound is an inhibitor of IRAKI, 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 the composition further comprises a formulary ingredient, an adjuvant, or a carrier.

27. A method of treating a disease or disorder in a subject, the method comprising administering 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 of interleukin-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 parenteral administration, 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 the subject 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 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 not rel ap sed / refractory.

32. The method of any one of claims 27 to 30, wherein the disease or disorder is rel ap sed / 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 venetoclax relapsed / refractory disease or disorder,a hypomethylating agent relapsed / refractory disease or disorder, preferably an azacitidine relapsed / 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 a hematopoietic 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 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 autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes 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 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.

38. The method of any one of claims 27 to 37, further comprising administering to the subject 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 antibodydrug 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 / VEGFRl / 2 / 3 / FLT3 / CSF-lR / Kit / PDGFRA / B inhibitor, an AKT 1, 2, and / or 3 inhibitor, a ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, afamesyltransferase 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 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.

40. The method of claim 38 or 39, wherein the additional therapy is at least one of a BCL2 inhibitor, 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 the hypomethylating 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 which is not relapsed / refractory and the additional therapy is:a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof, ora hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof, ora combination of a BCL2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof and a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 38 to 41, wherein the disease or disorder is MDS which is not relapsed / refractory and the additional therapy is a hypomethylating agent, preferably azacitidine 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 or disorder, ora hypomethylating agent resistant disease or disorder, preferably an azacitidine resistant disease or disorder, ora BCL2 inhibitor and a hypomethylating agent resistant disease or disorder, preferably a venetoclax and an azacitidine resistant disease or disorder, ora 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, orBCL2 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, orBCL2 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, orhypomethylating agent resistant refractory 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 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 pharmaceutically acceptable salt of any one thereof, orBCL-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 of venetoclax or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt of any one thereof, orBCL-2 inhibitor and hypomethylating agent resistant relapsed 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 a combination of venetoclax or a pharmaceutically acceptable salt of thereof and azacitidine or a pharmaceutically acceptable salt of 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 azacitidine resistant MDS, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt of any one thereof, orhypomethylating agent resistant refractory MDS, preferably azacitidine resistant refractory MDS, and the additional therapy is a hypomethylating agent, preferably azacitidine or a pharmaceutically acceptable salt of any one thereof, orhypomethylating 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.

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 the composition of claim 26 and the one or more additional therapies are administered together in one administration or composition.

52. The method of claim 38, wherein the compound of any one of claims 1 to 25 or the composition of claim 26 and the one or more additional therapies are administered separately in more 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 IRAKI, IRAK4, and FLT3 in the subject, wherein the disease or disorder is alleviated by inhibiting at least two of IRAKI, IRAK4, and FLT3 in the subject, wherein the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject, or wherein the disease or disorder is alleviated by inhibiting IRAKI, IRAK4, and FLT3 in the subject.

54. The method of claim 53, 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.

55. The method of any one of claims 27 to 54, wherein 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.