Polycyclic IRAK and FLT3 inhibitor compounds and uses thereof

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to U.S. Provisional Application No. 63 / 125,654, filed December 15, 2020, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE DISCLOSURE This disclosure relates generally to compounds and compositions that are kinase inhibitors and their use in the treatment of diseases and disorders, including cancer. [Background technology]

[0003] Myelodysplastic syndromes (MDS) are malignant and potentially fatal hematologic disorders resulting from a deficiency of hematopoietic stem / progenitor cells, predisposing to acute myeloid leukemia (AML) (Corey et al., 2007; Nimer, 2008), often progressing to chemotherapy-resistant secondary acute myeloid leukemia (sAML). Many patients with MDS die from bone marrow failure, immune dysfunction, and / or transformation to overt leukemia.

[0004] MDS is a heterogeneous disease with few treatment options due to the lack of effective medications that can provide durable responses. Current treatment options for MDS are limited and include allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapy (Ebert, 2010). While hematopoietic stem cell (HSC) transplantation can be used as a curative treatment for MDS, this option is unavailable to many elderly patients, who instead receive supportive care and blood transfusions to ameliorate disease complications. Unfortunately, the MDS clone can persist in the bone marrow even after HSC transplantation, and the disease invariably progresses (Tehranchi et al., 2010). In cases of progressive disease or high-risk MDS, patients may also receive immunosuppressive therapy, epigenetic modifying drugs, and / or chemotherapy (Greenberg, 2010). Despite recent advances, the majority of MDS patients experience treatment-related toxicity or relapse (Sekeres, 2010a). Overall, the effectiveness of these treatments varies and usually results in only a modest improvement in lifespan compared with supportive care.The complexity and heterogeneity of MDS and the lack of human xenograft models present difficult obstacles to identifying and evaluating novel molecular targets for this disease.

[0005] Approximately 30% of MDS patients also develop progressive AML due to the acquisition of additional mutations in defective hematopoietic stem / progenitor cells (HSPCs) (Greenberg et al., 1997). AML is a cancer of the myeloid blood cells characterized by the rapid proliferation of abnormal white blood cells that accumulate in the bone marrow and prevent normal blood cell production. AML is the most common acute leukemia affecting adults, and its incidence increases with age. AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, but its incidence is expected to increase as the population ages. Although several risk factors and chromosomal abnormalities have been identified, the specific cause remains unclear. Acute leukemia AML progresses rapidly and, if left untreated, usually leads to death within weeks or months. The prognosis for AML due to MDS is poorer than that of other types of AML.

[0006] Although several compounds are known to treat hematological disorders and cancers (e.g., MDS, AML), their efficacy is insufficient. Although several known compounds, such as quizartinib, gilteritinib, and crenolanib, can be used to treat AML, some of these treatments do not result in complete or partial remission. In some cases, such as with quizartinib, treatment can result in adaptive resistance or the selection of mutations resistant to inhibitors, and repeated administration can lead to desensitization of tumor cell growth suppression (Melgar et al., 2019).

[0007] In the treatment of MDS and / or AML, there is a need to develop therapies that can inhibit adaptive resistance mechanisms to improve survival in the setting of AML and MDS. There is also an unmet need in AML for agents that can extend overall survival, reduce hospitalization and readmission rates, overcome acquired resistance to other therapies, and increase the success of hematopoietic stem cell transplantation. There is also a need for agents for the treatment of MDS that can slow the rate of transformation to AML and reduce transfusion dependency.

[0008] Thus, there is a need to develop therapies and methods to effectively treat MDS and / or AML, and / or other conditions or disorders characterized by dysregulated (e.g., hyperactive) IRAK (e.g., IRAK1 and / or 4). Furthermore, in doing so, it becomes important to determine whether a patient is likely to respond to a particular treatment or method of treatment. Certain embodiments of the present disclosure may address one or more of these concerns. Summary of the Invention [Problem to be solved by the invention]

[0009] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein R 1 is selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein said amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is selected from halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; oxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 2is selected from H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein said amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is selected from halogen, hydroxy, oxo, methanoyl (-COH), -COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, fused-ring aryl, heteroaryl, fused-ring heteroaryl, or C-C alkyl substituted with cycloalkyl; R 3 , R 4 , and R 5are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and said methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl. R is optionally substituted with one or more of aryloxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 6 teeth, [ka] and R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and ... -C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl are optionally substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0010] In one embodiment, the compound of formula (I) has the formula (IIf): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; 20f is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and —O—(C3-C6 cycloalkyl), wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, and the C3-C6 cycloalkyl and —O—(C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 21f , R 22f , and R 23f are each independently selected from H and halogen; R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms. 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 20f is H. In one embodiment, at least one of the following (i) to (iii) applies: (i) R 20f is Cl, below: [ka] , unsubstituted C3 cycloalkyl, and [ka] (ii) R 21f , R 22f , and R 23f are H, respectively; (iii) R 25fa , R 25fb , R 26fa , and R 26fb are H and R, respectively. 24fa and / or R 24fb is F. In one embodiment, the compound is selected from: [ka]

[0011] In one embodiment, the compound of formula (I) has the formula (IIg): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; 20g is selected from H and C1-C6 alkoxy; R 21g is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C6-C 12 aryl), C3-C9 heterocyclyl, and -NR 28ga R 28gb wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and said C3-C9 heterocyclyl are optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R 22g , R 23g , and R 24g are each independently selected from H and halogen; R 25ga , R 25gb, R 26ga , R 26gb , R 27ga , and R 27gb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; R 28ga and R 28gb are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl. 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 20g is H. In one embodiment, at least one of the following (i) to (ix) applies: (i) R 20g is -OCH3 and the following: [ka] (ii) R 21g is t-butyl, unsubstituted C3 cycloalkyl, morpholinyl, azetidinyl, piperidinyl, isoxazolyl, Cl, -CF3, -OCH3, -O-phenyl, [ka] wherein G is N or CH, and [ka] (wherein c is 1 or 2); R 21g is as follows: [ka] and R 29gis H, isopropyl, unsubstituted C3 cycloalkyl, azetidinyl, tetrahydropyranyl-CH3, [ka] (iv) R 21g is -NR 28ga R 28gb (wherein R 28ga is H and R 28gb is selected from —CH3, cyclobutyl, and cyclohexyl, or R 28ga and R 28gb are -CH3, respectively; (v) R 22g , R 23g , and R 24g are H, respectively; (vi) R 22g and R 24g are F and R, respectively. 23g is H; (vii) R 22g and R 24g are H and R, respectively. 23g is F; (viii) R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb are H, respectively; (ix) R 26ga , R 26gb , R 27ga , and R 27gb are H and R, respectively. 25ga and / or R 25gb teeth 、 F, -CH3, -OH, -CF3, the following: [ka] and -OCH3. In one embodiment, the compound is selected from: [ka] TIFF2024500378000015.tif158124TIFF2024500378000016.tif152124TIFF2024500378000017.tif154125JPEG2024500378000018.jpg125125

[0012] In one embodiment, the compound of formula (I) has the formula (IIh): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein R 20h is selected from H and C1-C6 alkoxy; R 21h is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen, and the C3-C6 cycloalkyl and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen; R 22ha , R 22hb , R 23ha , and R 23hb are each independently selected from H and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen atoms; R 24h , R 25h , and R 26h are each independently selected from H and halogen. In one embodiment, at least one of the following (i) to (iv) applies: (i) R 20h is H; (ii) R 21h is as follows: [ka] (iii) R 22ha , R 22hb , R 23ha , and R 23hb are H, respectively; (iii) R 24h , R 25h , and R26h are each H. In one embodiment, the compound is: [ka]

[0013] In one embodiment, the compound of formula (I) has the formula (IIi): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein: [ka] is as follows: [ka] Selected from;R 20i is selected from H and C1-C6 alkoxy; R 21i is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and said C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, -C=O, and halogen; R 22i , R 23i , and R 24i are each independently selected from H and halogen; R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ibare each independently selected from H, halogen, —OH, or C1-C6 alkyl. 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is independently selected from halogen, —OH, and C1-C6 alkyl. 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is H. In one embodiment, at least one of the following (i) to (xi) is true: (i) R 20i is selected from H and —OCH; (ii) R 21i is as follows: [ka] , unsubstituted C3 cycloalkyl, [ka] wherein J is N or CH, and [ka] (iii) R 21i is as follows: [ka] where R 220i is H, -CH3, as follows: [ka] and unsubstituted C cycloalkyl; (iv) R 22i , R 23i, and R 24i are H, respectively; (v) R 22i and R 24i are F and R, respectively. 23i is H; (vi) R 22i and R 24i are H and R, respectively. 23i is F; (vii) the following: [ka] is as follows: [ka] and R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib Each of is H and R 25ib is F; (viii) the following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib each of which is H; (ix) the following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 28ib、 R 29ia , and R29ib each of which is H; (x) the following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 29ia , and R 29ib Each of is H and R 28ib is F; (xi) the following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib Each of is H and R 27ib is F. In one embodiment, the compound is selected from: [ka] JPEG2024500378000041.jpg160124JPEG2024500378000042.jpg130125

[0014] In one embodiment, the compound of formula (I) has the formula (IIj): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein: [ka] is as follows: [ka] Selected from;R 20j is selected from H and C1-C6 alkoxy; R 21j is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and —OH, and said C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 22j , R 23j , and R 24j are each independently selected from H and halogen. In one embodiment, at least one of the following (i) to (iv) applies: (i) R 20j is selected from H and —OCH; (ii) R 21j is unsubstituted C3 cycloalkyl; (iii) R 22j , R 23j , and R 24j are each H; (iv) the following: [ka] is as follows: [ka] In one embodiment, the compound is selected from: [ka]

[0015] In one embodiment, the compound of formula (I) has the formula (IIIq): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein R 30qis selected from H and C1-C6 alkoxy; R 31q is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 32q , R 33q , and R 34q are each independently selected from H and halogen. In one embodiment, at least one of the following (i) to (iv) applies: (i) R 30q is H; (ii) R 31q is as follows: [ka] wherein d is 1 or 2, and [ka] wherein K is N or CH; (iii) R 31q is as follows: [ka] where R 35q is selected from H, —CH, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iv) R 32q , R 33q , and R 34q are each H. In one embodiment, the compound is selected from: [ka] JPEG2024500378000054.jpg67124

[0016] In one embodiment, the compound of formula (I) has the formula (IIIr): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein R 30r is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 31r is selected from H and C1-C6 alkoxy; R 32r , R 33r , and R 34r are each independently selected from H and halogen. In one embodiment, at least one of the following (i) to (iv) applies: (i) R 30r is as follows: [ka] wherein L is N or CH and: [ka] (ii) R 30r is as follows: [ka] where R 35ris selected from H, —CH, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iii) R 31r is H; (iv) R 32r , R 33r , and R 34r are each H. In one embodiment, the compound is selected from: [ka] JPEG2024500378000060.jpg88125

[0017] In one embodiment, the compound of formula (I) has formula (IIIs): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein R 30s is selected from H and C1-C6 alkoxy; R 31s is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 32s , R 33s , and R 34s are each independently selected from H and halogen. In one embodiment, at least one of the following (i) to (iv) applies: (i) R 30s is H; (ii) R 31s is as follows: [ka] wherein M is N or CH and: [ka] (iii) R 31s is as follows: [ka] where R 35s is selected from H, —CH, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iv) R 32s , R 33s , and R 34s are each H. In one embodiment, the compound is selected from: [ka] JPEG2024500378000066.jpg75124

[0018] In another aspect, the disclosure relates to a compound of any of the formulas disclosed herein, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3. In one embodiment, the compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3. In one embodiment, the compound is an inhibitor of IRAK1 and IRAK4. In one embodiment, the compound is an inhibitor of IRAK1, IRAK4, and FLT3. In one embodiment, the FLT3 is selected from WT FLT3, activated FLT3, and mutant FLT3. In one embodiment, the mutant FLT3 is D835Y mutant FLT3 or F691L mutant FLT3.

[0019] In another aspect, the disclosure relates to a composition comprising a compound of any one of the formulae disclosed herein, said composition further comprising a formulation ingredient, adjuvant, or carrier. In one embodiment, the composition is selected from the group consisting of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2 / MAPK1 or ERK1 / MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a topoisomerase inhibitor, a ribozyme ... In one embodiment, the composition is used in combination with one or more of a BCL2 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, a NEDD8 activator, an MDM2 inhibitor, a PLK1 inhibitor, an AuraA inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a Menin-KMT2A / MLL inhibitor, and a multikinase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the disclosure relates to 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 of the formulas disclosed herein or a composition comprising a compound of any of the formulas disclosed herein. In one embodiment, the method comprises administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (I) and a formulation ingredient, adjuvant, or carrier. In one embodiment, the disease or disorder responds to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition. In one embodiment, the administration comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. In one embodiment, the compound is administered to the subject in an amount of about 0.005 mg / kg to about 1,000 mg / kg of the subject's body weight. In one embodiment, the disease or disorder comprises a hematopoietic cancer. In one embodiment, the disease or disorder comprises myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML). In one embodiment, the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid carcinoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MYD88-mutated DLBCL, follicular lymphoma, or marginal zone lymphoma. In one embodiment, the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof.In one embodiment, the disease or disorder comprises one or more inflammatory or autoimmune diseases 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, or a combination thereof. In one embodiment, the disease or disorder comprises (i) MDS, MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2; or (ii) AML with splicing factor mutations, AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or AML that is not driven by FLT3 mutations but expresses IRAK4-Long. In one embodiment, the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1, and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1. In one embodiment, the disease or disorder comprises DLBCL, and the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL or the S219C MYD88 mutant (GCB) subtype of DLBCL.In one embodiment, the method further comprises administering to a subject a therapeutic agent selected from the group consisting of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, 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 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, a NEDD8 activator, an MDM2 inhibitor, a PLK1 inhibitor, an AuraA inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a Menin-KMT2A / MLL inhibitor, and a multikinase inhibitor. In one embodiment, the method further comprises administering a BCL2 inhibitor to the subject. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is a BCL2 inhibitor-resistant disease or disorder. In one embodiment, the disease or disorder is a venetoclax-resistant disease or disorder. In one embodiment, the disease or disorder is an FLT3 inhibitor-resistant disease or disorder. 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 FLT3 inhibitor-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 FLT3 inhibitor-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 FLT3 inhibitor-resistant relapsed acute myeloid leukemia (AML). In one embodiment, the compound of any of the formulas disclosed herein or a composition comprising a compound of any of the formulas disclosed herein and the one or more additional therapeutic agents are administered together in a single dose or composition. In one embodiment, the compound of any of the formulas disclosed herein or a composition comprising a compound of any of the formulas disclosed herein and the one or more additional therapeutic agents are administered separately in multiple doses or compositions. In one embodiment, the disease or disorder is alleviated in a subject by inhibiting at least one of IRAK1, IRAK4, and FLT3. In one embodiment, the disease or disorder is alleviated in a subject by inhibiting at least two of IRAK1, IRAK4, and FLT3. In one embodiment, the disease or disorder is alleviated in a subject by inhibiting IRAK1 and IRAK4. In one embodiment, the disease or disorder is alleviated in a subject by inhibiting IRAK1, IRAK4, and FLT3. In one embodiment, the FLT3 is selected from WT FLT3, activated FLT3, and mutant FLT3. In one embodiment, the mutant FLT3 is a D835Y mutant FLT3 or an F691L mutant FLT3. [Brief explanation of the drawings]

[0021] [Figure 1A] Figure 1A shows the concentration (nM) response of Compound 106 and venetoclax to inhibition of cell viability measured at 48 hours. The number in each cell represents the % of viable cells at each given concentration combination (Figure 1A). Figure 1A: 10x10 combinations of venetoclax and Compound 106 in MOLM14 (D835Y) cells. The number in each cell represents the % response at each given concentration combination. [Figure 1B] Figure 1B shows the concentration (nM) response of Compound 106 and venetoclax for inhibition of cell viability measured at 48 hours. The number in each cell represents the excess HSA score (Figure 1B). Figure 1B: 10x10 combinations of venetoclax and Compound 106 in MOLM14(D835Y) cells. The number in each cell represents the excess HSA score for each given concentration combination. A negative excess HSA score indicates that the drug combination is superior to either drug alone; the more negative the excess HSA score, the greater the synergistic effect observed.

[0022] [Figure 2A] Figure 2A shows the concentration (nM) response of Compound 108 and venetoclax to inhibition of cell viability measured at 48 hours. The number in each cell represents the % of viable cells at each given concentration combination (Figure 2A). Figure 2A: 10x10 combinations of venetoclax and Compound 108 in MOLM14 (D835Y) cells. The number in each cell represents the % response at each given concentration combination. [Figure 2B] Figure 2B shows the concentration (nM) response of Compound 108 and venetoclax for inhibition of cell viability measured at 48 hours. The number in each cell represents the excess HSA score (Figure 2B). Figure 2B: 10x10 combinations of venetoclax and Compound 108 in MOLM14(D835Y) cells. The number in each cell represents the excess HSA score for each given concentration combination. A negative excess HSA score indicates that the drug combination is superior to either drug alone; the more negative the excess HSA score, the greater the synergistic effect observed.

[0023] [Figure 3A] Figure 3A shows the relative potency of various compounds to synergize with venetoclax in 10x10 combinations in MOLM14(D835Y) cells. Here, relative potency is expressed as the concentration of compound required to sufficiently enhance a 7.8 nM concentration of venetoclax to less than 5% of the maximal response in cell viability experiments. The numbers in each cell represent the percent response at each given concentration combination. Figure 3A: Compound 106 (see structure below chart) at 3.1 nM sufficiently enhances the 7.8 nM venetoclax response, while the FLT3 / BTK inhibitor CG-806 (see structure on the right side of chart) requires significantly higher concentrations to achieve similar enhancement levels at the same 7.8 nM venetoclax concentration. [Figure 3B] Figure 3B shows the relative potency of various compounds to synergize with venetoclax in 10x10 combinations in MOLM14(D835Y) cells. Here, relative potency is expressed as the concentration of compound required to sufficiently potentiate venetoclax at 7.8 nM to less than 5% of the maximal response in cell viability experiments. The numbers in each cell represent the percent response at each given concentration combination. Figure 3B: Other FLT3 inhibitors, gilteritinib hemifumarate (see structure below chart), quizartinib (see structure on the right side of chart), and CA-4948 (see structure on the right side of chart), also require significantly higher concentrations to achieve similar potentiation levels as compound 106 at the same 7.8 nM venetoclax concentration.

[0024] Detailed Description of the Disclosure The following related applications are incorporated by reference in their entirety for all purposes: U.S. Patent Application No. 62 / 414,058, "Overexpression of U2AF1 as a Genetic Predictor of Activated IRAK," filed October 28, 2016; U.S. Patent Application No. 62 / 429,289, "Overexpression of U2AF1 as a Genetic Predictor of Activated IRAK," filed December 2, 2016; PCT Patent Publication No. WO2018081738, "Treatment of Diseases Associated with Activated IRAK," filed October 30, 2017; U.S. Patent Application No. 16 / 339,692, "Treatment of Diseases Associated with Activated IRAK." IRAK, filed April 4, 2019; U.S. Patent Application No. 61 / 826,211, Combination Therapy for MDS, filed May 22, 2013; PCT Patent Publication No. WO2014190163, 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; U.S. Patent No. 10,487,329, Methods and Compositions for the Treatment of Head and Neck Cancer, issued November 26, 2019; U.S. Patent Application No. 62 / 375,965, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 17, 2016;PCT Patent Publication No. WO2018038988, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 16, 2017; U.S. Patent Application No. 16 / 326,571, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed February 19, 2019; U.S. Patent Application No. 16 / 804,518, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed February 28, 2020; U.S. Patent Application No. 62 / 812,948, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing COMPOUNDS, filed March 1, 2019; U.S. Patent Application No. 63 / 059,815, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 31, 2020; International Patent Application No. PCT / US2021 / 044089, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 31, 2021; U.S. Patent Application No. 63 / 129,895, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed December 23, 2020; and U.S. Patent Application No. 63 / 285,663, IRAK Inhibitors Combination Therapies, filed December 3, 2021.

[0025] While embodiments embodying the general inventive concept may take a variety of forms, various embodiments are described herein with the understanding that the disclosure should be considered merely as exemplary and that the general inventive concept is not intended to be limited to the disclosed embodiments.

[0026] Some embodiments of the present invention include compounds of the present invention (e.g., compounds of Formula (I)). Other embodiments include compositions (e.g., pharmaceutical compositions) including compounds of the present invention. Still other embodiments of the present invention include compositions using compounds of the present invention, for example, to treat specific diseases. Some embodiments include methods of using compounds of the present invention (e.g., in compositions or pharmaceutical compositions) for administration and treatment. Further embodiments include methods of making compounds of the present invention. Still other embodiments include methods for determining whether a particular patient is likely to respond to treatment with compounds and compositions of the present invention.

[0027] Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.

[0028] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are drawn up according to the standard rules of chemical valency known in the chemical arts.

[0029] Where substituents are designated by a conventional chemical formula written from left to right, they also encompass the chemically identical substituents obtained by writing the structure from right to left. For example, -CHO- is equivalent to -OCH-.

[0030] As used herein, with respect to compounds of Formula (I), (II), (III), etc., the term "attached" means a stable covalent bond, with particular preferred points of attachment being apparent to those skilled in the art.

[0031] As used herein (unless otherwise specified), the term "alkyl" refers to a monovalent, straight- or branched-chain hydrocarbon chain having the specified number of carbon atoms (i.e., C-C means 1 to 10 carbons), which can be fully saturated, monovalent, or polyunsaturated, and which can include divalent and polyvalent radicals. For example, the terms "C-C alkyl" or "C-C alkyl" refer to a straight- or branched-chain saturated hydrocarbon group having 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7) or 1 to 4 (e.g., 1, 2, 3, or 4) carbon atoms, respectively. Examples of C-C 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.

[0032] As used herein (unless otherwise specified), the term "alkenyl" refers to a monovalent straight or branched hydrocarbon chain containing one or more (e.g., 1, 2, 3, or 4) double bonds. The double bond may occur at any stable point along the chain, and the carbon-carbon double bond may have a cis or trans configuration. For example, this definition includes, but is not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, 1-pentenyl-3-cyclohexenyl, and the like. Similarly, "heteroalkenyl" refers to a heteroalkyl having one or more double bonds. Further examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0033] As used herein (unless otherwise specified), the term "alkynyl" refers to a monovalent straight or branched hydrocarbon chain that contains one or more (e.g., 1, 2, 3, or 4) triple bonds and optionally contains one or more (e.g., 1, 2, 3, or 4) double bonds within the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0034] As used herein (unless otherwise specified), the term "alkoxy" means any of the above alkyl, alkenyl, or alkynyl groups attached to the remainder of the molecule by an oxygen atom (alkyl-O-). Examples of alkoxy groups include, but are not limited to, methoxy (sometimes written as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy.

[0035] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, exemplified but not limited by -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms.

[0036] As used herein (unless otherwise specified), the term "cycloalkyl" refers to a monovalent, monocyclic or bicyclic, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon group. The ring may be saturated or partially unsaturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyl (e.g., bicyclooctanes, such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane; bicyclononanes, such as [4.3.0]bicyclononane; and bicyclodecanes, such as [4.4.0]bicyclodecane (decalin), or spiro compounds). In the case of a monocyclic cycloalkyl, the ring is not aromatic. In the case of a bicyclic cycloalkyl, if one ring is aromatic, the other ring is not aromatic. In the case of bicyclic cycloalkyls, one or both rings may be substituted.

[0037] The term "heteroalkyl," by itself or in combination with other terms, means, unless otherwise stated, stable, linear or branched chains, or combinations thereof, which consist of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms can be oxidized, and the nitrogen heteroatom can be quaternized. The heteroatom(s) O, N, P, S, and Si can be placed at any position within the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two heteroatoms may be consecutive, e.g., -CH2-NH-OCH3.

[0038] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, as used herein, heteroalkyl groups include groups that are attached to the remainder of the molecule through a heteroatom, e.g., —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and / or —SOR′. When “heteroalkyl” is recited followed by a specific heteroalkyl group, such as —NR′R″, it is understood that the terms heteroalkyl and —NR′R″ are not overlapping or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term “heteroalkyl,” as used herein, should not be construed as excluding specific heteroalkyl groups, such as —NR′R″.

[0039] As used herein (unless otherwise specified), the term "halogen" or "halo" refers to monovalent Cl, F, Br, or I. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0040] As used herein (unless otherwise specified), the term "aryl" refers to a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic hydrocarbon group, which may be monocyclic or polycyclic (preferably 1 to 3 rings) that are fused together (i.e., fused-ring aryl) or covalently linked to each other. Fused-ring aryl refers to multiple rings fused together, where at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. In the case of bicyclic aryls, one or both rings may be substituted.

[0041] As used herein (unless otherwise specified), the term "heteroaryl" refers to a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon group in which 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic ring system is aromatic. A heteroaryl group (or ring) can contain 1 to 4 heteroatoms selected from N, O, and S, and the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen atom can be quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together in which at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, one of which has 5 members and the other has 6 members, and at least one ring is a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one of which has 6 members and the other has 6 members, and at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, one of which has 6 members and the other has 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group can be attached to the rest of the molecule through a carbon or heteroatom. Examples of heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisoxazolyl, 1H-pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl. In the case of bicyclic heteroaryls, if one ring is aryl, the other ring is heteroaryl. In the case of bicyclic heteroaryls, one or both rings can have one or more heteroatoms. In the case of bicyclic heteroaryls, one or both rings can be substituted.

[0042] "Arylene" and "heteroarylene," alone or as part of another substituent, refer to divalent radicals derived from aryl and heteroaryl, respectively. Thus, the term "aryl" can refer to unsubstituted, monosubstituted, disubstituted, or trisubstituted monocyclic, polycyclic, biaryl, and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, with particular preferred points of attachment being apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl). Aryl substituents can independently be halo, nitro, cyano, trihalomethyl, C 1-16 Alkyl, aryl C 1-16 Alkyl, C0- 16 Alkyloxy C0- 16 Alkyl, aryl C0- 16 Alkyloxy C0- 16 Alkyl, C0- 16 AlkylthioC0- 16 Alkyl, aryl C0- 16 AlkylthioC0- 16 Alkyl, C0- 16 Alkylamino C0- 16 Alkyl, aryl C0- 16 Alkylamino C0- 16 Alkyl, di(aryl C1- 16 Alkyl)aminoC0- 16 Alkyl, C1- 16 Alkylcarbonyl C0- 16 Alkyl, aryl C 1-16 Alkylcarbonyl C0- 16 Alkyl, C1- 16 Alkyl carboxy C0- 16 Alkyl, aryl C1- 16 Alkyl carboxy C0- 16 Alkyl, C 1-16 AlkylcarbonylaminoC0- 16 Alkyl, aryl C1- 16 AlkylcarbonylaminoC0- 16 Alkyl, -C0- 16 Alkyl COOR4, -C0- 16alkylCONR5R6, where R4, R5, and R6 are independently hydrogen, C1-C 11 Alkyl, aryl C0-C 11 alkyl, or R5 and R6, when joined, form one C 1-16 Alkyl, aryl C0-C 16 Alkyl, or C0-Cl 16 and (together with the nitrogen to form a ring system containing 3 to 8 carbon atoms, with or without alkylaryl substituents). Aryl includes, but is not limited to, pyrazolyl and triazolyl.

[0043] Briefly, the term "aryl," when used in conjunction with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the terms "arylalkyl," "aralkyl," and the like are intended to include radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like), wherein the alkyl group includes alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like) or a sulfur atom. Thus, terms such as "arylalkyl" (e.g., (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represent an aryl group, as defined above, attached via an alkyl group, as defined above, having the indicated number of carbon atoms.

[0044] The terms "cycloalkyl" and "heterocycloalkyl," also referred to as "heterocyclyl," by themselves or in combination with other terms, refer to cyclic versions of "alkyl" and "heteroalkyl," respectively, unless otherwise stated. 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 stated), the term "heterocycloalkyl" or "heterocyclyl" means a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon ring in which 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic ring system is not aromatic. Furthermore, 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, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, Examples of heterocyclic rings include pyrrolidin-3-yl, 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, piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl), and morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl). In the case of a bicyclic heterocyclyl, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), the other ring is not aromatic. In the case of a bicyclic heterocyclyl, one or both rings can have one or more heteroatoms.For bicyclic heterocyclyls, one or both rings can be substituted, etc. "Cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0045] As used herein (unless otherwise specified), the term "heteroatom" means an atom selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0046] As used herein (unless otherwise specified), the term "hydroxy" or "hydroxyl" refers to the monovalent --OH group.

[0047] The term "acyl," unless otherwise indicated, means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0048] As used herein, the term "oxo" means an oxygen that is double bonded to a carbon atom.

[0049] As used herein, the term "alkylsulfonyl" means a moiety having the formula -S(O2)-R', where R' is an alkyl group as defined above. R' can have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0050] The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge.

[0051] In the above definitions, the terms "alkyl" and "alkenyl" can be used interchangeably as long as a stable chemical entity is formed, as will be apparent to those skilled in the art.

[0052] The term "linker" refers to a linking group that is interposed between substituents. In some embodiments, the linker is an amide (-CONH-R n or -NHCO-R n ), thioamide (-CSNH-R n or -NHCS-R n ), carboxyl (-CO2-R n or -OCOR n ), carbonyl (-CO-R n ), urea (-NHCONH-R n ), thiourea (-NHCSNH-R n ), sulfonamide (-NHSO2-R n or -SO2NH-R n ), ether (-OR n ), sulfonyl (-SO2-R n ), sulfoxyl (-SO-R n ), carbamoyl (-NHCO2-R n or -OCONH-R n ), or amino (-NHR n ) including the connecting portion.

[0053] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl," and "heteroaryl," etc.) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein.

[0054] As used herein (unless otherwise specified), the term "substituted" (e.g., in substituted alkyl) means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from a specified set of options. The substitution can occur at one or more positions. The term "optionally substituted" means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) can be replaced, but is not required to be replaced.

[0055] As used herein, "substituent group" means a non-hydrogen substituent that may be, and preferably is, a group selected from the following moieties: (A) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), -CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties 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 perfluoroalkyl, 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 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties substituted with at least one substituent selected from: (a) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), -CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties substituted with at least one substituent selected from the following: -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-S03H), -CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0056] As used herein, a "size-limited substituent" or "size-limited substituent group" means, for example, a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4- to 8-membered heterocycloalkyl.

[0057] As used herein, a "lower substituent" or "lower substituent group" means, for example, a group selected from all of the substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C5-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5- to 7-membered heterocycloalkyl.

[0058] The term "about" when used in the context of a numerical value indicates a range of + / - 10% of the numerical value, unless otherwise specified.

[0059] Some compounds of the present invention may have one or more chiral centers and may exist and be isolated in optically active racemic forms with respect to any one or more chiral centers. Some compounds may exhibit polymorphism. The compounds of the present invention (e.g., Formula I) encompass any optically active form, racemate, stereoisomeric form, polymorph, or mixture thereof. When a chiral center does not provide an indication of its configuration (i.e., R or S) in the chemical structure, it is considered to represent R, S, or racemic.

[0060] As used herein, the term "sample" encompasses samples obtained from a subject or patient. The sample can be any biological tissue or fluid. Such samples include, but are not limited to, sputum, saliva, buccal samples, oral cavity samples, blood, serum, mucus, plasma, urine, blood cells (e.g., white blood cells), circulating cells (e.g., stem cells or endothelial cells in blood), tissue, core or fine needle biopsy samples, cell-containing body fluids, free-floating nucleic acids, urine, stool, peritoneal fluid, and pleural fluid, tears, or cells derived therefrom. Samples can also include tissue sections, such as frozen or fixed sections taken for histological purposes, or microdissected cells or their extracellular portions. The sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch, excision, or other surgical methods resulting in biopsy or excised cellular material. Such samples can include cells obtained from a subject or patient. In some embodiments, the sample is a bodily fluid, including, but not limited to, blood fluid, serum, mucus, plasma, lymph, peritoneal fluid, gynecological fluids, or urine, hi some embodiments, the sample can be a non-invasive sample, such as, for example, a saline swish, buccal scrape, or buccal swab.

[0061] As used herein, "blood" can include, for example, plasma, serum, whole blood, blood lysate, and the like.

[0062] As used herein, the term "assessing" includes any form of measurement and includes determining whether 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.

[0063] As used herein, the term "monitoring" with respect to a cancer type refers to a method or process of determining the severity or extent of the cancer type or stratifying the cancer type based on the risk and / or probability of death. In some embodiments, monitoring relates to a method or process of determining the therapeutic effectiveness of a treatment being administered to a patient.

[0064] As used herein, "outcome" can refer to the outcome studied. In some embodiments, "outcome" can refer to survival / mortality over a given period of time. For example, "outcome" can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or more. In some embodiments, an increased risk of poor prognosis indicates poor efficacy of the treatment, and a decreased risk of poor prognosis indicates good efficacy of the treatment.

[0065] As used herein, the term "high-risk clinical trial" refers to a clinical trial in which the investigational agent poses "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 clinical trial.

[0066] As used herein, the term "low-risk clinical trial" refers to a clinical trial in which the risk of the investigational agent is "minimal" (as defined by the terminology used by the IRB). In some embodiments, a low-risk clinical trial is a clinical trial that is not a clinical trial. In some embodiments, a low-risk clinical trial involves the use of monitoring or clinical practice processes. In some embodiments, a low-risk clinical trial is an observational clinical trial.

[0067] As used herein, unless otherwise specified or clear from the context of a particular usage, the terms "modulated" or "modulation," or "regulated" or "regulation" and "differentially regulated" can mean both upregulation (i.e., activation or stimulation, e.g., by stimulating or enhancing) and downregulation (i.e., inhibition or suppression, e.g., by antagonizing, decreasing, or inhibiting).

[0068] As used herein, the term "subject" refers to any suitable (e.g., treatable) member of the animal kingdom. In the methods, the subject is preferably a mammal. In the methods, the subject is preferably a human patient. In the methods, the subject may be a pediatric mammalian patient. In the methods, a pediatric patient is a mammalian (e.g., preferably human) patient under the age of 18, while an adult patient is 18 or older.

[0069] As used herein, the term "treat" (and variations thereof, such as "treatment," "treat," "treating," etc.) is intended in its broadest context, unless otherwise indicated, to mean obtaining a desired pharmacological and / or physiological effect. In particular, for example, the term "treat" does not necessarily imply or require that an animal be treated until complete recovery. Thus, "treating" includes amelioration of symptoms, alleviation of symptoms or effects associated with a condition, reduction in the severity of a condition, or prevention of symptoms, prophylactic amelioration of symptoms, or reduction in the risk of developing a particular condition. In some aspects, "treatment" does not require or include prevention. As used herein, reference to "treating" an animal includes, but is not limited to, prophylactic and therapeutic treatment. The effect may be prophylactic, in that a disease or its symptoms are completely or partially prevented, and / or therapeutic, in that a disease and / or side effects that may result from the disease are partially or completely cured. As used herein, "treatment" encompasses any treatment of a disease in a subject, preferably a mammal (e.g., a human), and may include one or more of the following: (a) preventing the onset of the disease in a subject who may be predisposed to the disease but has not yet been diagnosed as having the disease; (b) inhibiting the disease, i.e., preventing its onset; and (c) alleviating the disease, i.e., causing regression or elimination of the disease and / or alleviating one or more disease symptoms. In certain aspects of the method, such as for conditions or disorders characterized by dysregulated IRAK expression or a dysregulated (e.g., overactive) IRAK-mediated signaling pathway, treatment can be or include reducing such expression or signaling. "Treatment" can also encompass the delivery of an agent or administration of a therapeutic agent to provide a pharmacological effect, even in the absence of a disease or condition. Any of the compositions (e.g., pharmaceutical compositions) described herein can be used to treat a suitable subject.

[0070] A "therapeutically effective amount" refers to an amount effective to achieve a desired and / or beneficial effect. An effective amount can be administered in one or more administrations. In the methods, a therapeutically effective amount is an amount adequate to treat an indication. Treating an indication means achieving any desired effect, such as one or more of palliating, ameliorating, stabilizing, reversing, slowing, or delaying the progression of a disease, improving quality of life, or extending lifespan. Such achievement can be measured by any suitable method, such as measuring tumor size or blood counts, or any other suitable measurement.

[0071] As used herein, the term "marker" or "biomarker" refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, etc., whose presence or concentration can be detected and correlated with a known condition, such as a diseased state. It can also be used to refer to a differentially expressed gene whose expression pattern can be used as part of a predictive, prognostic, or diagnostic process in healthy or diseased states, or can be used in methods to identify useful therapeutic or preventative measures.

[0072] As used herein, an mRNA "isoform" is an alternative transcript of a particular mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, truncated, shortened, or aberrant mRNA, modified mRNA (including, for example, any residue modification, capping variants, polyadenylation variants, etc.), and the like.

[0073] "Antibody" or "antibody peptide" refers to an intact antibody or a binding fragment thereof that competes with the intact antibody for specific binding; this definition 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. For example, an antibody substantially inhibits the adhesion of a receptor to its counter-receptor when an excess of the antibody reduces the amount of receptor bound to the counter-receptor by at least about 20%, 40%, 60%, or 80%, more typically by greater than about 85%, as measured in an in vitro competitive binding assay.

[0074] Embodiments of the invention described herein include compounds of the invention (e.g., compounds of Formula (I), such as compounds of Formula (II) and Formula (III)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising compounds of the invention. Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) using compounds of the invention, for example, to treat a particular disease. Some embodiments include methods of administering and using compounds of the invention (e.g., in compositions or pharmaceutical compositions) for treatment (e.g., of a disease such as cancer or a blood disorder). Some embodiments include methods of determining whether a patient is suitable for or may respond favorably to a particular treatment. Further embodiments include methods of making compounds of the invention. Additional embodiments of the invention are also described herein.

[0075] Compounds and compositions containing pharmaceutical compositions Some embodiments of the present invention relate to compounds of formula (I-5008): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof having a structure according to Formula (I-5008). In some embodiments, the compound is a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative of Formula (I-5008). In some embodiments, the compound is not an ester, is not a solvate, or is not a prodrug.

[0076] In an exemplary embodiment, R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, and each of said amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is independently selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; The heteroaryl may be optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl.

[0077] In some embodiments, R 1can be H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein the amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl can be H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl. optionally substituted with one or more of hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 2can be H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein the amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl can be H, halogen, hydroxy, oxo, methanoyl (optionally substituted with one or more of -COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, fused-ring aryl, heteroaryl, fused-ring heteroaryl, or C-C alkyl substituted with cycloalkyl); R 3 , R 4 , and R 5can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl. , oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl).

[0078] R 6 can be: [ka]

[0079] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, as defined above, C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl may be substituted with one or more halogens); m, n, o, p, q, r, s, t, u, v, w, and x can be 0, 1, 2, 3, 4, or 5, and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0080] In some embodiments, R 1is H, halogen, -CONH2, -CONHCH3, -CON(CH3)2, benzyl, C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl, wherein said C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl is optionally substituted with one or more halogen, hydroxyl, C1-C7 alkyl, or C1-C7 haloalkyl. 1 is H, Cl, -CONH2, -CONHCH3, methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl, wherein said methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl is optionally substituted with one or more F, -OH, methoxy, or CF3. 1 is not H.

[0081] In some embodiments, R 2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, wherein said 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 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 2is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl, wherein said 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, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 2 is H, Cl, hydroxy, -NHCH, -N(CH), -OCH, -OCF, -OCHF, -OPh, -CF, -CHF, unsubstituted C-C alkyl, substituted amino, substituted C-C alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl. In some embodiments, R 2 is not H.

[0082] In some embodiments, R 3is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, wherein said C1-C7 alkyl or C2-C6 alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), 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 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 3 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0083] In some embodiments, R 4 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, wherein said C1-C7 alkyl or C2-C6 alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), 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 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 4 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0084] In some embodiments, R5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, wherein said C1-C7 alkyl or C2-C6 alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), 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 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 5 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0085] In some embodiments, R 4 is methyl or -CF3, and R 3 and R 5 At least one of is H or halogen.

[0086] In some embodiments, R 6 A chiral center exists at the bond carbon. In some embodiments, the chiral center is an R chiral center. In some embodiments, the chiral center is an S chiral center. In certain embodiments, the chiral center can be represented by the following bond: [ka] As will be appreciated by those skilled in the art, where chiral centers can exist at other positions in compounds according to formula (I), the depicted straight bond can also be: [ka]

[0087] In some embodiments, R 6 is as follows: [ka]

[0088] In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and each independently selected from methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; is optionally substituted with one or more halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), nitro (—NO), —NH, —N(CH), cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH, —CONHCH, —CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl, with the proviso that R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14At least one of R is not H. In some embodiments, 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and each of said methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; The alkyl group may be optionally substituted with one or more halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5; and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0089] In one embodiment, R 7, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 At least one of R is not H. In another embodiment, 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 Each of, if present, is H.

[0090] In one embodiment, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 At least one of R is not H. In another embodiment, 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 Each of, if present, is H.

[0091] In some embodiments, R 6 is as follows: [ka]

[0092] In some embodiments, R 6 is as follows: [ka]

[0093] Some embodiments of the present invention include compounds having a structure according to formula (I): [ka] In the formula, Y to R 6 Wave coupling to: [ka] In some cases, R 6 indicates the presence of a chiral center at the bonding carbon. In some embodiments, R 6 When a chiral center is present at the bonded carbon, the wavy bond can represent an R chiral center, an S chiral center, or a racemate. [ka] is as follows: [ka] As will be appreciated by those skilled in the art, where chiral centers can exist at other positions in compounds according to formula (I), the depicted direct bond can also be: [ka]

[0094] In some embodiments, R 6 is (Ia) and gives the structure of formula (II) below: [ka]

[0095] 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.

[0096] In some embodiments, R 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14 At least one of is not H, and / or R 11 , R 12 , R 13 , and R 14 is H and R 7 , R 8 , R 9 , and R 10 At least one of R is not H. In specific embodiments, 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkoxy, or spiro-fused cycloalkyl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogens. 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14At least one of is halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, wherein said methanoyl (—COH), carboxy (—COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogens. 11 , R 12 , R 13 , and R 14 is H and R 7 , R 8 , R 9 , and R 10 At least one of is halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, wherein said methanoyl (—COH), carboxy (—COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogens. 7 , R 8 , R 9 , and R 10 At least one of R is halogen, hydroxyl, C-C alkyl, C-C haloalkyl, C-C alkoxy, or spiro-fused cycloalkyl. 7 , R 8 , R 9 , and R 10 At least one of R is F, hydroxyl, methyl, methoxy, —CHF, —CF, spirofused cyclopropyl, spirofused cyclobutyl, or spirofused cyclopentyl. 7 and R 8 Both or R 9 and R 10 Both are F, or R 7 and R 8 Both or R 9 and R 10In some embodiments, both R 11 , R 12 , R 13 , and R 14 At least one of R is halogen, hydroxyl, C-C alkyl, C-C haloalkyl, C-C alkoxy, or spiro-fused cycloalkyl. 11 , R 12 , R 13 , and R 14 At least one of R is F, hydroxyl, methyl, methoxy, —CHF, —CF, spirofused cyclopropyl, spirofused cyclobutyl, or spirofused cyclopentyl. 11 and R 12 Both or R 13 and R 14 Both are F, or R 11 and R 12 Both or R 13 and R 14 Both are methyl.

[0097] In addition to the embodiment in which the compound has the structure of formula (II), the compound can have a structure according to any of (IIa)-(IIe), where V, W, X, Y, and Z are independently selected from R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , or R 14 and at least one of V, W, X, Y, and Z is not H. [ka] TIFF2024500378000081.tif130124

[0098] In one embodiment, the compound of formula (II) has the formula (IIf): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20f is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O-(C3-C6 cycloalkyl), wherein said C1-C6 alkyl and C1-C6 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 C1-C6 alkyl and halogen; R 21f , R 22f , and R 23f are each independently selected from H and halogen; R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more halogen atoms.

[0099] In one embodiment, R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb Each of these is H.

[0100] In one embodiment, R 20f is H. In another embodiment, R 20fis not H. In one embodiment, R 20f is halogen. In one embodiment, R 20f is Cl. In another embodiment, R 20f is unsubstituted C1-C6 alkoxy. In one embodiment, R 20f is as follows: [ka] In another embodiment, R 20f is C1-C6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20f is as follows: [ka] In another embodiment, R 21g is C1-C6 alkyl substituted with one or more -OH. In one embodiment, R 20f is as follows: [ka] In another embodiment, R 20f is C-C cycloalkyl. In one embodiment, R 20f is an unsubstituted C cycloalkyl. In one embodiment, R 20f is as follows: [ka]

[0101] In one embodiment, R 21f , R 22f , and R 23f is H. In another embodiment, R 21f and R 23f are each independently a halogen, and R 22f is H. In one embodiment, R 21f and R 23f are F and R, respectively. 22f is H. In one embodiment, R 21f and R 23f are H and R, respectively.22f is halogen. In one embodiment, R 21f and R 23f are H and R, respectively. 22f is F.

[0102] In one embodiment, R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R 24fa and / or R 24fb is halogen. In one embodiment, R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R 24fa is F. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R 24fa and R 24fb Each of R is F. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb are H and R, respectively. 24fa and / or R 24fb is C1-C6 alkyl. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R 24fa and R 24fb Each of R is -CH3. 24fb , R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R 24fa is -CH3.

[0103] In one embodiment, the compound of formula (IIf) has one or more stereocenters. In one embodiment, the compound of formula (IIf) has the following moiety: [ka] contains a stereocenter at the point of attachment to the remainder of formula (IIf). In one embodiment, the compound of formula (IIf) is 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and / or R 26fb In one embodiment, the compound of formula (IIf) contains a stereocenter at one or more of R 20f contains a stereocenter.

[0104] In one embodiment, the compound of formula (IIf) is selected from: [ka]

[0105] In one embodiment, the compound of formula (II) has the formula (IIg): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony: R 20g is selected from H and C1-C6 alkoxy; R 21g is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C6-C 12 aryl), C3-C9 heterocyclyl, and -NR 28ga R 28gbwherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and said C3-C9 heterocyclyl are optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R 22g , R 23g , and R 24g are each independently selected from H and halogen; R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; R 28ga and R 28gb are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0106] In one embodiment, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H.

[0107] In one embodiment, R 20g is H. In one embodiment, R20g is unsubstituted C1-C6 alkoxy. In one embodiment, R 20g are -OCH3, -OCH2CH3, and the following: [ka] is selected from.

[0108] In one embodiment, R 21g is halogen. In one embodiment, R 21g is Cl. In one embodiment, R 21g is unsubstituted C1-C6 alkyl. In one embodiment, R 21g is t-butyl. In another embodiment, R 21g is C1-C6 alkyl substituted with one or more F and / or —OH. In one embodiment, R 21g is as follows: [ka] In another embodiment, R 21g is unsubstituted C1-C6 alkoxy. In one embodiment, R 21g is —OCH3. In another embodiment, R 21g is C1-C6 alkoxy substituted with one or more halogen atoms. 21g is -O-(C6-C 12 aryl). In one embodiment, R 21g is -O-phenyl. In another embodiment, R 21g is unsubstituted C-C cycloalkyl. In one embodiment, R 21g is an unsubstituted C cycloalkyl. In one embodiment, R 21g is a C cycloalkyl substituted with one or more fluorine atoms. 21g is as follows: [ka] In another embodiment, R 21g is an unsubstituted C-C heterocyclyl. In one embodiment, R21g is morpholinyl, acetidinyl, piperidinyl, isoxazolyl, pyrazolyl, [ka] wherein G is N or CH, and [ka] wherein c is 1 or 2. In another embodiment, R 21g is C-C alkyl, C-C cycloalkyl, C-C heterocyclyl, -OH, and C-C heterocyclyl substituted with one or more substituents selected from halogen. 21g is as follows: [ka] where R 29g is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens and / or —OH. 21g is as follows: [ka] where R 29g is H. In one embodiment, R 21g is as follows: [ka] where R 29g is unsubstituted C1-C6 alkyl. In one embodiment, R 21g is as follows: [ka] where R 29g is selected from -CH3 and isopropyl. In one embodiment, R 21g is as follows: [ka] where R 29g is C1-C6 alkyl substituted with one or more -OH and / or F. In one embodiment, R 21g is as follows: [ka] where R 29g is as follows: [ka] In another embodiment, R 21g is as follows: [ka] where R 29g is selected from unsubstituted C cycloalkyl, azetidinyl, and tetrahydropyranyl. 21g is as follows: [ka] wherein a is 1, 2, or 3, G is N or CH, and each X is independently a halogen. 21g is as follows: [ka] In another embodiment, R 21g is as follows: [ka] wherein b is 0, 1, 2, 3, 4, 5, or 6, c is 1 or 2, and each R 220g is independently C1-C6 alkyl. In one embodiment, R 21g is as follows: [ka] In another embodiment, R 21g is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R 21g is isoxazolyl monosubstituted with -CH. In another embodiment, R 21g is -NR 28ga R 28gb where R 28ga is H and R 28gb In another embodiment, R 21g is -NR 28ga R 28gb where R 28ga and R 28gb are each independently C1-C6 alkyl. In one embodiment, R 21g is -NR 28ga R 28gb and R 28ga and R 28gb are -CH3, respectively.

[0109] In one embodiment, R 22g , R 23g , and R 24g are each H. In one embodiment, R 22g and R 24g are each independently a halogen, and R 23g is H. In one embodiment, R 22g and R 24g are F and R, respectively. 23g is H. In one embodiment, R 22g and R 24g are H and R, respectively. 23g is halogen. In one embodiment, R 22g and R 24g are H and R, respectively. 23g is F.

[0110] In one embodiment, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gbis H. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga and / or R 25gb is halogen. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga is F. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga and R 25gb Each of R is F. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga and / or R 25gb is C1-C6 alkyl. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb are H and R, respectively. 25ga and R 25gb are each -CH3. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga is -CH3. In another embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga is selected from substituted C1-C6 alkyl and —OH. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25gais —OH. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga is -CF3 and the following: [ka] In another embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga is unsubstituted C1-C6 alkoxy. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga is -OCH3.

[0111] In one embodiment, R 25ga , R 25gb , R 26gb , R 27ga , and R 27gb Each of is H and R 26ga is unsubstituted C1-C6 alkyl. In one embodiment, R 25ga , R 25gb , R 26gb , R 27ga , and R 27gb Each of is H and R 26ga is -CH3.

[0112] In one embodiment, R 25ga , R 25gb , R 26ga , and R 26gb Each of is H and R 27ga and R 27gb Each of R is an unsubstituted C-C alkyl. 25ga , R 25gb , R 26ga , and R 26gb Each of is H and R27ga and R 27gb Each of is -CH3.

[0113] In one embodiment, the compound of formula (IIg) contains one or more stereocenters. In one embodiment, the compound of formula (IIg) contains R 21g In one embodiment, the compound of formula (IIg) contains a stereocenter at: [ka] contains a stereocenter at the point of attachment to the remainder of formula (IIg). In one embodiment, the compound of formula (IIg) is 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and / or R 27gb contains one or more stereocenters.

[0114] In one embodiment, the compound of formula (IIg) is selected from: [ka] TIFF2024500378000110.tif142125TIFF2024500378000111.tif155125TIFF2024500378 000112.tif152124TIFF2024500378000113.tif148124JPEG2024500378000114.jpg63125

[0115] In one embodiment, the compound of formula (II) has the formula (IIh): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20h is selected from H and C1-C6 alkoxy; R 21his selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen, and said C3-C6 cycloalkyl and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen; R 22ha , R 22hb , R 23ha , and R 23hb are each independently selected from H and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen atoms; R 24h , R 25h , and R 26h are each independently selected from H and halogen.

[0116] In one embodiment, R 20h is H.

[0117] In one embodiment, R 21h is a C3-C9 heterocyclyl substituted with one or more substituents selected from C1-C6 alkyl, —OH, and halogen. 21h is pyrazolyl substituted with C-C alkyl and F. In one embodiment, R 21h is as follows: [ka] In one embodiment, R 21h is as follows: [ka]

[0118] In one embodiment, R 22ha , R 22hb , R 23ha , and R 23hb In another embodiment, one or more of R22ha , R 22hb , R 23ha , and R 23hb is H. In one embodiment, R 22ha , R 22hb Each of is H and R 23ha and / or R 23hb is C1-C6 alkyl. In one embodiment, R 22ha , R 22hb , and R 23ha Each of is H and R 23hb is -CH3. In another embodiment, R 22ha and R 22hb Each of is H and R 23ha and R 23hb Each of is -CH3.

[0119] In one embodiment, R 24h , R 25h , and R 26h are each H. In one embodiment, R 24h and R 26h are each independently a halogen, and R 25h is H. In one embodiment, R 24h and R 26h are F and R, respectively. 25h is H. In one embodiment, R 24h and R 26h are H and R, respectively. 25h is halogen. In one embodiment, R 24h and R 26h are H and R, respectively. 25h is F.

[0120] In one embodiment, the compound of formula (IIh) contains one or more stereocenters. In one embodiment, the compound of formula (IIh) contains R 21h In one embodiment, the compound of formula (IIh) contains a stereocenter at: [ka] contains a stereocenter at the point of attachment to the remainder of formula (IIh).22ha , R 22hb , R 23ha , and / or R 23hb At least one of the groups contains a stereocenter.

[0121] In one embodiment, the compound of formula (IIh) is: [ka]

[0122] In one embodiment, the compound of formula (II) has the formula (IIi): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein: [ka] is as follows: [ka] is selected from R 20i is selected from H and C1-C6 alkoxy; R 21i is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; said C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; said C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, -C=O, and halogen; R 22i , R 23i , and R 24i are each independently selected from H and halogen; R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib are each independently selected from H, halogen, —OH, or C1-C6 alkyl.

[0123] In one embodiment, R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is independently selected from halogen, —OH, and C1-C6 alkyl. 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib Each of is H.

[0124] In one embodiment, R 20i is H. In another embodiment, R 20i is unsubstituted C1-C6 alkoxy. In one embodiment, R 20i is -OCH3.

[0125] In one embodiment, R 21i is C1-C6 alkyl substituted with one or more F and / or —OH. In one embodiment, R 21i is as follows: [ka] In another embodiment, R 21i is unsubstituted C-C cycloalkyl. In one embodiment, R21i is an unsubstituted C cycloalkyl. In one embodiment, R 21i is a C cycloalkyl substituted with C-C alkyl. 21i is as follows: [ka] In one embodiment, R 21i is a Ccycloalkyl substituted with one or more C-C alkyl and one or more fluorine atoms. 21i is as follows: [ka] In another embodiment, R 21i is an unsubstituted C-C heterocyclyl. In one embodiment, R 21i is pyrazolyl. In one embodiment, R 21i is as follows: [ka] wherein J is N or CH. In another embodiment, R 21i is C-C alkyl, C-C cycloalkyl, C-C heterocyclyl, C-C heterocyclyl substituted with one or more substituents selected from -OH, -C=O, and halogen. 21i is pyrrolidinyl monosubstituted with -C=O. In one embodiment, R 21i is as follows: [ka] In one embodiment, R 21i is as follows: [ka] where R 220iis selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens and / or —OH. 21i is as follows: [ka] where R 220i is H. In one embodiment, R 21i is as follows: [ka] where R 220i is unsubstituted C1-C6 alkyl. In one embodiment, R 21i is as follows: [ka] where R 220i is —CH3. In one embodiment, R 21i is as follows: [ka] where R 220i is C1-C6 alkyl substituted with one or more -OH and / or F. In one embodiment, R 21i is as follows: [ka] where R 220i is as follows: [ka] In another embodiment, R 21i is as follows: [ka] where R 220i is an unsubstituted C3 cycloalkyl.

[0126] In one embodiment, R 22i , R 23i , and R 24i is H. In one embodiment, R 22i and R 24i are each independently a halogen, and R 23i is H. In one embodiment, R 22i and R 24i are F and R, respectively. 23i is H. In one embodiment, R 22i and R 24i are H and R, respectively. 23i is halogen. In one embodiment, R 22i and R 24i are H and R, respectively. 23i is F.

[0127] In one embodiment, the following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H. In one embodiment, R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib Each of is H and R 25ia and / or R 25ib is halogen. In one embodiment, R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib Each of is H and R 25ia and R 25ibEach of R is F. In one embodiment, R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib Each of is H and R 25ib is F.

[0128] In one embodiment, the following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 28ib、 R 29ia , and R 29ib is H. In one embodiment, R 25ia , R 25ib , R 27ia , R 27ib , R 29ia , and R 29ib Each of is H and R 28ia and / or R 28ib is halogen. In one embodiment, R 25ia , R 25ib , R 27ia , R 27ib , R 29ia , and R 29ib Each of is H and R 28ia and R 28ib Each of R is F. In one embodiment, R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 29ia , and R 29ib Each of is H and R 28ib is F. In another embodiment, R 25ia , R 25ib , R 28ia , R28ib , R 29ia , and R 29ib Each of is H and R 27ia and / or R 27ib is halogen. In one embodiment, R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib Each of is H and R 27ib is F. In one embodiment, R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib Each of is H and R 27ia and R 27ib Each of these is F.

[0129] In one embodiment, the compound of formula (IIi) contains one or more stereocenters. In one embodiment, the compound of formula (IIi) contains R 20i In one embodiment, the compound of formula (IIi) contains a stereocenter at R 21i In one embodiment, the compound of formula (IIi) contains a stereocenter at: [ka] contains a stereocenter at the point of attachment to the remainder of formula (IIi). 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and / or R 29ib At least one of the groups contains a stereocenter.

[0130] In one embodiment, the compound of formula (IIi) is selected from: [ka] JPEG2024500378000142.jpg160124JPEG2024500378000143.jpg130125

[0131] In one embodiment, the compound of formula (II) has the formula (IIj): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein: [ka] is as follows: [ka] Selected from; R 20j is selected from H and C1-C6 alkoxy; R 21j is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and —OH, and said C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 22j , R 23j , and R 24j are each independently selected from H and halogen.

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

[0133] In one embodiment, R 21jis an optionally substituted C-C cycloalkyl. In one embodiment, R 21j is an optionally substituted C cycloalkyl. In one embodiment, R 21j is an unsubstituted C3 cycloalkyl.

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

[0135] In one embodiment, the following: [ka] is as follows: [ka] is.

[0136] In one embodiment, the compound of formula (IIj) contains one or more stereocenters. In one embodiment, the compound of formula (IIj) contains R 21j In one embodiment, the compound of formula (IIj) contains a stereocenter at: [ka] contains a stereogenic center at the point of attachment to the remainder of formula (IIj).

[0137] In one embodiment, the compound of formula (IIj) is selected from: [ka]

[0138] In some embodiments, R 6 is (Ib), giving the structure of formula (III) below: [ka]

[0139] 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.

[0140] In some embodiments, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkoxy, or spiro-fused cycloalkyl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogens. 15 , R 16 , R 17 , R18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 One or more of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are both H.

[0141] In addition to the embodiment in which the compound has the structure of formula (III), the compound can have a structure according to any of (IIIa)-(IIIp) below. [ka] JPEG2024500378000153.jpg192125JPEG2024500378000154.jpg196125TIFF20245003780 00155.tif214144TIFF2024500378000156.tif195125TIFF2024500378000157.tif131124

[0142] In one embodiment, the compound of formula (III) has the formula (IIIq): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 30q is selected from H and C1-C6 alkoxy; R 31q is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; and the C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 32q , R 33q , and R 34q are each independently selected from H and halogen.

[0143] In one embodiment, R 30q is H.

[0144] In one embodiment, R 31q is an unsubstituted C-C heterocyclyl. In one embodiment, R 31q is pyrazolyl. In one embodiment, R 31q is as follows: [ka] (wherein K is N or CH), [ka] wherein d is 1 or 2. In one embodiment, R 31q is as follows: [ka] wherein d is 2. In another embodiment, R 31qis C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C 12 and C3-C9 heterocyclyl substituted with one or more substituents selected from aryl, -OH, -C=O, and halogen. 31q is as follows: [ka] where R 35q is H, unsubstituted C1-C6 alkyl, unsubstituted C6-C 12 aryl, and unsubstituted C-C heterocyclyl. In one embodiment, R 31q is as follows: [ka] where R 35q is H. In one embodiment, R 31q is as follows: [ka] where R 35q is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. 31q is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R 31q is isoxazolyl monosubstituted with -CH. In one embodiment, R 31q is as follows: [ka] In another embodiment, R 31q is as follows: [ka] wherein e is 1, 2, or 3, K is N or CH, and each X is independently a halogen. 31q is as follows: [ka]

[0145] In one embodiment, R 32q , R 33q , and R 34q are each H. In one embodiment, R 32q and R 34q are each independently a halogen, and R 33q is H. In one embodiment, R 32q and R 34q are F and R, respectively. 33q i is H. In one embodiment, R 32q and R 34q are H and R, respectively. 33q is halogen. In one embodiment, R 32q and R 34q are H and R, respectively. 33q is F.

[0146] In one embodiment, the compound of formula (IIIq) contains one or more stereocenters.

[0147] In one embodiment, the compound of formula (IIIq) is selected from: [ka] JPEG2024500378000169.jpg97125

[0148] In one embodiment, the compound of formula (III) has the formula (IIIr): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 30ris selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 31r H and C1-C6 alkoxy; R 32r , R 33r , and R 34r are each independently selected from H and halogen.

[0149] In one embodiment, R 30r is an unsubstituted C-C heterocyclyl. In one embodiment, R 30r is unsubstituted pyrazolyl. In one embodiment, R 30r is as follows: [ka] (wherein L is N or CH), [ka] wherein f is 1 or 2. In one embodiment, R 30r is as follows: [ka] wherein f is 2. In another embodiment, R 30r is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C 12and C3-C9 heterocyclyl substituted with one or more substituents selected from aryl, -OH, -C=O, and halogen. 30r is as follows: [ka] where R 35r is H, unsubstituted C1-C6 alkyl, unsubstituted C6-C 12 aryl, and unsubstituted C-C heterocyclyl. In one embodiment, R 30r is as follows: [ka] (In the formula, R 35r is H. In one embodiment, R 30r is as follows: [ka] where R 35r is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. 30r is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R 30r is isoxazolyl monosubstituted with -CH. In one embodiment, R 30r is as follows: [ka] In another embodiment, R 30r is as follows: [ka] wherein g is 1, 2, or 3, L is N or CH, and each X is independently a halogen. 30r is as follows: [ka] is.

[0150] In one embodiment, R 31r is H.

[0151] In one embodiment, R 32r , R 33r , and R 34r are each H. In one embodiment, R 32r and R 34r are each independently a halogen, and R 33r is H. In one embodiment, R 32r and R 34r are F and R, respectively. 33r is H. In one embodiment, R 32r and R 34r are H and R, respectively. 33r is halogen. In one embodiment, R 32r and R 34r are H and R, respectively. 33r is F.

[0152] In one embodiment, the compound of formula (IIIr) contains one or more stereocenters.

[0153] In one embodiment, the compound of formula (IIIr) is selected from: [ka] JPEG2024500378000181.jpg86125

[0154] In one embodiment, the compound of formula (III) has the formula (IIIs): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 30s is selected from H and C1-C6 alkoxy; R 31sis selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 32s , R 33s , and R 34s are each independently selected from H and halogen.

[0155] In one embodiment, R 30s is H.

[0156] In one embodiment, R 31s is an unsubstituted C-C heterocyclyl. In one embodiment, R 31s is pyrazolyl. In one embodiment, R 31s is as follows: [ka] (wherein M is N or CH), [ka] wherein h is 1 or 2. In one embodiment, R 31s is as follows: [ka] wherein h is 2. In another embodiment, R 31s is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocyclyl, C6-C 12and C3-C9 heterocyclyl substituted with one or more substituents selected from aryl, -OH, -C=O, and halogen. 31s is as follows: [ka] where R 35s is H, unsubstituted C1-C6 alkyl, unsubstituted C6-C 12 aryl, and unsubstituted C-C heterocyclyl. In one embodiment, R 31s is as follows: [ka] (In the formula, R 35s is H. In one embodiment, R 31s is as follows: [ka] where R 35s is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. 31s is isoxazolyl substituted with C1-C6 alkyl. In one embodiment, R 31s is isoxazolyl monosubstituted with -CH. In one embodiment, R 31s is as follows: [ka] In another embodiment, R 31s is as follows: [ka] wherein i is 1, 2, or 3, M is N or CH, and each X is independently a halogen. 31s is as follows: [ka]

[0157] In one embodiment, R 32s , R 33s , and R 34s are each H. In one embodiment, R 32s and R 34s are each independently a halogen, and R 33s is H. In one embodiment, R 32s and R 34s are F and R, respectively. 33s is H. In one embodiment, R 32s and R 34s are H and R, respectively. 33s is halogen. In one embodiment, R 32s and R 34s are H and R, respectively. 33s is F.

[0158] In one embodiment, the compounds of formula (IIIs) contain one or more stereocenters.

[0159] In one embodiment, the compound of formula (IIIs) is selected from: [ka]

[0160] In some embodiments, a compound of Formula (I), such as a compound of Formula (II) or Formula III, can be any of those identified as Compounds 1-137 in Tables 1-15. In some embodiments, the compound can be Compound 1, Compound 9, Compound 19, Compound 20, Compound 21, Compound 26, Compound 31, Compound 38, Compound 45, Compound 56, Compound 60, Compound 61, Compound 62, Compound 63, Compound 81, Compound 84, Compound 96, Compound 97, or Compound 99.

[0161] In some embodiments, compounds of Formula (I), such as compounds of Formula (II) or Formula (III), 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, hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates. In some cases, in the case of salts of acidic compounds, the salts can include metals, amines, or organic cations (e.g., quaternary ammonium). In still other embodiments, simple derivatives of compounds (e.g., ethers, esters, or amides) can be used that have desirable retention and release characteristics but are easily hydrolyzed by body pH, enzymes, or other suitable means.

[0162] In some embodiments, compounds of the present disclosure have chiral centers and can exist and be isolated in optically active, racemic form. In other embodiments, the compounds may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomer of the compounds described herein, including isotopically and radiolabeled compounds, or mixtures thereof. See, e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be isolated by standard resolution techniques, including, for example, fractional crystallization, chiral chromatography, and the like. See, e.g., Eliel, EL & Wilen SH, 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. Preparation of optically active forms can be accomplished by any suitable method, including, but not limited to, resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0163] In some embodiments, the compounds disclosed herein have asymmetric centers and can exist as racemates, racemic mixtures, and individual enantiomers or diastereoisomers, and all isomeric forms and mixtures thereof are contemplated for use in the compounds and methods described herein. Compounds contemplated for use in the compounds and methods described herein do not include compounds known in the art to be unstable and unable to be synthesized and / or isolated.

[0164] The compounds disclosed herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 The compounds can be radiolabeled with radioactive isotopes such as C. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the intended scope.

[0165] In some embodiments, metabolites of the compounds disclosed herein are useful in the methods disclosed herein.

[0166] In some embodiments, compounds contemplated herein may be provided in the form of a prodrug. The term "prodrug" refers to a compound that can be converted in vivo to a compound described herein (e.g., a biologically active compound). Prodrugs may be useful for a variety of reasons known in the art, including ease of administration, e.g., by improving oral bioavailability. Prodrugs may also have improved solubility in pharmaceutical compositions relative to the biologically active compound. Non-limiting examples of prodrugs include compounds that are administered as esters (i.e., "prodrugs") to facilitate penetration across cell membranes, where water solubility is a disadvantage, but that are metabolically hydrolyzed to the active carboxylic acid once inside the cell, where water solubility is advantageous. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in *Design of Prodrugs* (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference for the limited purpose of describing the procedures and preparation of suitable prodrug derivatives.

[0167] Certain compounds disclosed herein can exist in solvated forms, including hydrated forms, as well as unsolvated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the intended compounds. Certain compounds disclosed herein can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods intended herein and are intended to be within the scope of the disclosed compounds.

[0168] In certain embodiments, one or more compounds of the present disclosure (e.g., Formula (I)) can be part of the composition and can be at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, It can be an amount (by weight of the total composition) of at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, or about 99.99% or less, about 0.0001% to about 99%, about 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%.

[0169] In some embodiments, one or more compounds of the present disclosure (e.g., Formula (I)) are present in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 15%, at least about 20%, at least about 25 ... Both can be purified or isolated in an amount of about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, about 99.99% or less, about 0.0001% to about 99%, about 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%.

[0170] Process for preparing compounds of formula (I) Some embodiments of the present disclosure include methods for preparing compounds of Formula (I). In certain embodiments, compounds of Formula (I) can be prepared including one or more steps described in Examples 1-25 herein. The synthetic routes shown and described in Examples 1-25 can be used to prepare, for example, compounds 1-137 shown in Tables 1-15, and structurally related compounds.

[0171] Pharmaceutical Compositions and Formulations Some embodiments of the present disclosure include compositions comprising one or more compounds of the present disclosure (e.g., Formula (I)). In certain embodiments, the composition is a pharmaceutical composition, such as a composition suitable for administration to an animal (e.g., a mammal, a primate, a monkey, a human, a dog, a cat, a pig, a mouse, a rabbit, a rat, etc.). In some embodiments, a pharmaceutical composition is provided comprising a compound disclosed herein and a pharmaceutically acceptable excipient. The compound can be a compound of any of Formulas (I)-(III) disclosed herein, a compound shown in Tables 1-16, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof. In some embodiments, the compound is shown in any of Tables 1-16 herein.

[0172] Further embodiments of the present disclosure relate to compositions comprising the compound. In some embodiments, the amount of the compound can be from about 0.0001% (by weight of the total composition) to about 99%. In some embodiments, the composition can further comprise a formulation component, adjuvant, or carrier. In some embodiments, the composition can further comprise a BCL2 inhibitor. In some embodiments, the composition can be used in combination with a second composition comprising a BCL2 inhibitor. In some embodiments, the BCL2 can be venetoclax, or a salt, isomer, derivative, or analog thereof.

[0173] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds disclosed herein contain a relatively acidic functional group, base addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salts, or similar salts. When compounds disclosed herein contain a relatively basic functional group, acid addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, bicarbonate, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphoric acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0174] The compounds disclosed herein can exist as salts with pharmaceutically acceptable acids, etc. Accordingly, the compounds contemplated herein include such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, salts with amino acids such as glutamic acid, etc. These salts can be prepared by methods known to those skilled in the art.

[0175] 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.

[0176] Pharmaceutically acceptable salts of the compounds described above, in which basic or acidic groups are present in the structure, are also included within the scope of the compounds contemplated herein. When acidic substituents such as -NHSOH, -COOH, and -P(O)(OH) are present, ammonium, sodium, potassium, calcium salts, and the like, may be formed for use as dosage forms. Basic groups such as amino or basic heteroaryl radicals, or acid salts such as pyridyl, and hydrochloride, hydrobromide, acetate, maleate, pamoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as dosage forms.

[0177] Additionally, in embodiments where R—COOH is present, pharmaceutically acceptable esters can be used (e.g., methyl, ethyl, tert-butyl, pivaloyloxymethyl, etc.) and esters known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations can be used.

[0178] In some cases, the pharmaceutical compositions are non-toxic, do not cause side effects, or both, while in some embodiments, they may exhibit inherent side effects (e.g., may be harmful to the patient or may exhibit some degree of toxicity or harm in some patients).

[0179] In some embodiments, one or more compounds of the present disclosure (e.g., Formula (I)) can be part of a pharmaceutical composition, and may be present in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, The amount can be at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, or about 99.99% or less, about 0.001% to about 99%, about 0.001% to about 50%, about 0.1% to about 99%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%. In some embodiments, the pharmaceutical composition can be in a dosage form suitable for topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, dermal, nasal, vaginal, or ocular administration. In other embodiments, the pharmaceutical composition can be in a dosage form suitable for parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. The pharmaceutical composition can be in the form of, for example, a tablet, capsule, pill, powder, suspension, emulsion, solution, gel (including hydrogel), paste, ointment, cream, poultice, lotion, delivery device, suppository, enema, injectable, implant, spray, aerosol, or other suitable form.

[0180] In some embodiments, the compounds disclosed herein can be orally administered as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups, or elixirs. Oral compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to produce pharmaceutically elegant and palatable formulations. Thus, pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein are also provided.

[0181] In some embodiments, tablets contain the active 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 cornstarch or alginic acid; (3) binders such as starch, gelatin, or acacia; and (4) lubricants such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used.

[0182] When preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid.Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.A solid carrier can be one or more substances that also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0183] The compounds disclosed herein can be administered parenterally for in vivo applications, either as free compounds or in the form of pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts, by injection or by gradual perfusion over time. Administration can be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavity, or transdermal. For in vitro studies, the compounds can be added or dissolved in an appropriate biologically acceptable buffer and added to cells or tissues.

[0184] In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0185] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "formulation" is intended to include formulations of the active compound with encapsulating materials as carriers to provide a capsule in which the active ingredient is surrounded by a carrier in which it is associated, with or without other carriers. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0186] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously by stirring, The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.

[0187] Liquid 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.

[0188] When parenteral application is necessary or desired, particularly suitable mixtures for the compounds disclosed herein are injectables, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants (including suppositories). These suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectables can also be prepared as sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles, carriers, and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables. In particular, carriers for parenteral administration include aqueous solutions such as dextrose, saline, purified water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, and polyoxyethylene block polymers. Ampoules are convenient unit doses. The compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical mixtures suitable for use in the pharmaceutical compositions and methods disclosed herein include, for example, those described in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of both of which are incorporated herein by reference.

[0189] In some embodiments, formulations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions (including saline and buffered media). Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol, and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents (e.g., sterile water, alcohol, glycerol, and polyols). Intravenous vehicles include fluid and nutrient replenishers. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose, and sodium chloride. Lactated Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (e.g., those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, growth factors, and inert gases and the like.

[0190] Preservatives include antimicrobial agents, antioxidants, chelating agents, and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients including salts, preservatives, buffers, and the like, as described in, for example, Remington's Pharmaceutical Sciences, 15th ed., Easton: Mack Publishing Co., pp. 1405-1412, 1461-1487 (1975) and The National Formulary XIV., 14th ed., Washington: American Pharmaceutical Association (1975), the contents of which are incorporated herein by reference. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to ordinary skill in the art. See, for example, Goodman and Gilman (eds.), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).

[0191] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the micronized active ingredient in water together with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Aqueous suspensions usually contain the active ingredient mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and the like; (2) dispersing or wetting agents which can be (a) a naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, e.g., polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long-chain aliphatic alcohol, e.g., heptadecaethyleneoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).

[0192] Also included are solid preparations intended to be converted, shortly before use, to liquid preparations for oral administration. Such liquid preparations include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0193] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form is a packaged preparation, the package containing individual doses of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0194] In some embodiments, the pharmaceutical composition can include one or more formulary ingredients. A "formulary ingredient" refers to any suitable ingredient (e.g., suitable for the drug, suitable for the drug dosage, suitable for the timing of drug release, suitable for the disease, suitable for the pathology, or suitable for the delivery route), including, but not limited to, water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water containing chloroform), sugar (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made therefrom), ethanol, glycerol, glycol (e.g., propylene glycol), acetone, ether, DMSO, surfactants (e.g., The composition may include any suitable ingredients, including, for example, anionic surfactants, cationic surfactants, zwitterionic surfactants, or nonionic surfactants (e.g., polysorbates), oils (e.g., animal oils, vegetable oils (e.g., coconut oil or peanut oil), mineral oil), oil derivatives (e.g., ethyl oleate, glyceryl monostearate, or hydrogenated glycerides), excipients, preservatives (e.g., vitamins (e.g., A, E, or C), selenium, retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens (e.g., methylparaben or propylparaben)), or combinations thereof.

[0195] In certain embodiments, pharmaceutical compositions can be formulated to release the active ingredient (e.g., one or more disclosed compounds, such as Formula (I)) immediately upon administration or at a substantially predetermined time or time after administration. Such formulations include controlled release formulations, such as various controlled release compositions and coatings.

[0196] Other formulations (eg, formulations of pharmaceutical compositions) can, in certain embodiments, include inclusion of the drug (or controlled release formulation) in a food, foodstuff, feed, or beverage.

[0197] Some compounds may have limited solubility in water and therefore may require a surfactant or other suitable co-solvent in the composition. Such co-solvents include polysorbates 20, 60, and 80; Pluronic® F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically used in amounts of about 0.01% to about 2% by weight.

[0198] A viscosity higher than that of a simple aqueous solution may be desirable to reduce variability during dispensing of the formulation, to reduce physical separation of components of a suspension or emulsion formulation, and / or to improve formulation. Such viscosity-building agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations thereof. Such agents are typically used in amounts of about 0.01% to about 2% by weight.

[0199] The compositions disclosed herein can further include ingredients to provide sustained release and / or comfort. Such ingredients include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and micronized drug carrier matrices. These ingredients are described in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760, the entire contents of which are incorporated herein by reference for all purposes.

[0200] Various pharmaceutical compositions useful for ameliorating specific diseases and disorders are provided. In one embodiment, pharmaceutical compositions are prepared by formulating a compound disclosed herein, alone or with other pharmaceutical agents, in the form of a free compound or a pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt, using carriers, excipients, and additives or adjuvants suitable for administration to a subject. Frequently used carriers or adjuvants 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 glycol, and solvents (e.g., sterile water, alcohol, glycerol, and polyols). Intravenous vehicles include fluid and nutrient replenishers.

[0201] Various pharmaceutical compositions useful for ameliorating specific diseases and disorders are provided. In one embodiment, pharmaceutical compositions are prepared by formulating a compound disclosed herein, alone or with other pharmaceutical agents, in the form of a free compound or a pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt, using carriers, excipients, and additives or adjuvants suitable for administration to a subject. Frequently used carriers or adjuvants 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 glycol, and solvents (e.g., sterile water, alcohol, glycerol, and polyols). Intravenous vehicles include fluid and nutrient replenishers.

[0202] Methods for treating and preventing diseases Further embodiments of the present disclosure relate to methods of providing a compound to a subject, comprising one or more administrations of one or more compositions comprising the compound, wherein multiple administrations are provided, and the compositions may be the same or different. In some embodiments, at least one of the one or more compositions further comprises a formulation component. In some embodiments, at least one of the one or more compositions comprises a composition comprising the compound. In some embodiments, at least one of the one or more administrations comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. In some embodiments, when multiple administrations are provided, at least one composition used in at least one administration is different from the composition used in at least one other administration. In some embodiments, at least one compound of the one or more compositions may be administered to the subject in an amount of about 0.005 mg / kg (of the subject's body weight) to about 50 mg / kg (of the subject's body weight). In some embodiments, the subject is a mammal, preferably a human, a rodent, or a primate.

[0203] Further embodiments of the present disclosure relate to methods for treating a disease or disorder, the method comprising one or more administrations to a subject of one or more compositions comprising the compound, wherein the compositions, if administered multiple times, can be the same or different. In some embodiments, the disease or disorder can respond to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition. In some embodiments, at least one of the one or more compositions further comprises a formulating ingredient. In some embodiments, at least one of the one or more compositions comprises the composition.

[0204] In some embodiments, at least one of the one or more administrations comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, transdermal, oral, sublingual, intranasal, or intramuscular administration. In some embodiments, at least one of the one or more administrations comprises oral administration. In some embodiments, when multiple administrations are performed, at least one composition used in at least one administration is different from the composition used in at least one other administration. In some embodiments, at least one compound of the one or more compositions is administered to the subject in an amount of about 0.005 mg / kg (of the subject's body weight) to about 50 mg / kg (of the subject's body weight). In some embodiments, the subject may be a mammal, preferably a human, rodent, or primate. In some embodiments, the subject is in need of the treatment.

[0205] In some embodiments, the method is for treating a hematopoietic cancer. In some embodiments, the method is for treating myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML). In some embodiments, the method includes lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid carcinoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MYD88-mutated DLBCL, follicular lymphoma, or marginal zone lymphoma. In one embodiment, the disease or disorder is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof. In some embodiments, the method is for treating one or more inflammatory or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof. In some embodiments, the method is for treating MDS, MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2, or the method is for treating AML with increased expression and / or activity of IRAK4-Long relative to IRAK4-Short and / or AML that is not driven by FLT3 mutations but expresses IRAK4-Long.In some embodiments, the method is for treating DLBCL, wherein the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL.

[0206] In some embodiments, the method further comprises administering a composition comprising a BTK inhibitor, hi some embodiments, the BTK inhibitor comprises ibrutinib.

[0207] 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 is performed after one or more of: suffering from a myelodysplastic syndrome, suffering from a myeloproliferative disorder, experiencing exposure to a chemical, exposure to ionizing radiation, or treatment for cancer.

[0208] In some embodiments, the method further comprises administering a composition comprising a BCL2 inhibitor, or at least one of the compositions comprising the compound further comprises a BCL2 inhibitor. In some embodiments, the compound 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 comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0209] In some embodiments, the method further comprises administration of one or more additional therapeutic agents selected from one or more chemotherapeutics, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof. In some embodiments, the DNA methyltransferase / hypomethylating agent comprises azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a fixed molar ratio of 5:1 combination of cytarabine and daunorubicin); and the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, badecitrin, thiazolinone ... the purine nucleoside analogs (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab); the mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, covinib, the CDK9 inhibitors include alvocidib and / or voruciclib; the CDK8 inhibitors include SEL120; the retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activators include APR-246 (Eprenetapt); the smoothened receptor antagonists include glasdegib; the ERK inhibitors include ulixertinib, S The inhibitors include ERK2 / MAPK1 inhibitors or ERK1 / MAPK3 inhibitors, including CH772984, lavoxertinib, MK-8353, and / or VTX-11e; the PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-86 69, AP-23573), everolimus, bisertib (AZD2014); the glucocorticoid receptor modulator is an agonist including prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist including mifepristone, myricorant, and / or onapristone, and / or another binding ligand including vamorolone (VBP15); and / or the EZH2 inhibitor is tazemetostat.

[0210] Further embodiments of the present disclosure relate to the compounds for use in a method for treating a disease or disorder, the method comprising inhibiting at least one of IRAK and FLT3 by administering one or more compositions comprising the compound, wherein, when multiple administrations are present, the compositions can be the same or different. In some embodiments, the disease or disorder can respond to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition. In some embodiments, at least one of the one or more compositions further comprises a formulating ingredient. In some embodiments, at least one of the one or more compositions comprises the composition. In some embodiments, at least one of the one or more administrations comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, transdermal, oral, sublingual, intranasal, or intramuscular administration. In some embodiments, at least one of the one or more administrations comprises oral administration. In some embodiments, when multiple administrations are present, at least one composition used in at least one administration is different from the composition used in at least one other administration.

[0211] In some embodiments, at least one compound of the one or more compositions can be administered to the subject in an amount of about 0.005 mg / kg (of the subject's body weight) to about 50 mg / kg (of the subject's body weight). In some embodiments, the subject is a mammal, preferably a human, rodent, or primate. In some embodiments, the subject is in need of treatment.

[0212] In some embodiments, the method is for treating a hematopoietic cancer. In some embodiments, the method is for treating MDS and / or AML. In some embodiments, the method is for treating at least one of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MYD88-mutated DLBCL, follicular lymphoma, or marginal zone lymphoma. In one embodiment, the disease or disorder is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof. In some embodiments, the method is for treating one or more inflammatory or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof. In some embodiments, the method is for treating MDS, MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2, or the method is for treating AML with increased expression and / or activity of IRAK4-Long relative to IRAK4-Short and / or AML that is not driven by FLT3 mutations but expresses IRAK4-Long.In some embodiments, the method is for treating DLBCL, wherein the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL.

[0213] In some embodiments, the method further comprises administering a composition comprising a BTK inhibitor, hi some embodiments, the BTK inhibitor comprises ibrutinib.

[0214] 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 is performed after one or more of: myelodysplastic syndrome, myeloproliferative disorder, chemical exposure, ionizing radiation exposure, or cancer treatment. In some embodiments, the method further comprises administering a composition comprising a BCL2 inhibitor, or at least one of the compositions comprising a compound of any of claims 1-39 further comprises 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 comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0215] In some embodiments, the method further comprises administration of one or more additional therapeutic agents selected from one or more chemotherapeutics, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof. In some embodiments, the DNA methyltransferase / hypomethylating agent comprises azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a fixed molar ratio of 5:1 combination of cytarabine and daunorubicin); and the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, badecitrin, thiazolinone ... the purine nucleoside analogs (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab); the mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, covinib, the CDK9 inhibitors include alvocidib and / or voruciclib; the CDK8 inhibitors include SEL120; the retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activators include APR-246 (Eprenetapt); the smoothened receptor antagonists include glasdegib; the ERK inhibitors include ulixertinib, S The inhibitors include ERK2 / MAPK1 inhibitors or ERK1 / MAPK3 inhibitors, including CH772984, lavoxertinib, MK-8353, and / or VTX-11e; the PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-86 69, AP-23573), everolimus, bisertib (AZD2014); the glucocorticoid receptor modulator is an agonist including prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist including mifepristone, myricorant, and / or onapristone, and / or another binding ligand including vamorolone (VBP15); and / or the EZH2 inhibitor is tazemetostat.

[0216] In addition to their ability to inhibit IRAK, IRAK inhibitors have been shown to have selectivity toward multiple kinases. In some embodiments, compounds described herein according to Formula (I), such as compounds 1-137 listed in Tables 1-15, exhibit inhibitory activity against one or more kinases, such as interleukin-1 receptor-associated kinase (IRAK) and FMS-like tyrosine kinase 3 (FLT3). The inhibitory effect on one or more kinases, such as IRAK and FLT3, enables the treatment and / or prevention of diseases in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cows, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using compounds of the present disclosure (e.g., Formula (I)) including, but not limited to, hematopoietic cancers (e.g., disorders of hematopoietic stem cells in the bone marrow or disorders associated with the myeloid lineage), MDS, AML, myeloproliferative disorders, and diseases (e.g., hematopoietic cancers) associated with mutations in IRAK1, IRAK4, and / or FLT3 (e.g., a mutation in the juxtamembrane region of FLT3, a mutation in the kinase domain of FLT3, a FLT3 point mutation, a FLT3 internal tandem duplication mutation, a FLT3-ITD mutation, a D835Y FLT3 mutation, a D835V FLT3 mutation, a F691L FLT3 mutation, or a R834Q FLT3 mutation).

[0217] In some embodiments, compounds of the present disclosure can inhibit one or more activities of FLT3, a FLT3 mutation (e.g., a FLT3 juxtamembrane region mutation, a FLT3 kinase domain mutation, a FLT3 point mutation, a FLT3 internal tandem duplication mutation, a FLT3-ITD mutation, a D835Y FLT3 mutation, a D835V FLT3 mutation, a F691L FLT3 mutation, or a R834Q FLT3 mutation), IRAK4 (interleukin-1 receptor-associated kinase 4), an isoform of IRAK4, a mutation of IRAK4, IRAK1 (interleukin-1 receptor-associated kinase 1), an isoform of IRAK1, and / or a mutation of IRAK1. In some embodiments, compounds of the present disclosure can inhibit the activity of one or both of FLT3 and FLT3 mutations (e.g., FLT3 juxtamembrane region mutations, FLT3 kinase domain mutations, FLT3 point mutations, FLT3 internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and may inhibit one or more of IRAK4, isoforms of IRAK4, mutations of IRAK4, IRAK1, isoforms of IRAK1, or mutations of IRAK1. In some embodiments, compounds of the present disclosure can inhibit the activity of one or both of FLT3 and FLT3 mutations (e.g., FLT3 juxtamembrane region mutations, FLT3 kinase domain mutations, FLT3 point mutations, FLT3 internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and may inhibit one or both of IRAK4 and IRAK1, or isoforms or mutations thereof. In some embodiments, compounds of the present disclosure can inhibit FLT3 in combination with IRAK4, in combination with IRAK1, or in combination with IRAK4 and IRAK1.

[0218] In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3 that is 1 μM or greater, 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 greater. In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3 at a level 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, the compounds described herein exhibit inhibitory activity against IRAK and / or FLT-3 at a level of 0.1 μM or less, e.g., about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of values ​​using any combination of the values ​​recited herein as upper and / or lower limits are also contemplated, for example, but not limited to, 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM. In some embodiments, the inhibitory activity is in the range of about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or even 500-1000 μM.For purposes of quantification, it is understood that terms such as "activity," "inhibitory activity," "biological activity," "IRAK activity," "IRAK1 activity," "IRAK4 activity," "FLT-3 activity," and the like, in the context of the inhibitory compounds disclosed herein, can be quantified by various methods known in the art. Unless otherwise specified, as used herein, such terms refer to IC in their conventional sense. 50 (i.e., the concentration to achieve half-maximal inhibition).

[0219] In some embodiments, hematopoietic cancers that can be treated in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, humans) using compounds of the present disclosure (e.g., Formula (I)) include, but are not limited to, hematopoietic cancers and cancers of myeloid blood cells, cancers at increased risk due to other blood disorders, cancers at increased risk due to chemical exposure (e.g., anti-cancer treatments or occupational chemical exposure), cancers at increased risk due to ionizing radiation (e.g., anti-cancer therapy), cancers arising from myelodysplastic syndromes, cancers arising from myeloproliferative disorders, and cancers of B cells.

[0220] 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's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., ABC DLBCL with MYD88 mutations (e.g., L265P)), follicular lymphoma, or marginal zone lymphoma, or a combination thereof.

[0221] In some embodiments, cancers characterized by dysregulated IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling that can be treated include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof.

[0222] In some embodiments, compounds of the present disclosure can be used to inhibit targets in the context of additional conditions characterized by overactive IRAK1 and / or IRAK4. According to specific aspects of the present disclosure, compounds of the present disclosure can be used to inhibit overactive IRAK1 and / or IRAK4 in conditions such as inflammatory and autoimmune diseases, where the inflammatory and autoimmune diseases are characterized by overactive IRAK1 and / or IRAK4. In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., overactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling can be treated, including, but not limited to, chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, and the like, and combinations thereof.

[0223] In certain embodiments, MDS that can be treated in subjects (e.g., mammals, pigs, dogs, birds (e.g., chickens), cows, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using compounds of the present disclosure (e.g., Formula (I)) include, but are not limited to, MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, MDS with mutations in isocitrate dehydrogenase 2, refractory hematopoietic stem cell transplants with single blood cell lineage dysplasia, and MDS with mutations in isocitrate dehydrogenase 2. Cytopenias (e.g., refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ringed sideroblasts, animals / humans with pathological changes not limited to erythroid cells such as prominent leukocyte progenitor and / or platelet progenitor (megakaryocyte) dysplasia), refractory anemia with excess blasts I and II, 5q syndrome, megakaryocytic dysplasia with fibrosis, and refractory cytopenia of childhood. In some embodiments, MDS that can be treated includes, but is not limited to, hereditary MDS, MDS with an increased risk due to a genetic predisposition, MDS with an increased risk due to other blood disorders, MDS with an increased risk due to exposure to chemicals, MDS with an increased risk due to ionizing radiation, MDS with an increased risk due to cancer treatment (e.g., radiation in combination with a radiomimetic alkylating agent such as busulfan, nitrosoureas, or procarbazine (latency period 5-7 years) or a DNA topoisomerase inhibitor), MDS that evolves from acquired aplastic anemia and Fanconi anemia after immunosuppressive therapy, MDS with an increased risk due to mutations in splicing factors, MDS with an increased risk due to mutations in isocitrate dehydrogenase 1, and MDS with an increased risk due to mutations in isocitrate dehydrogenase 2. Animals that can be treated include, but are not limited to, mammals, rodents, primates, monkeys (e.g., macaques, rhesus monkeys, pig-tailed monkeys), humans, dogs, cats, pigs, birds (e.g., chickens), cows, mice, rabbits, and rats. In the methods, the term "subject" can refer to both human and non-human subjects.In some settings, the subject is in need of treatment (eg, exhibits symptoms of a disease such as MDS, AML, cancer, an autoimmune disease, an inflammatory condition, or has a low blood count).

[0224] In some embodiments, MDS that can be treated in a subject (e.g., a mammal, pig, dog, bird (e.g., chicken), cow, cat, primate, rodent, monkey, rabbit, mouse, rat, and human) using a compound of the present disclosure (e.g., Formula (I)) include, but are not limited to, MDS that can be treated by inhibiting one or more of FLT3 (e.g., with a FLT3 inhibitor), a FLT3 mutation (e.g., with an inhibitor of a FLT3 mutation), IRAK4 (e.g., with an IRAK4 inhibitor), a IRAK4 mutation (e.g., with an inhibitor of a IRAK4 mutation), IRAK1 (e.g., with an IRAK1 inhibitor), and / or a IRAK1 mutation (e.g., with an inhibitor of a IRAK1 mutation). In some embodiments, MDS that can be treated include, but are not limited to, MDS that can be treated by inhibiting IRAK4 (or mutations thereof), MDS that can be treated by inhibiting IRAK1 (or mutations thereof), or MDS that can be treated by inhibiting IRAK4 (or mutations thereof) and IRAK1 (or mutations thereof). In some embodiments, MDS that can be treated include, but are not limited to, MDS that can be treated by inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 makes it possible to treat tumors with FLT3 mutations that may be resistant or become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms caused by IRAK.In some embodiments, the MDS that can be treated is characterized as an MDS with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or an MDS that is not caused by a FLT3 mutation but expresses IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (see, e.g., U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies."). Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties.

[0225] In some embodiments, AML that can be treated in a subject (e.g., mammal, pig, dog, bird (e.g., chicken), cow, cat, primate, rodent, monkey, rabbit, mouse, rat, and human) using a compound of the present disclosure (e.g., Formula (I)) includes, but is not limited to, hereditary AML, AML with an increased risk of developing due to a genetic predisposition, AML with one or more recurrent genetic abnormalities (e.g., those involving the following inversions or translocations, e.g., MLLT3 / MLL ("MLL"), a translocation between chromosomes 9 and 11, AML with a translocation between chromosomes 8 and 21, and AML with a translocation between chromosomes 16). or inversion, AML with translocation between chromosomes 9 and 11, APL with translocation between chromosomes 15 and 17 (M3), AML with translocation between chromosomes 6 and 9, AML with translocation or inversion on chromosome 3, AML with translocation between chromosomes 1 and 22, AML with myelodysplasia-related changes, AML related to previous chemotherapy or radiotherapy (e.g., alkylating agent-related AML, topoisomerase II inhibitor-related AML, etc.), AML not elsewhere classified (those not falling into the above categories (similar to the FAB classification); for example, AML minimally differentiated (M0), AML with minimal maturation (M1), AML with mature AML (M2), etc.) Maturation (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroblastic leukemia (M6), acute megakaryoblastic leukemia (M7), acute basophilic leukemia, acute panmyelosis with fibrosis, etc.), myeloid sarcoma (also known as granulocytic sarcoma, chloroma, or extramedullary myeloblastoma), undifferentiated and biphenotypic acute leukemia (also known as mixed phenotype acute leukemia), AML at increased risk due to other blood disorders, AML at increased risk due to exposure to chemicals, AML at increased risk due to ionizing radiation, AML evolving from myelodysplastic syndrome, AML evolving from myeloproliferative disorder, AML at increased risk due to FLT3 mutations, AML at increased risk due to FLT3 mutations in the juxtamembrane region of FLT3, AML at increased risk due to FLT3 mutations in the juxtamembrane region of FLT3,These include AML with increased risk due to a FLT3 mutation in the kinase domain of FLT3, AML with increased risk due to a FLT3 mutation D835Y, AML with increased risk due to a FLT3 mutation D835V, AML with increased risk due to a FLT3 mutation F691L, AML with increased risk due to a FLT3 mutation R834Q, etc. In some embodiments, AML that can be treated includes AML that can be treated by inhibiting one or more of FLT3 (e.g., with a FLT3 inhibitor), a FLT3 mutation (e.g., with an inhibitor of a FLT3 mutation), IRAK4 (e.g., with an IRAK4 inhibitor), a IRAK4 mutation (e.g., with an inhibitor of an IRAK4 mutation), IRAK1 (e.g., with an IRAK1 inhibitor), and / or a IRAK1 mutation (e.g., with an inhibitor of an IRAK1 mutation). In certain embodiments, AML that can be treated includes, but is not limited to, AML that can be treated by inhibiting IRAK4 (or mutations thereof), MDS that can be treated by inhibiting IRAK1 (or mutations thereof), or AML that can be treated by inhibiting IRAK4 (or mutations thereof) and IRAK1 (or mutations thereof). In some embodiments, AML that can be treated includes, but is not limited to, AML that can be treated by inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 allows for the treatment of tumors with FLT3 mutations that may be resistant or become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms caused by IRAK. In some embodiments, the AML that can be treated is characterized as AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or the AML is characterized as AML that is not caused by a FLT3 mutation but expresses IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (e.g.,U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies." Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties.

[0226] In some embodiments, hematopoietic cancers that can be treated in a subject (e.g., a mammal, pig, dog, bird (e.g., chicken), cow, cat, primate, rodent, monkey, rabbit, mouse, rat, and human) using a compound of the present disclosure (e.g., Formula (I)) include, but are not limited to, hematopoietic cancers (e.g., MDS, AML, DLBCL, etc.) that can be treated by inhibiting (e.g., reducing the activity or expression of) one or more of FLT3 (e.g., with an FLT3 inhibitor), a FLT3 mutation (e.g., with an inhibitor of an FLT3 mutation), IRAK4 (e.g., with an IRAK4 inhibitor), an IRAK4 isoform, an IRAK4 mutation (e.g., with an inhibitor of an IRAK4 mutation), IRAK1 (e.g., with an IRAK1 inhibitor), an IRAK1 isoform, or an IRAK1 mutation (e.g., with an inhibitor of an IRAK1 mutation). 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 mutations thereof) and IRAK4 (or mutations thereof), hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof) and IRAK1 (or mutations thereof), or hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof), IRAK4 (or isoforms or mutations thereof), and IRAK1 (or isoforms or mutations thereof). In some embodiments, hematopoietic cancers that can be treated include, but are not limited to, hematopoietic cancers that can be treated by inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 along with IRAK4, IRAK1, or both IRAK4 and IRAK1 allows for the treatment of tumors with FLT3 mutations that may be resistant or may become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms caused by IRAK.In some embodiments, the hematopoietic cancer that can be treated is characterized as a hematopoietic cancer with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or the hematopoietic cancer is characterized as a hematopoietic cancer that is not caused by a FLT3 mutation but expresses IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (see, e.g., U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies."). Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties.

[0227] 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, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, and combinations thereof, which can be treated by inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 allows for the treatment of tumors with FLT3 mutations that may be resistant or become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms caused by IRAK. In some embodiments, the cancer that can be treated is characterized as a cancer with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or the cancer is characterized as a cancer that is not caused by a FLT3 mutation but expresses IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (see, e.g., U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies."). Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties.

[0228] In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., overactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling that can be treated include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, and the like, and combinations thereof. In some embodiments, inhibiting FLT3 in conjunction with IRAK4, IRAK1, or both IRAK4 and IRAK1 allows for the treatment of inflammatory and autoimmune diseases with FLT3 mutations that may be resistant or become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms driven by IRAK. In some embodiments, the cancers that can be treated are characterized by inflammatory and autoimmune diseases with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or the inflammatory and autoimmune diseases are not caused by FLT3 mutations but express IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies." Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties).

[0229] In relation to the treatment of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2), treatment can include, but is not limited to, prophylactic treatment and therapeutic treatment. As such, treatment includes, but is not limited to, preventing MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS); reducing the risk of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS); alleviating or reducing the symptoms of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS); inducing a body response to MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS); inhibiting the onset or progression of MDS (e.g., MDS with 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 ...) reduction in 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); amelioration of one or more symptoms associated with MDS (e.g., an increase in blood counts); remission of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2);Remission of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations); prevention of relapse of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); or prevention of relapse of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) in animals / humans with intrinsic or acquired resistance to other MDS treatments. In some embodiments, treatment does not include prophylactic treatment of MDS (e.g., prevention or amelioration of future MDS).

[0230] In relation to the treatment of hematopoietic cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation (e.g., ABC DLBCL with MYD88 mutation L265P), follicular lymphoma, or marginal zone lymphoma, and combinations thereof), treatment can include, but is not limited to, prophylactic treatment and therapeutic treatment. As such, treatments include, but are not limited to, cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, prevention of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, reducing the risk of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); alleviating or reducing the symptoms of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof);eliciting a body response to cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); eliciting a body response to cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); inhibiting the onset or progression of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, inhibiting or preventing the onset of symptoms associated with cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, reduction in the severity of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); amelioration of one or more symptoms associated with cancer (e.g., reduction in tumor size);Cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL remission of cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations); remission of acute myeloid leukemia by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations); remission of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, prevention of recurrence of cancers (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof) in animals / humans with intrinsic or acquired resistance to other cancer therapies (such as with some FLT3 inhibitors or MLL); prevention of recurrence of cancers (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof);or prevention of recurrence of acute myeloid leukemia in animals / humans with intrinsic or acquired resistance to other cancer treatments (e.g., with some FLT3 inhibitors or MLL). In some embodiments, treatment does not include prophylactic treatment of cancer (e.g., prevention or amelioration of future cancers);

[0231] Treatment of a subject can be carried out using any suitable administration method (e.g., a method disclosed herein) and any suitable amount of a compound of the present disclosure (e.g., Formula (I)). In some embodiments, the method of treatment includes treating an animal or human for MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2). In some embodiments, methods of treatment include treating a hematopoietic cancer in an animal or human (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutated, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.). Other embodiments include treatment following one or more of suffering from a blood disorder, suffering from a myelodysplastic syndrome, suffering from a myeloproliferative disorder, exposure to a chemical, exposure to ionizing radiation, or treatment for a hematopoietic cancer (e.g., with chemotherapy, ionizing radiation, or both). Some embodiments of the present disclosure include methods of treating a subject (e.g., a human or an animal such as a primate) with a composition (e.g., a pharmaceutical composition) comprising a compound of the present disclosure (e.g., Formula (I)), comprising one or more administrations of one or more such compositions; if there are two or more administrations, the compositions may be the same or different.

[0232] In some embodiments, the method of treatment comprises administering to a subject an effective amount of a composition comprising a compound of the present disclosure (eg, Formula (I)). The term "effective amount," as used herein, refers to a dose or series of doses sufficient to affect treatment (e.g., but not limited to, treatment of MDS (e.g., MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2)); or to treat a hematopoietic cancer, such as, but not limited to, acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid carcinoma, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, in a subject. In some embodiments, an effective amount can include a therapeutically effective amount, as disclosed herein. In certain embodiments, the effective amount may vary depending on the subject and the particular treatment being affected. The exact amount required may vary, for example, from subject to subject, and may vary depending on the subject's age and general condition, the particular adjuvant used (if any), the administration protocol, etc. Thus, the effective amount may vary, for example, depending on the particular circumstances, and an appropriate effective amount can be determined in a particular case. The effective amount may include, for example, any of the doses or amounts of compositions disclosed herein.In some embodiments, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, compounds 1-137 listed in Tables 1-15), which can be administered to a subject, such as a mammal, primate, monkey, or human, can be about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, or about 15 mg / kg. For some embodiments, the dose can be about 0.5 mg / kg body weight or about 6.5 mg / kg body weight. In some cases, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, compounds 1-137 listed in Tables 1-15), which can be administered to a subject such as a mammal, rodent, mouse, rabbit, cat, pig, or dog, can be about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 80 mg / kg, about 100 mg / kg, or about 150 mg / kg.In some embodiments, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, compounds 1-1137 listed in Tables 1-15), which can be administered to a subject, such as a mammal, primate, monkey, or human, can be about 1 to about 1000 mg / kg body weight, about 5 to about 500 mg / kg body weight, about 10 to about 200 mg / kg body weight, about 25 to about 100 mg / kg body weight, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1000 mg / kg. For some conditions, the dose can be about 20 mg / kg human body weight or about 100 mg / kg human body weight. In some cases, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, Compounds 1-137 listed in Tables 1-15), which can be administered to an animal such as a mammal, rodent, mouse, rabbit, cat, pig, or dog, can be about 1 to about 1000 mg / kg body weight, about 5 to about 500 mg / kg body weight, about 10 to about 200 mg / kg body weight, about 25 to about 100 mg / kg body weight, or about 100 mg / kg body weight. The amount can be about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1000 mg / kg.

[0233] In some embodiments, the treatment may include one or more of surgical intervention, chemotherapy, radiation therapy, hormone therapy, immunotherapy, and adjuvant systemic therapy. Adjuvant therapy may include, but is not limited to, chemotherapy (e.g., temozolomide), radiation therapy, antiangiogenic therapy (e.g., bevacizumab), and hormone therapy such as administration of LHRH agonists; antiestrogens such as tamoxifen; high-dose progestogens; aromatase inhibitors; and / or adrenalectomy. Chemotherapeutic agents may be used alone or in combination with known or new therapeutic agents.

[0234] In some embodiments, administration of at least one compound of the present disclosure (e.g., Formula (I)) to a subject is an adjuvant or part of an adjuvant cancer therapy. Adjuvant therapy includes treatments by the mechanisms disclosed herein and cancer treatments of the present disclosure, including, but not limited to, tumors. Corresponding primary therapy includes, but is not limited to, surgery, chemotherapy, or radiation therapy. In some cases, adjuvant therapy may be a combination of a chemokine receptor antagonist with a conventional chemotoxic agent or immunotherapy, which may enhance the specificity of treatment for cancer and limit additional systemic side effects. In yet other embodiments, a compound of the present disclosure (e.g., Formula (I)) can be used as an adjuvant with other chemotherapeutic agents. The use of a compound of the present disclosure (e.g., Formula (I)) can, in some cases, shorten the administration period of both the drug and the drug combination, reducing side effects.

[0235] In some embodiments, administration to a subject can reduce the occurrence of one or more symptoms associated with MDS / AML / hematopoietic malignancies, ie, bone marrow failure, immune dysfunction, transformation to overt leukemia, or a combination thereof, in the subject compared to a subject not administered the composition.

[0236] In some embodiments, the method can reduce a viability marker of MDS cells, AML cells, or cancer cells in a subject. In one aspect, the method can reduce a viability marker of MDS, AML, and / or cancer cells. The marker is selected from survival over time, proliferation, growth, migration, colony formation, chromosome assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or a combination thereof.

[0237] Combination therapy In some embodiments, the treatments disclosed herein can include other drugs (e.g., antibiotics) or therapeutic agents for treating diseases (e.g., MDS / AML / hematopoietic cancers). For example, antibiotics can be used to treat infections and can be combined with compounds of the present disclosure for treating diseases (e.g., infections). In other embodiments, intravenous immunoglobulin (IVIG) therapy can be used as part of a treatment regimen (i.e., in addition to administration of a compound of the present disclosure). For example, treatment regimens for various types of cancer can include one or more elements selected from chemotherapy, targeted therapy, alternative therapy, immunotherapy, etc.

[0238] Thus, in some embodiments, a compound and / or composition described herein can be combined with one or more BCL2 inhibitors, BTK inhibitors, chemotherapy, targeted therapy, replacement therapy, immunotherapy, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or the like, or one or more combinations thereof, in one or more administrations to a subject; where multiple administrations are present, the compositions can be the same or different. In some embodiments, when there are multiple administrations, at least one composition used in at least one administration is different from the composition in at least one other administration.

[0239] In particular, IRAK inhibitors have been shown to have synergistic effects when administered in combination with apoptosis modulators / inhibitors, such as BCL2 inhibitors.As described in U.S. Patent Application No. 16 / 804,518 (incorporated herein by reference in its entirety), exemplary apoptosis / BCL2 inhibitors have been shown to have synergistic effects when combined with exemplary IRAK inhibitors in multiple AML cell lines.Venetoclax was used as a representative apoptosis / BCL2 inhibitor.

[0240] When the concentration of an exemplary IRAK inhibitor was combined with venetoclax, the efficacy of venetoclax unexpectedly increased by ~50-fold. According to certain embodiments of the present disclosure, this synergistic combination can enhance the efficacy of venetoclax at low doses, avoiding at least some of the toxicities observed in the clinic. According to certain embodiments, the extent of the interaction depends on the dose ratio combination used, with the exemplary IRAK inhibitor resulting in a greater change in venetoclax IC50 at lower concentrations. This unexpected and dramatic change in venetoclax IC50 is substantially more than an additive response, demonstrating an unexpected synergistic interaction of the two agents, even in cell lines that do not express activating FLT3 mutants.

[0241] Accordingly, the present disclosure includes methods for treating a disease or disorder responsive to inhibition of IRAK, comprising administering to a subject a composition comprising an IRAK inhibitor compound; some embodiments of the methods can further comprise administering an apoptosis modulator. The apoptosis modulator can comprise a BTK and / or a BCL2 inhibitor. BTK and BCL2 inhibitors can be, for example, those known in the art. In some embodiments, the methods can comprise administering to the subject an apoptosis modulator. In some embodiments, the apoptosis modulator can include a BCL2 inhibitor selected from ABT-263 (navitoclax), ABT-737, ABT-199 (venetoclax), GDC-0199, GX15-070 (obatoclax) (all available from Abbott Laboratories), HA14-1, S1, 2-methoxyantimycin A3, gossypol, AT-101, apogossypol, WEHI-539, A-1155463, BXI-61, BXI-72, TW37, MIM1, UMI-77, and the like, and combinations thereof. One of skill in the art will appreciate that there are many known BCL2 inhibitors that can be used in accordance with the present disclosure. In some embodiments, the BCL2 inhibitor includes venetoclax.

[0242] In some embodiments, the administering step comprises administering to the subject a composition comprising an IRAK inhibitor compound and a BCL2 inhibitor, hi some embodiments, the administering step comprises administering a composition comprising an IRAK inhibitor compound in combination with a composition comprising a BCL2 inhibitor.

[0243] In some embodiments, the IRAK inhibitor compound is selected from compounds 1-137, or a salt, isomer, derivative, or analog thereof, and the BCL2 inhibitor is venetoclax, or a salt, isomer, derivative, or analog thereof.

[0244] In some embodiments, the method can further include administering to the subject an immune modulator. The immune modulator can include, for example, lenalidomide (Revlimid; Celgene Corporation). In some embodiments, the method can include administering an epigenetic modulator. The epigenetic modulator can include, for example, a hypomethylating agent, such as azacitidine, decitabine, or a combination thereof.

[0245] In some embodiments, the compounds and / or compositions described herein can be used in conjunction with or in combination with one or more BTK inhibitors, such as ibrutinib, or a salt, isomer, derivative, or analog thereof, for one or more administrations to a subject.

[0246] For example, the compounds and / or compositions described herein may be used in combination with other compounds, such as DNA methyltransferase / hypomethylating agents, such as, for example, azacitidine, decitabine, cytarabine, and / or guadecitabine; anthracyclines, such as, for example, daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a fixed molar ratio combination of cytarabine and daunorubicin at 5:1); or other compounds, such as, for example, vorinostat, panobinostat, valproic acid, and / or histone deacetylase (HDAC) inhibitors, such as pracinostat; purine nucleoside analogs (antimetabolites), such as fludarabine, cladribine, and / or clofarabine; isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, such as ivosidenib and / or enasidenib; anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin), and / or anti-CD45 (e.g., I 131- antibody drug conjugates such as rapamycin; mAbs / immunotherapies such as anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); Plk inhibitors such as volasertib and / or rigosertib; MEK inhibitors such as lametinib, cobimetinib, selumetinib, pimasertib, and / or refametinib; CDK9 inhibitors such as alvocidib and / or voruciclib; CDK8 inhibitors such as SEL120; retinoic acid receptor agonists such as ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); TP53 activators such as APR-246 (eprenetapopt); smoothened receptor antagonists such as glasdegib; ERK inhibitors, such as, for example, ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, such as xertinib, SCH772984, lavoxertinib, MK-8353, and / or VTX-11e; PI3K inhibitors, such as, for example, fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); for example, bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridafone mTOR inhibitors such as rolimus (MK-8669, AP-23573), everolimus, and / or vistasertib (AZD2014); glucocorticoid receptor modulators such as agonists including, for example, prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or antagonists including mifepristone, myricholant, and / or onapristone, and / or other binding ligands including, for example, vamorolone (VBP15);and / or can be used in one or more administrations with or in combination with an EZH2 inhibitor, such as, for example, tazemetostat. In some embodiments, the compounds and pharmaceutical compositions containing same can be used to prevent secondary malignancies when used in combination with an EZH2 inhibitor. Additional therapeutic agents are described below, and combination therapy within the context of this disclosure is contemplated.

[0247] Chemotherapy / targeted therapy / alternative therapy Cancers are commonly treated with chemotherapy, and / or targeted therapy, and / or alternative therapies. While chemotherapy works by indiscriminately targeting rapidly dividing cells, including tumor cells as well as normal cells, targeted cancer therapies work by interfering with specific molecules or molecular targets involved in the growth and progression of cancer. Targeted therapies typically target only cancer cells, minimizing damage to normal cells. Chemotherapeutic and targeted therapy agents that are approved and / or in clinical trials are known to those skilled in the art. Any such compounds can be utilized in the practice of the present disclosure.

[0248] For example, approved chemotherapy drugs include Abitrexate (methotrexate injection), Abraxane (paclitaxel injection), Adcetris (brentuximab vedotin injection), Adriamycin (doxorubicin), Adrsil injection (5-FU (fluorouracil)), Afinitor (everolimus), Afinitor Disperse (everolimus), Alimta (pemetrexed), Alkeran injection (melphalan injection), Alkeran tablets (melphalan), Aredia (pamidronate), Arimidex (anastrozole), and Aromasin. (exemestane), Alanon (nelarabine), Alzera (ofatumumab injection), Avastin (bevacizumab), Beleodac (belinostat injection), Beksar (tositumomab), BiCNU (carmustine), Blenoxane (bleomycin), Blincyto (blinatumomab injection), Bosulif (bosutinib), Busulfex injection (busulfan injection), Campath (alemtuzumab), Camptosar (irinotecan), Caprelsa (vandetanib), Casodex (bicalutamide), CeeNU (lomustine), CeeNU Dose Pack (lomustine), Cervizin (daunorubicin), Chlorar (clofarabine injection), Cometrik (cabozantinib), Cosmegen (dactinomycin), Cotellic (cobimetinib), Cyramza (ramucirumab injection), Cytosar (cytarabine), Cytoxan (cytoxan), Cytoxan injection (cyclophosphamide injection), Dacogen (decitabine), Daunoxome (daunorubicin lipid complex injection), Decadron (dexamethasone), Depocyt (cytarabine lipid complex injection), Dexamethasone Intensor (dexamethasone), Dexpak Taperpak (dexamethasone), Docefrez (docetaxel), Doxil (doxorubicin lipid complex injection), Droxia (hydroxyurea), DTIC (decarbazine), Eligard (leuprolide), Elence (Elance (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Erspar (asparaginase), Emcyte (estramustine), Erbitux (cetuximab), Erivage (vismodegib), Erwinase (asparaginase Erwinia chrysanthemi),Ethyol (amifostine), Etopofos (etoposide injection), Eurexin (flutamide), Fareston (toremifene), Faridak (panobinostat), Faslodex (fulvestrant), Femara (letrozole), Filmagon (degarelix injection), Fludara (fludarabine), Folex (methotrexate injection), Folotin (pralatrexate injection), FUDR (FUDR (floxuridine)), Gadiva (obiotic) Nutuzumab injection), Gemzar (gemcitabine), Gilotrif (afatinib), Gleevec (imatinib mesylate), Gliadel wafer (carmustine wafer), Halaven (eribulin injection), Herceptin (trastuzumab), Hexalen (altretamine), Hycamtin (topotecan), Hydrea (hydroxyurea), Ibrance (palbociclib), Iclusig (ponatinib), Idamycin PFS (idarubicin), Ifex (ifosfamide), Imbruvica (ibrutinib), Inlyta (axitinib), Intron A Alphab (interferon alfa-2a), Iressa (gefitinib), Istodax (romidepsin injection), Ixempra (ixabepilone injection), Jakafi (ruxolitinib), Jevtana (cabazitaxel injection), Kadcyla (ado-trastuzumab emtansine), Keytruda (pembrolizumab injection), Kyprolis (carfilzomib), Ranvima (lenvatinib), Leukeran (chlorambucil), Leukin (sargramostim), Leustatin (cladribine), Lonsurf (trifluridine and tipiracil), Lupron (leuprolide), Lupron Depot (leuprolide), Lupron Depot PE (leuprolide), Lynparza (olaparib), Risodren (mitotane), Marquibo Kit (vincristine lipid complex injection), Maturan (procarbazine), Megas (megestrol), Mekinist (trametinib), Mesnex (mesna), Mesnex (mesna injection), Metastron (strontium-89 chloride), Mexate (methotrexate injection), Mustagen (mechlorethamine), Mutamycin (mitomycin), Myleran (busulfan),Mylotarg (gemtuzumab ozogamicin), Navelbine (vinorelbine), Neosar injection (cyclophosphamide injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (sorafenib), Nilandrone (nilandrone (nilutamide)), Nipent (pentostatin), Nolvadex (tamoxifen), Novantrone (mitoxantrone), Odomzo (sonidegib), Oncaspar (pegaspargas), Oncovin (vincristine), Ontak (denileukin-10) Diftitox), Onxol (paclitaxel injection), Opdivo (nivolumab injection), Panretin (alitretinoin), Paraplatin (carboplatin), Perjeta (pertuzumab injection), Platinol (cisplatin), Platinol (cisplatin injection), Platinol AQ (cisplatin), Platinol AQ (cisplatin injection), Pomalyst (pomalidomide), Prednisone Intensor (prednisone), Proleukin (aldesleukin), Purinetol (mercaptopurine), Reclust (zoledronic acid), Revlimid (lenalidomide), Rheumatrex (methotrexate), Rituxan (rituximab), Roferon A alpha a (interferon) alpha-2a), Rubex (doxorubicin), Sandostatin (octreotide), Sandostatin LAR Depot (octreotide), Soltamox (tamoxifen), Sprycel (dasatinib), Sterup Red (prednisone), Sterup Red DS (prednisone), Stivarga (regorafenib), Suprenin LA (histrelin implant), Sutent (sunitinib), Silatron (peginterferon alpha-2b injection (Silatron)), Silvant (siltuximab injection), Synribo (omacetaxine injection), Tabloid (thioguanine), Taflinal (dabrafenib), Tarceva (erlotinib), Targretin capsules (bexarotene), Tasigna (decarbazine), Taxol (paclitaxel injection), Taxotere (docetaxel), Temodar (temozolomide), Temodar (temozolomide injection), Tepadina (thiotepa), Thalomid (thalidomide),theraCys BCG (BCG), Thioplex (thiotepa), TICE BCG (BCG), Toposar (etoposide injection), Torisel (temsirolimus), Tranda (bendamustine hydrochloride), Trelstar (triptorelin injection), Trexol (methotrexate), Trisenox (arsenic trioxide), Tycarb (lapatinib), Unituxin (dinutuximab injection), Valstar (valrubicin intravesical injection), Vantas (histrelin implant), Vectibix (panitumumab), Velban (vinblastine), Velcade (bortezomib), Bepesid (etoposide), Bepesid (etoposide injection), Vesanoid (tretinoin), Vidaza (azacitidine), Vincasar PFS (vincristine), Vincrex (vincristine) , Votrient (pazopanib), Bumon (teniposide), Wellcovorin IV (leucovorin injection), Xalkori (crizotinib), Xeloda (capecitabine), Xtandi (enzalutamide), Yervoy (ipilimumab injection), Yondelis (trabectedin injection), Zaltrap (dibuaflibercept injection), Zanosar (streptozocin), Zelboraf (vemurafenib), Zevalin (ibritumomab tiusetan), Zoladex (goserelin), Zolinza (vorinostat), Zometa (zoledronic acid), Zoltrex (everolimus), Zydelig (idelalisib), Zykadia (ceritinib), Zytiga (abiraterone), and others, as well as their analogs and derivatives. For example, approved targeted therapies include ado-trastuzumab emtansine (Kadcyla), afatinib (Giotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campus), axitinib (Inrita), belimumab (Benlysta), belinstat (Veleodac), bevacizumab (Avastin), bortezomib (Velcade), Bosutinib (Bosurif), brentuximab vedotin (Adcetris), cabozantinib (Cabometyx [tablets], Cometrix [capsules]), canakinumab (Ilaris), carfilzomib (Cyprolis), ceritinib (Zykadia), cetuximab (Erbitux), cobimetinib (Cotellic), crizotinib (Xalkori), dabrafenib (Tafinlar),Daratumumab (Darzalex), dasatinib (Sprycel), denosumab (Kusugeba), dinutuximab (Unituxin), elotuzumab (Emplicici), erlotinib (Tarceva), everolimus (Afinitor), gefitinib (Iressa), ibritumomab tiuxetan (Zevalin), ibrutinib (Imbruvica), idelalisib (Zydelig), imatinib (Gleevec), ipilimumab (Yervoy), ixazomib (Ninlaro), lapatinib (Tykerb), lenvatinib (Lenvima), necitumumab (Portolaza), nilotinib (Tasigna), nivolumab (Opdivo), obinutuzumab (Gazyva), ofatumumab (Alvarez-Richards), Zela, HuMax-CD20), olaparib (Lympaz), osimertinib (Tagrisso), palbociclib (Ibrance), panitumumab (Vectibix), panobinostat (Faridak), pazopanib (Votrient), pembrolizumab (Keytruda), pertuzumab (Perjeta), ponatinib (Iclusig), ramucirumab (Cyramza), rapamycin, Gorafenib (Stivarga), rituximab (Rituxan, MabThera), romidepsin (Istodax), ruxolitinib (Jakafi), siltuximab (Sylvanto), sipuleucel-T (Provenge), sirolimus, sonidegib (Odomzo), sorafenib (Nexavar), sunitinib, tamoxifen, temsirolimus (Toricel), tocilizumab (Actemra), and Tofa These include citinib (Xeljanz), tositumomab (Bexar), trametinib (Mekinist), trastuzumab (Herceptin), vandetanib (Caprelsa), vemurafenib (Zelboraf), venetoclax (Venclexta), vismodegib (Elivege), vorinostat (Zolinza), dib-aflibercept (Zaltrap), and analogs and derivatives thereof.

[0249] Those skilled in the art can determine appropriate chemotherapy and / or targeted therapy and / or alternative therapy options, including approved therapies and therapies in clinical trials or development. Some targeted therapies are also immunotherapies. In practicing the present disclosure, any relevant chemotherapy, targeted therapy, and alternative therapy treatment strategies can be used alone or in combination with one or more additional cancer therapies.

[0250] immunotherapy In some embodiments, immunotherapy involves the treatment of cells that affect the immune response (e.g., lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTLs), antibodies and antibody derivatives (e.g., monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemically labeled antibodies, etc.), immune checkpoint inhibitors, vaccines (e.g., cancer vaccines (e.g., tumor cell vaccines, antigen vaccines, dendritic cell vaccines, vector-based vaccines, etc.), e.g., oncophage, sipuleucel-T), immunomodulatory agents (e.g., interleukins, cytokines, chemokines, etc.), topical immunotherapy (e.g., imiquimod, etc.), injectable immunotherapy, adoptive cell transfer, oncolytic virotherapy (e.g., talimozyme, etc.), and the like. Immunotherapy includes cell-based immunotherapies, including leukemia, leukemia-associated lymphomas (e.g., laherparepvec (T-VEC)), immunosuppressants, helminth therapy, other non-specific immunotherapies, and the like. Immune checkpoint inhibitor immunotherapies target one or more specific proteins or receptors, such as PD-1, PD-L1, CTLA-4, and the like. Immune checkpoint inhibitor immunotherapies include ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), and the like. Non-specific immunotherapies include cytokines, interleukins, interferons, and the like. In some embodiments, the immunotherapy assigned or administered to the subject is an interleukin. and / or administration of one or more suitable antibody-based reagents such as leukin, and / or interferon (IFN), and / or denileuxin diftitox, and / or an antibody-based reagent selected from the group consisting of ado-trastuzumab, emtansine, alemtuzumab, atezolizumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, catumaxomab, gemtuzumab, ibritumomab tiusetan, iripimumab, natalizumab, nimotuzumab, nivolumab, ofatumumab, panitumumab, pembrolizumab, rituximab, tositumomab, trastuzumab, bivataxin, and the like.In some embodiments, the immunotherapy assigned or administered to the subject can include indoleamine 2,3-dioxygenase (IDO) inhibitors, adoptive T cell therapy, viral therapy (T-VEC), and / or any other immunotherapy whose efficacy is significantly dependent on anti-tumor immunity.

[0251] Those skilled in the art can determine appropriate immunotherapeutic options, including approved therapies and therapies in clinical trials or development. Any relevant immunotherapeutic treatment strategy can be used in the practice of the present disclosure, alone or in combination with one or more additional cancer therapies.

[0252] Other cancer treatments In addition to chemotherapy, targeted therapy, alternative therapy, and immunotherapy, cancer can also be treated by other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplantation, precision medicine, etc., and such treatments and the compounds and compositions utilized therein are known to those skilled in the art. Any such treatment strategy can be utilized in the practice of the present disclosure.

[0253] Alternative treatment strategies are also used for various types of cancer. Such treatments can be used alone or in combination with other treatment modalities. These include exercise, massage, relaxation techniques, yoga, acupuncture, aromatherapy, hypnosis, music therapy, dietary changes, and nutritional dietary supplements, and such treatments are known to those skilled in the art. Any such treatment strategy can be used in the practice of the present disclosure, alone or in combination with one or more additional cancer therapies.

[0254] Dosage and Route of Administration Other embodiments of the present disclosure may include methods of administration or treatment to animals / humans, and may include treatment with an amount of at least one compound of the present disclosure (e.g., Formula (I)) effective to treat a disease, condition, or disorder from which the organism is afflicted or suspected of being afflicted or to which it is susceptible, or effective to produce a desired physiological effect. In some embodiments, a composition or pharmaceutical composition comprises at least one compound of the present disclosure (e.g., Formula (I)) that can be administered to an animal (e.g., a mammal, primate, monkey, or human) in an amount of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, or about 15 mg / kg. For some conditions, the dose can be about 0.5 mg / kg human body weight or about 6.5 mg / kg human body weight. In some cases, a subject (e.g., a mammal, mouse, rabbit, cat, pig, or dog) can be administered a dose of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 80 mg / kg, about 100 mg / kg, or about 150 mg / kg. Of course, one of ordinary skill in the art will understand that a variety of concentrations can be used in the methods of the present disclosure, and that any number of concentrations can be adjusted and tested, in part using the guidance provided herein, to find a concentration that achieves the desired result in a given situation.In some embodiments, the dose or therapeutically effective dose of a compound disclosed herein is an amount sufficient to achieve a plasma concentration of the compound or its active metabolite within the ranges set forth herein, e.g., 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or 500-1000 μM, preferably about 1-10 nM, 10-100 nM, or 0.1-1 μM. Without wishing to be bound by any theory, it is believed that such compounds are indicated for the treatment or management of, for example, hematopoietic cancers such as MDS and / or AML and / or DLBCL, other types of cancers described herein, inflammatory conditions, and / or autoimmune diseases.

[0255] In other embodiments, the compounds and / or pharmaceutical compounds of the present disclosure (e.g., compounds of Formula (I) and pharmaceutical compositions comprising same) can be administered in combination with one or more other therapeutic agents for a given disease, condition, or disorder.

[0256] The compounds and pharmaceutical compositions are preferably prepared and administered in dosage units.Solid dosage units are tablets, capsules, and suppositories.Different daily doses can be used to treat a subject, depending on the activity of the compound, the method of administration, the nature and severity of the disease or disorder, and the age and weight of the subject.

[0257] However, in certain circumstances, higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out by a single administration in the form of an individual dosage unit or several other smaller dosage units, or by multiple administration of divided doses at specific intervals.

[0258] The compounds and pharmaceutical compositions contemplated herein can be administered locally or systemically at a therapeutically effective dose. The amount effective for this use will, of course, depend on the severity of the disease or disorder, as well as the weight and general condition of the subject. Typically, the dosage used in vitro can provide a useful guide for the amount useful for in situ administration of the pharmaceutical composition, and animal models can be used to determine the effective dosage for treating a particular disorder.

[0259] Various considerations are described, for example, in Langer, 1990, Science, 249:1527; Goodman and Gilman's (eds.), 1990, Id., each of which is incorporated herein by reference for all purposes. A parenteral dose of an active agent can be converted to a corresponding oral dose by multiplying the parenteral dose by the appropriate conversion factor. For general applications, the parenteral dose in mg / mL is 1.8 times the corresponding oral dose in milligrams ("mg"). For oncology applications, the parenteral dose (mg / mL) is 1.6 times the corresponding oral dose (mg). The average adult weighs approximately 70 kg. See, e.g., Miller-Keane, 1992, Encyclopedia & Dictionary of Medicine, Nursing & Allied Health, 5th Ed., (WB Saunders Co.), pp. 1708 and 1651.

[0260] However, it will be understood that the specific dose level for a particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, concomitant drugs, and the severity of the particular disease being treated.

[0261] In some embodiments, compounds and / or pharmaceutical compositions can include a unit dose of one or more compounds of the present disclosure (e.g., compounds of Formula (I) and pharmaceutical compositions comprising same) in combination with a pharmaceutically acceptable carrier, and can further include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients. In certain embodiments, the carrier, vehicle, or excipient can facilitate administration, delivery, and / or improve the storage of the composition. In other embodiments, the one or more carriers include, but are not limited to, saline solutions such as saline, Ringer's solution, PBS (phosphate buffered saline), and mixtures of various salts, generally including potassium and phosphate salts, with or without sugar additives such as glucose. Carriers can include aqueous and non-aqueous sterile injectable solutions, which can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the body fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents. In other embodiments, the one or more excipients can include, but are not limited to, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. Non-toxic auxiliary substances, such as wetting agents, buffers, or emulsifying agents, can also be added to the compositions. Oral formulations can include commonly used excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.

[0262] The amount of active ingredient in a unit dosage preparation may be varied or adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1,000 mg, and most typically from 10 mg to 500 mg, depending on the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0263] The compounds of the present disclosure (e.g., compounds according to Formula (I)) can be administered to a subject by any number of suitable routes of administration or formulations. The compounds of the present disclosure (e.g., Formula (I)) can also be used to treat various diseases in a subject. Subjects include, but are not limited to, mammals, primates, monkeys (e.g., macaques, rhesus monkeys, or pig-tailed macaques), humans, dogs, cats, cows, pigs, birds (e.g., chickens), mice, rabbits, and rats. As used herein, the term "subject" encompasses both human and non-human subjects, unless otherwise specified.

[0264] The route of administration of the compounds of the present disclosure (e.g., Formula (I)) can be any suitable route. The route of administration can be, but is not limited to, oral, parenteral, cutaneous, nasal, rectal, vaginal, and ocular. In other embodiments, the route of administration can be parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular. The choice of administration route can vary depending on the identity of the compound (e.g., the physical and chemical properties of the compound), the age and weight of the animal / human, the specific disease (e.g., cancer or MDS), and the severity of the disease (e.g., the stage or severity of cancer or MDS). Of course, if desired, a combination of administration routes can be used.

[0265] Some embodiments of the present disclosure include methods for providing a subject with a composition (e.g., a pharmaceutical composition) comprising one or more compounds of the present disclosure (e.g., Formula (I)) described herein, comprising one or more administrations of one or more such compositions, where multiple administrations are present, the compositions may be the same or different.

[0266] toxicity The ratio between the toxicity and therapeutic effect of a particular compound is its therapeutic index, and the LD 50 (the amount of compound that is lethal to 50% of the population) and ED 50Therapeutic indices can be expressed as a ratio between the ED (the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from in vitro assays, cell culture assays, and / or animal studies can be used in formulating a dosage range for human use. Doses of such compounds can be administered with little or no toxicity and at an ED 50 Preferably, the plasma concentration range is within a range having a concentration of 0.05 to 0.05%. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. See, for example, Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 1, pl, 1975. The exact formulation, route of administration, and dosage can be selected by the individual practitioner, taking into account the patient's condition and the particular method in which the compound is used. For in vitro formulations, the exact formulation and dosage can be selected by the individual practitioner, taking into account the patient's condition and the particular method in which the compound is used.

[0267] Although the present disclosure has been described in detail, it will be apparent that modifications, variations, and equivalents are possible without departing from the scope of the present disclosure as defined in the appended claims. Furthermore, it will be understood that any examples in this disclosure are given by way of non-limiting examples.

[0268] The following sections describe specific embodiments.

[0269] Term 1. Formula (I): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof. (In the formula, R 1is H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and said amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is not halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl. optionally substituted with one or more of hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 2is H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, heteroaryl, or fused-ring heteroaryl, and said amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is halogen, hydroxy, oxo, methanoyl (- and optionally substituted with one or more of C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, fused-ring aryl, heteroaryl, fused-ring heteroaryl, or C1-C7 alkyl substituted with cycloalkyl; R 3 , R 4 , and R 5are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; optionally substituted with one or more of hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 6 teeth, [ka] and R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5; and q+r+s+t is at least 1, and u+v+w+x is at least 1.

[0270] Section 2.R 1 is H, halogen, -CONH2, -CONHCH3, -CON(CH3)2, benzyl, C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl, wherein the C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl is optionally substituted with one or more halogen, hydroxyl, C1-C7 alkyl, or C1-C7 haloalkyl.

[0271] Section 3.R 1 is H, Cl, -CONH2, -CONHCH3, methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl, and the methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl is optionally substituted with one or more F, -OH, methoxy, or CF3.

[0272] Section 4.R 1 The compound according to item 1 or 2, wherein is not H.

[0273] Section 5.R 2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, and wherein said 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 The compound according to any one of items 1 to 3, wherein the 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 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0274] Section 6.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, and the 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, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0275] Section 7.R 2 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.

[0276] Section 8.R 2 The compound according to any one of items 1 to 5, wherein is not H.

[0277] Section 9.R 3is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy is halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), hetero The compound according to any one of items 1 to 8, optionally substituted with one or more of cyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0278] Section 10.R 3 10. The compound according to any one of items 1 to 9, wherein is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0279] Section 11.R 4 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy is halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyano (-CN), The compound according to any one of items 1 to 10, optionally substituted with one or more of acryl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0280] Section 12.R4 12. The compound according to any one of items 1 to 11, wherein is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0281] Section 13.R 5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy is halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyano (-CN), The compound according to any one of items 1 to 12, optionally substituted with one or more of acryl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0282] Section 14.R 5 14. The compound according to any one of items 1 to 13, wherein is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0283] Section 15.R 4 is methyl or -CF3, and R 3 and R 5 Item 12. The compound according to any one of items 1 to 11, wherein at least one of is H or halogen.

[0284] Section 16.R 6 is as follows: [ka] Item 16. The compound according to any one of items 1 to 15, wherein

[0285] Item 17. The compound according to any one of items 1 to 16, wherein m is 0 or 1, n is 0 or 1, o is 0 or 1, and p is 0 or 1.

[0286] Section 18.R 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14 18. The compound according to any one of items 1 to 17, wherein at least one of is not H.

[0287] Section 19.R 11 , R 12 , R 13 , and R 14 is H and R 7 , R 8 , R 9 , and R 10 19. The compound according to any one of paragraphs 1 to 18, wherein at least one of is not H.

[0288] Section 20.R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 and (b) are H.

[0289] Section 21.R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, wherein the methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogens.

[0290] Section 22.R 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14 22. The compound according to item 21, wherein at least one of is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, and the methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogens.

[0291] Section 23.R 11 , R 12 , R 13 , and R 14 is H and R 7 , R 8 , R 9 , and R 10 22. The compound according to item 21, wherein at least one of is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, and the methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogens.

[0292] Section 24.R 7 , R 8 , R 9 , and R 10 24. The compound according to any one of items 1 to 23, wherein at least one of is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl.

[0293] Section 25.R 7 , R 8 , R 9 , and R 10 24. The compound according to item 23, wherein at least one of is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.

[0294] Section 26.R 7 and R 8 Both or R 9 and R 10 Both are F, or R 7 and R 8 Both or R 9 and R 10 Item 26. The compound according to item 25, wherein both of are methyl.

[0295] Section 27.R 11 , R 12 , R 13 , and R 14 27. The compound according to any one of items 1 to 26, wherein at least one of is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl.

[0296] Section 28.R 11 , R 12 , R 13 , and R 14 28. The compound according to item 27, wherein at least one of is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.

[0297] Section 29.R 11 and R 12 Both or R 13 and R 14 Both are F, or R 11 and R 12 Both or R 13 and R 14 Item 29. The compound according to item 28, wherein both of are methyl.

[0298] Section 30.R 6 is as follows: [ka] Item 16. The compound according to any one of items 1 to 15, wherein

[0299] Item 31. The compound according to any one of items 1 to 15 or 30, wherein q, r, s, t, u, v, w, and x are each independently 0, 1, or 2.

[0300] Item 32. 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. A compound according to any one of items 1 to 15 or 30 to 31.

[0301] Section 33.R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, wherein the methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogens.

[0302] Section 34.R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 one or more of R is H, or 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 and (iii) are H. The compound according to any one of items 1 to 15 or 30 to 33,

[0303] Section 35.R 6 is as follows: [ka] 35. The compound according to any one of items 1 to 15 or 30 to 34, wherein

[0304] Section 36.R 6 is as follows: [ka] 36. The compound according to any one of items 1 to 15 or 30 to 35,

[0305] Item 37. The compound according to any one of items 1 to 36, wherein the compound is selected from compounds 1 to 107 listed in Tables 1 to 9.

[0306] Item 38. The compound according to any one of items 1 to 37, wherein the compound is selected from Compound 1, Compound 9, Compound 19, Compound 20, Compound 21, Compound 26, Compound 31, Compound 38, Compound 45, Compound 56, Compound 60, Compound 61, Compound 62, Compound 63, Compound 81, Compound 84, Compound 96, Compound 97, and Compound 99.

[0307] Item 39. The compound according to any one of items 1 to 38, wherein the compound is selected from compound 9, compound 19, compound 20, compound 21, compound 26, compound 31, compound 38, compound 45, compound 56, compound 60, compound 61, compound 62, compound 63, compound 81, compound 84, compound 96, compound 97, and compound 99.

[0308] Item 40. A composition comprising a compound according to any one of items 1 to 39.

[0309] Item 41. The composition according to Item 40, wherein the amount of the compound is from about 0.0001% (based on the total composition weight) to about 99%.

[0310] Item 42. The composition of Item 40 or 41, further comprising a formulation component, adjuvant, or carrier.

[0311] Item 43. The composition according to any one of Items 40 to 42, further comprising a BCL2 inhibitor.

[0312] Item 44. The composition of any of items 40 to 42, wherein the composition is used in combination with a second composition comprising a BCL2 inhibitor.

[0313] Clause 45. The composition of any of clauses 40 to 44, wherein the BCL2 comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0314] Clause 46. The composition of any of clauses 40 to 45, wherein the composition is used in combination with one or more chemotherapeutics, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof.

[0315] Item 47. The DNA methyltransferase / hypomethylating agent includes azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a fixed molar ratio of 5:1); and the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproic acid. and / or pracinostat; the purine nucleoside analogs (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab); the mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, cobimetinib, the CDK9 inhibitors include alvocidib and / or voruciclib; the CDK8 inhibitors include SEL120; the retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activators include APR-246 (Eprenetapt); the smoothened receptor antagonists include glasdegib; the ERK inhibitors include ulixertinib, SCH772984, lambda The PI3K inhibitors include ERK2 / MAPK1 inhibitors or ERK1 / MAPK3 inhibitors, including voxertinibe, MK-8353, and / or VTX-11e; the PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), ebetiase inhibitors, and the like. 47. The composition of any one of paragraphs 40 to 46, wherein the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricholant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor comprises tazemetostat.

[0316] Clause 48. A method for providing a compound to a subject, comprising one or more administrations of one or more compositions comprising a compound according to any one of clauses 1 to 39, wherein when there are multiple administrations, the compositions may be the same or different.

[0317] Item 49. The method of Item 48, wherein at least one of the one or more compositions comprises a compounding ingredient.

[0318] Item 50. The method according to Item 48 or Item 49, wherein at least one of the one or more compositions comprises a composition according to any one of Items 40 to 47.

[0319] Clause 51. The method of any of clauses 48 to 50, wherein at least one of the one or more administrations comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.

[0320] Clause 52. The method of any one of clauses 48 to 51, wherein, if there are multiple administrations, at least one composition used in at least one administration is different from the composition in at least one other administration.

[0321] Item 53. The method of any of items 48 to 52, wherein at least one compound of the one or more compositions is administered to the subject in an amount of about 0.005 mg / kg (body weight of the subject) to about 50 mg / kg (body weight of the subject).

[0322] Clause 54. The method of any of clauses 48 to 53, wherein the subject is a mammal, preferably the subject is a human, a rodent, or a primate.

[0323] Clause 55. A method for treating a disease or disorder, comprising one or more administrations to a subject of one or more compositions comprising a compound according to any one of clauses 1 to 39, wherein the compositions, if administered multiple times, may be the same or different.

[0324] Clause 56. The method of clause 55, wherein the disease or disorder responds to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.

[0325] Item 57. The method according to Item 55 or 56, wherein at least one of the one or more compositions further comprises a formulation ingredient.

[0326] Item 58. The method of any one of items 55 to 57, wherein at least one of the one or more compositions comprises a composition according to any one of items 40 to 47.

[0327] Clause 59. The method of any of clauses 55 to 58, wherein at least one of the one or more administrations comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.

[0328] Clause 60. The method of any of clauses 55 to 59, wherein at least one of the one or more administrations comprises oral administration.

[0329] Clause 61. The method of any of clauses 55 to 60, wherein, if there are multiple administrations, at least one composition used in at least one administration is different from the composition in at least one other administration.

[0330] Item 62. The method of any one of items 55 to 61, wherein at least one compound of the one or more compositions is administered to the subject in an amount of about 0.005 mg / kg (body weight of the subject) to about 50 mg / kg (body weight of the subject).

[0331] Clause 63. The method of any of clauses 55 to 62, wherein the subject is a mammal, preferably the subject is a human, rodent, or primate.

[0332] Paragraph 64. The method of any one of paragraphs 55 to 63, wherein the subject is in need of the treatment.

[0333] Paragraph 65. The method according to any one of paragraphs 55 to 64, wherein the method is for treating hematopoietic cancer.

[0334] Paragraph 66. The method of any of paragraphs 55 to 65, wherein the method is for treating myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML).

[0335] Clause 67. The method of any of clauses 55 to 65, wherein the method is for treating lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with a MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.

[0336] Clause 68. The method of any of clauses 55 to 64, wherein the disease or disorder is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof.

[0337] Clause 69. The method of clause 68, wherein the method is for treating one or more inflammatory or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof.

[0338] Paragraph 70. The method of any of paragraphs 55 to 66, wherein the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2, or the method is for treating AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or AML that is not driven by a FLT3 mutation but expresses IRAK4-Long.

[0339] Clause 71. The method of any of clauses 55 to 67, wherein the method is for treating DLBCL, and the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL.

[0340] Item 72. The method of Item 71, wherein the method further comprises administering a composition comprising a BTK inhibitor.

[0341] Item 73. The method of Item 71, wherein the BTK inhibitor comprises ibrutinib.

[0342] Clause 74. The method of any of clauses 55 to 73, wherein the subject is susceptible to AML and / or MDS and / or the method prevents or ameliorates future AML and / or MDS.

[0343] Paragraph 75. The method of any of paragraphs 55 to 74, wherein the method is performed after one or more of the following: development of a myelodysplastic syndrome, development of a myeloproliferative disorder, exposure to a chemical, exposure to ionizing radiation, or treatment for cancer.

[0344] Clause 76. The method of any one of clauses 55 to 74, wherein the method further comprises administering a composition comprising a BCL2 inhibitor, or wherein at least one of the compositions comprising a compound according to any one of clauses 1 to 39 further comprises a BCL2 inhibitor.

[0345] Clause 77. The method of any of clauses 55 to 76, wherein the compound of any of clauses 1 to 39 and the BCL2 inhibitor may be administered together or separately in one or more administrations of one or more compositions.

[0346] Clause 78. The method of any of clauses 55 to 77, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0347] Clause 79. The method of any of clauses 55 to 78, wherein the method further comprises administration of one or more additional therapeutic agents selected from one or more chemotherapeutics, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof.

[0348] Item 80. The DNA methyltransferase / hypomethylating agent includes azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a fixed molar ratio of 5:1); and the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproic acid. and / or pracinostat; the purine nucleoside analogs (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab); the mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, cobimetinib, the CDK9 inhibitors include alvocidib and / or voruciclib; the CDK8 inhibitors include SEL120; the retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activators include APR-246 (Eprenetapt); the smoothened receptor antagonists include glasdegib; the ERK inhibitors include ulixertinib, SCH772984, The present invention relates to an ERK2 / MAPK1 inhibitor or an ERK1 / MAPK3 inhibitor, including lavoxertinib, MK-8353, and / or VTX-11e; the PI3K inhibitor includes fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitor includes bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), erlotinib (ERL-11), riboflavin (RI ... 80. The method of any one of clauses 55 to 79, wherein the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricholant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor comprises tazemetostat.

[0349] Clause 81. A compound according to any one of clauses 1 to 39 for use in a method for treating a disease or disorder, the method comprising inhibiting at least one of IRAK and FLT3 by administering one or more compositions comprising the compound, and when there are multiple administrations, the compositions may be the same or different.

[0350] Item 82. The compound according to Item 81, wherein the disease or disorder responds to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.

[0351] Item 83. The compound according to Item 81 or 82, wherein at least one of the one or more compositions further comprises a formulation ingredient.

[0352] Item 84. The compound according to any one of items 81 to 83, wherein at least one of the one or more compositions comprises a composition according to any one of items 40 to 47.

[0353] Paragraph 85. The compound of any of paragraphs 81 to 84, wherein at least one of the one or more administrations comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, transdermal, oral, sublingual, intranasal, or intramuscular administration.

[0354] Clause 86. The compound of any of clauses 81 to 85, wherein at least one of the one or more administrations comprises oral administration.

[0355] Clause 87. The compound according to any one of clauses 81 to 86, wherein, when multiple administrations are performed, at least one composition used in at least one administration is different from the composition of at least one other administration.

[0356] Item 88. The compound according to any one of items 81 to 87, wherein at least one compound of the one or more compositions is administered to the subject in an amount of about 0.005 mg / kg (body weight of the subject) to about 50 mg / kg (body weight of the subject).

[0357] Paragraph 89. The compound of any of paragraphs 81 to 88, wherein the subject is a mammal, preferably the subject is a human, a rodent, or a primate.

[0358] Paragraph 90. The compound of any of paragraphs 81 to 89, wherein the subject is in need of treatment.

[0359] Paragraph 91. The compound of any one of paragraphs 81 to 90, wherein the method is for treating hematopoietic cancer.

[0360] Paragraph 92. The compound of any of paragraphs 81 to 91, wherein the method is for treating MDS and / or AML.

[0361] Paragraph 93. The compound of any of paragraphs 81 to 91, wherein 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's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MYD88-mutated DLBCL, follicular lymphoma, or marginal zone lymphoma.

[0362] Clause 94. The compound according to any one of clauses 81 to 90, for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof.

[0363] Clause 95. The compound of clause 94, wherein the method is for treating one or more inflammatory or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof.

[0364] Paragraph 96. The compound according to any one of paragraphs 81 to 92, wherein the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2, or the method is for treating AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or AML that is not driven by a FLT3 mutation but expresses IRAK4-Long.

[0365] Paragraph 97. The compound of any of paragraphs 81 to 93, wherein the method is for treating DLBCL, and the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL.

[0366] Item 98. The compound of Item 97, wherein the method further comprises administering a composition comprising a BTK inhibitor.

[0367] Item 99. The compound according to Item 98, wherein the BTK inhibitor comprises ibrutinib.

[0368] Paragraph 100. The compound of any of paragraphs 81 to 99, wherein the subject is susceptible to AML and / or MDS and / or the method prevents or ameliorates future AML and / or MDS.

[0369] Item 101. The compound according to any one of items 81 to 100, wherein the method is performed after one or more of the following: development of myelodysplastic syndrome, development of myeloproliferative disorder, exposure to chemicals, exposure to ionizing radiation, or treatment for cancer.

[0370] Clause 102. The compound of any of clauses 81 to 101, wherein the method further comprises administering a composition comprising a BCL2 inhibitor, or wherein at least one of the compositions comprising a compound of any of claims 1 to 39 further comprises a BCL2 inhibitor.

[0371] Clause 103. The compound of any of clauses 81 to 102, wherein the compound of any of claims 1 to 39 and the BCL2 inhibitor may be administered together or separately in one or more administrations of one or more compositions.

[0372] Clause 104. The compound of any of clauses 81 to 103, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0373] Clause 105. The compound of any of clauses 81 to 104, wherein the method further comprises administration of one or more additional therapeutic agents selected from one or more chemotherapeutics, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof.

[0374] Item 106. The DNA methyltransferase / hypomethylating agent includes azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a fixed molar ratio of 5:1); and the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproate, the purine nucleoside analogs (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab); the mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, cobimetinib, the CDK9 inhibitors include alvocidib and / or voruciclib; the CDK8 inhibitors include SEL120; the retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activators include APR-246 (Eprenetapt); the smoothened receptor antagonists include glasdegib; the ERK inhibitors include ulixertinib, SCH772984, lambda The PI3K inhibitors include ERK2 / MAPK1 inhibitors or ERK1 / MAPK3 inhibitors, including voxertinibe, MK-8353, and / or VTX-11e; the PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), everolisib (ALPHA-111), rivaroxaban (RIV ... 106. The compound of any of clauses 81 to 105, wherein the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricholant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor comprises tazemetostat.

[0375] Section 201. Formula (I): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof. (In the formula, R 1 is selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, and said amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is selected from halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl. optionally substituted with one or more of hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 2is selected from H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, heteroaryl, or fused-ring heteroaryl, and said amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is selected from halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C-C alkyl substituted with cycloalkyl; R 3 , R 4 , and R 5are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and said methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl. optionally substituted with one or more of hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 6 teeth, [ka] and R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0376] Item 202. The compound of formula (I) has the formula (IIf): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; During the ceremony, R 20f is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O-(C3-C6 cycloalkyl), wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and said C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 21f , R 22f , and R 23f are each independently selected from H and halogen; R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms.

[0377] Section 203.R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb 203. The compound according to claim 202, wherein one or more of are independently selected from halogen, -OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

[0378] Section 204.R 20fItem 204. The compound according to item 202 or 203, wherein is H.

[0379] Item 205: A compound according to any one of Items 202 to 204, wherein at least one of the following (i) to (iii) applies: (i)R 20f is Cl, below: [ka] , unsubstituted C3 cycloalkyl, and [ka] Selected from; (ii)R 21f , R 22f , and R 23f are H, respectively; (iii)R 25fa , R 25fb , R 26fa , and R 26fb are H and R, respectively. 24fa and / or R 24fb is F.

[0380] Item 206. The compound according to any one of items 202 to 2055, wherein the compound is selected from the following: [ka]

[0381] Item 207. The compound of formula (I) has the formula (IIg): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; During the ceremony, R 20g is selected from H and C1-C6 alkoxy; R 21g is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C6-C12 aryl), C3-C9 heterocyclyl, and -NR 28ga R 28gb wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and said C3-C9 heterocyclyl are optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen; R 22g , R 23g , and R 24g are each independently selected from H and halogen; R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; R 28ga and R 28gb are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0382] Section 208.R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb 208. The compound according to item 207, wherein one or more of are independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

[0383] Section 209.R 20g Item 209. The compound according to item 207 or 208, wherein is H.

[0384] Item 210: A compound according to any one of Items 206 to 209, wherein at least one of the following (i) to (ix) applies: (i)R 20g is -OCH3 and the following: [ka] Selected from; (ii)R 21g is t-butyl, unsubstituted C3 cycloalkyl, morpholinyl, azetidinyl, piperidinyl, isoxazolyl, Cl, -CF3, -OCH3, -O-phenyl, [ka] wherein G is N or CH, and [ka] wherein c is 1 or 2; (iii)R 21g is as follows: [ka] and R 29g is H, isopropyl, unsubstituted C3 cycloalkyl, azetidinyl, tetrahydropyranyl-CH3, [ka] Selected from; (iv)R 21g is -NR 28ga R 28gb (wherein R 28ga is H and R 28gb is selected from —CH3, cyclobutyl, and cyclohexyl, or R 28ga and R 28gb are -CH3, respectively); (v)R 22g , R 23g , and R 24g are H, respectively; (vi)R 22g and R 24g are F and R, respectively. 23g is H; (vii)R 22g and R 24g are H and R, respectively. 23g is F; (viii)R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb are H, respectively; (ix)R 26ga , R 26gb , R 27ga , and R 27gb are H and R, respectively. 25ga and / or R 25gb teeth 、 F, -CH3, -OH, -CF3, the following: [ka] and —OCH3.

[0385] Item 211. The compound according to any one of items 207 to 210, wherein the compound is selected from the following: [ka] TIFF2024500378000213.tif158124TIFF2024500378000214.tif152124TIFF2024500378000215.tif154125JPEG2024500378000216.jpg125125

[0386] Item 212. The compound of formula (I) has the formula (IIh): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R 20his selected from H and C1-C6 alkoxy; R 21h is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen, and said C3-C6 cycloalkyl and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen; R 22ha , R 22hb , R 23ha , and R 23hb are each independently selected from H and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen atoms; R 24h , R 25h , and R 26h 213. The compound according to item 212, wherein each of R is independently selected from H and halogen.

[0387] Item 213. The compound according to Item 212, wherein at least one of the following (i) to (iv) applies: (i)R 20h is H; (ii)R 21h is as follows: [ka] is; (iii)R 22ha , R 22hb , R 23ha , and R 23hb are H, respectively; (iii)R 24h , R 25h , and R 26h are H, respectively.

[0388] Item 214. The compound according to Item 212 or 213, wherein the compound is: [ka]

[0389] Item 215. The compound of formula (I) has the formula (IIi): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, the below described: [ka] is as follows: [ka] Selected from; R 20i is selected from H and C1-C6 alkoxy; R 21i is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and said C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, -C=O, and halogen; R 22i , R 23i , and R 24i are each independently selected from H and halogen; R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ibare each independently selected from H, halogen, —OH, or C1-C6 alkyl.

[0390] Section 216.R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib 216. The compound according to paragraph 215, wherein one or more of are independently selected from halogen, —OH, and C1-C6 alkyl.

[0391] Section 217.R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib 216. The compound according to paragraph 215, wherein each of is H.

[0392] Item 218. The compound according to any one of Items 215 to 217, wherein at least one of the following (i) to (xi) applies: (i)R 20i is selected from H and —OCH3; (ii)R 21i is as follows: [ka] , unsubstituted C3 cycloalkyl, [ka] wherein J is N or CH, and [ka] Selected from; (iii)R 21i is as follows: [ka] where R 220i is H, -CH3, as follows: [ka] and unsubstituted C3 cycloalkyl; (iv)R 22i , R 23i , and R 24i are H, respectively; (v)R 22i and R 24i are F and R, respectively. 23i is H; (vi)R 22i and R 24i are H and R, respectively. 23i is F; (vii) The following: [ka] is as follows: [ka] and R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib Each of is H and R 25ib is F; (viii) The following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ibEach of is H; (ix) The following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 28ib、 R 29ia , and R 29ib Each of is H; (x) The following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 29ia , and R 29ib Each of is H and R 28ib is F; (xi) The following: [ka] is as follows: [ka] and R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib Each of is H and R 27ib is F.

[0393] Item 219. The compound according to any one of items 215 to 218, wherein the compound is selected from the following: [ka]

[0394] [ka] JPEG2024500378000240.jpg168125JPEG2024500378000241.jpg98124

[0395] Item 220. The compound of formula (I) is represented by formula (IIj): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, the below described: [ka] is as follows: [ka] Selected from; R 20j is selected from H and C1-C6 alkoxy; R 21j is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and —OH, and said C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 22j , R 23j , and R 24j 202. The compound according to paragraph 201, wherein each is independently selected from H and halogen.

[0396] Item 221. The compound according to Item 220, which satisfies at least one of the following (i) to (iv): (i)R 20j is selected from H and —OCH3; (ii)R 21j is unsubstituted C3 cycloalkyl; (iii)R 22j , R 23j , and R 24j are H, respectively; (iv) The following: [ka] is as follows: [ka] is.

[0397] Item 222. The compound according to item 220 or 201, wherein the compound is selected from the following: [ka]

[0398] Item 223. The compound of formula (I) is represented by formula (IIIq): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony: R 30q is selected from H and C1-C6 alkoxy; R 31q is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 32q , R 33q , and R 34q 202. The compound according to paragraph 201, wherein each is independently selected from H and halogen.

[0399] Item 224. The compound according to Item 223, wherein at least one of the following (i) to (iv) applies: (i)R 30q is H; (ii)R 31q is as follows: [ka] wherein d is 1 or 2, and [ka] wherein K is N or CH; (iii)R 31q is as follows: [ka] where R 35q is selected from H, —CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iv)R 32q , R 33q , and R 34q are H, respectively.

[0400] Item 225. The compound according to Item 223 or 224, wherein the compound is selected from the following: [ka] JPEG2024500378000253.jpg67124

[0401] Item 226. The compound of formula (I) has the formula (IIIr): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony: R 30r is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, C6-C 12 optionally substituted with one or more substituents selected from aryl, —OH, —C═O, and halogen; R 31r is selected from H and C1-C6 alkoxy; R 32r , R 33r , and R 34r 202. The compound according to paragraph 201, wherein each is independently selected from H and halogen.

[0402] Item 227. The compound according to Item 226, wherein at least one of the following (i) to (iv) applies: (i)R 30r is as follows: [ka] wherein L is N or CH and: [ka] Selected from; (ii)R 30r is as follows: [ka] where R 35ris selected from H, —CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iii)R 31r is H; (iv)R 32r , R 33r , and R 34r are H, respectively.

[0403] Item 228. The compound according to Item 226 or 227, wherein the compound is selected from the following: [ka] JPEG2024500378000259.jpg88125

[0404] Item 229. The compound of formula (I) has the formula (IIIs): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony: R 30s is selected from H and C1-C6 alkoxy; R 31s is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heter...

Claims

1. A compound represented by the following formula (I), or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof: 【Chemistry 1】 (In the formula: R １ is H, halogen, hydroxy, oxo, -CN, amide, methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ Heteroalkyl, C １ -C ７ alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ Alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl are selected from the group consisting of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO ２ H), nitro (-NO ２ ), -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO ３ H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , C １ -C ７ Alkyl, C １ -C ７ Heteroalkyl, C １ -C ７ Haloalkyl, C １ -C ７ Perfluoroalkyl, C １ -C ７ Alkoxy, C １ -C ７ Haloalkoxy or cycloalkyl substituted C １ -C ７ may be substituted with one or more of alkyl; R ２ is H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl; and wherein the amino, O-aryl, methanoyl (—COH), carboxy (—CO ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ Heteroalkyl, C １ -C ７ Alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl are selected from the group consisting of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO ２ H), nitro (-NO ２ ), -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO ３ H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , C １ -C ７ Alkyl, C １ -C ７ Heteroalkyl, C １ -C ７ Haloalkyl, C １ -C ７ Perfluoroalkyl, C １ -C ７ Alkoxy, C １ -C ７ C substituted with haloalkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or cycloalkyl １ -C ７ may be substituted with one or more of alkyl; R ３ , R ４ , and R ５ are each independently H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ Alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl are selected from the group consisting of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO ２ H), nitro (-NO ２ ), -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO ３ H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , C １ -C ７ Alkyl, C １ -C ７ Haloalkyl, C １ -C ７ Perfluoroalkyl, C １ -C ７ Alkoxy, C １ -C ７ Haloalkoxy or cycloalkyl substituted C １ -C ７ may be substituted with one or more of alkyl; R ６ teeth, 【Chemistry 2】 and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ are each independently H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ An alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl may be optionally substituted with one or more halogens; R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２９ , R ２９ , and R ３０ are each independently H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ An alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl may be optionally substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, and q+r+s+t is at least 1, and u+v+w+x is at least 1.

2. A compound of formula (IIf) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof: 【Chemistry 3】 (In the formula: R ２０ｆ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, and —O—(C ３ -C ６ cycloalkyl), wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from -OH and halogen; ３ -C ６ Cycloalkyl and -O-(C ３ -C ６ Cycloalkyl) are each C １ -C ６ optionally substituted with one or more substituents selected from alkyl and halogen; R ２１ｆ , R ２２ｆ , and R ２３ｆ are each independently selected from H and halogen; R ２４ｆａ , R ２４ｆｂ , R ２５ｆａ , R ２５ｆｂ , R ２６ｆａ , and R ２６ｆｂ are each independently H, a halogen, —OH, or C １ -C ６ Alkyl, and C １ -C ６ alkoxy, １ -C ６ Alkyl and C １ -C ６ each alkoxy may be optionally substituted with one or more halogen atoms, or A compound of formula (IIg) or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof: 【Chemistry 4】 (In the formula: R 20g is selected from H and C 1 -C 6 alkoxy; R 21g is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, -O-(C 6 -C 12 aryl), C 3 -C 9 heterocyclyl, and -NR 28ga R 28gb , wherein said C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C 3 -C 6 cycloalkyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and said C 3 -C 9 heterocyclyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 9 -heterocyclyl, -OH, and halogen; R 22g , R 23g , and R 24g are each independently selected from H and halogen; R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb are each independently selected from H, halogen, —OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, each of which is optionally substituted with one or more halogen atoms; R 28ga and R 28gb are each independently selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; 2. The compound of claim 1, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

3. R ２４ｆａ , R ２４ｆｂ , R ２５ｆａ , R ２５ｆｂ , R ２６ｆａ , and R ２６ｆｂ One or more of the following are independently selected from halogen, —OH, and optionally substituted C １ -C ６ Alkyl and optionally substituted C １ -C ６ alkoxy; or one or more of R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb are independently selected from halogen, —OH, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkoxy; 3. The compound of claim 2, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

4. R ２０ｆ is H, or R 20g is H; 4. The compound according to claim 2 or 3, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof.

5. The compound is a compound of formula (IIf), and at least one of the following (i) to (iii) applies: (i) R ２０ｆ is Cl, as follows: 【Chemistry 5】 , unsubstituted C ３ Cycloalkyl, and the following: 【Chemistry 6】 Selected from: (ii) R ２１ｆ , R ２２ｆ , and R ２３ｆ are each H; (iii) R ２５ｆａ , R ２５ｆｂ , R ２６ｆａ , and R ２６ｆｂ are H, and R ２４ｆａ and / or R ２４ｆｂ is F, or The compound is a compound of formula (IIg), and at least one of the following (i) to (ix) is true: (i) R 20g is —OCH 3 or the following: 【Chemistry 7】 Selected from: (ii) R 21g is t-butyl, unsubstituted C 3 cycloalkyl, morpholinyl, azetidinyl, piperidinyl, isoxazolyl, Cl, —CF 3 , —OCH 3 , —O-phenyl, 【Chemistry 8】 wherein G is N or CH, and 【Chemistry 9】 wherein c is 1 or 2; (iii) R 21g is the following: 【Chemistry 10】 and R 29g is H, isopropyl, unsubstituted C 3 cycloalkyl, azetidinyl, tetrahydropyranyl-CH 3 , 【Chemistry 11】 Selected from: (iv) R 21g is -NR 28ga R 28gb , where R 28ga is H and R 28gb is selected from -CH 3 , cyclobutyl, and cyclohexyl, or R 28ga and R 28gb are each -CH 3 ; (v) R 22g , R 23g , and R 24g are each H; (vi) R 22g and R 24g are each F and R 23g is H; (vii) R 22g and R 24g are each H and R 23g is F; (viii) R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb are each H; (ix) R 26ga , R 26gb , R 27ga and R 27gb are each H; and R 25ga and / or R 25gb are each F, —CH 3 , —OH, —CF 3 , any of the following: 【Chemistry 12】 and -OCH 3 ; 5. A compound according to any one of claims 2 to 4, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

6. 6. The compound of any one of claims 2 to 5, wherein the compound is selected from the following: or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】

7. A compound of formula (IIh) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof: 【Chemistry 19】 (In the formula: R 20h is selected from H and C 1 -C 6 alkoxy; R 21h is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein said C 1 -C 6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen, and said C 3 -C 6 cycloalkyl and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, -OH, and halogen; R 22ha , R 22hb , R 23ha , and R 23hb are each independently selected from H and C 1 -C 6 alkyl, which C 1 -C 6 alkyl may be substituted with one or more halogen atoms; R 24h , R 25h , and R 26h are each independently selected from H and halogen; or A compound of formula (IIi) or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof: 【Chemistry 20】 (In the formula: the below described: 【Chemistry 21】 below: 【Chemical 22】 Selected from: R 20i is selected from H and C 1 -C 6 alkoxy; R 21i is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein said C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C 3 -C 6 cycloalkyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and said C 3 -C 9 heterocyclyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 9 -heterocyclyl, -OH, -C═O, and halogen; R 22i , R 23i , and R 24i are each independently selected from H and halogen; R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib are each independently selected from H, halogen, —OH, or C 1 -C 6 alkyl; 2. The compound of claim 1, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

8. The compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof of claim 7, wherein one or more of R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib are independently selected from halogen, -OH, and C1-C6 alkyl.

9. The compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof of claim 7, wherein each of R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is H.

10. The compound is represented by formula (IIh), and at least one of the following (i) to (iv) is satisfied: (i) R 20h is H; (ii) R 21h is the following: 【Chemistry 23】 is; (iii) R 22ha , R 22hb , R 23ha , and R 23hb are each H; (iv) R 24h , R 25h and R 26h are each H; or The compound is a compound of formula (IIi) and at least one of the following (i) to (xi) is true: (i) R 20i is selected from H and —OCH 3 ; (ii) R 21i is the following: 【Chemistry 24】 , unsubstituted C 3 cycloalkyl, 【Chemistry 25】 where J is N or CH, and 【Chemistry 26】 Selected from: (iii) R 21i is the following: 【Chemistry 27】 In the formula, R 220i is H, —CH 3 , 【Chemistry 28】 and unsubstituted C 3 cycloalkyl; (iv) R 22i , R 23i , and R 24i are each H; (v) R 22i and R 24i are each F and R 23i is H; (vi) R 22i and R 24i are each H and R 23i is F; (vii) the following: 【Chemical 29】 below: 【Chemistry 30】 wherein each of R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H and R 25ib is F; (viii) the following: 【Chemistry 31】 below: 【Chemistry 32】 wherein each of R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H; (ix) the following: 【Chemical 33】 below: 【Chemical 34】 wherein each of R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 28ib, R 29ia , and R 29ib is H; (x) the following: 【Chemistry 35】 below: 【Chemical Formula 36】 wherein each of R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 29ia , and R 29ib is H and R 28ib is F; (xi) the following: 【Chemical 37】 below: 【Chemical 38】 each of R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib is H; and R 27ib is F; 10. A compound according to any one of claims 7 to 9, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

11. The compound or its salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative described in any one of claims 7 to 10, wherein the compound is selected from the following: 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】

12. A compound of the following formula (IIj) or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof: 【Chemistry 43】 (In the formula: the below described: 【Chemistry 44】 below: 【Chemistry 45】 Selected from: R 20j is selected from H and C 1 -C 6 alkoxy; R 21j is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl, wherein said C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from halogen and —OH, and said C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; R 22j , R 23j , and R 24j are each independently selected from H and halogen; or A compound of formula (IIIq) or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof: 【Chemistry 46】 (In the formula: R 30q is selected from H and C 1 -C 6 alkoxy; R 31q is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein said C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C 3 -C 6 cycloalkyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and said C 3 -C 9 heterocyclyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 9 -heterocyclyl, C 6 -C 12 aryl, -OH, -C═O, and halogen; R 32q , R 33q , and R 34q are each independently selected from H and halogen; 2. The compound of claim 1, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

13. The compound is represented by formula (IIj), and at least one of the following (i) to (iv) applies: (i) R 20j is selected from H and —OCH 3 ; (ii) R 21j is unsubstituted C 3 cycloalkyl; (iii) R 22j , R 23j , and R 24j are each H; (iv) the following: 【Chemistry 47】 below: 【Chemistry 48】 or The compound is of formula (IIIq) and at least one of the following (i) to (iv) is true: (i) R 30q is H; (ii) R 31q is the following: 【Chemistry 49】 (wherein d is 1 or 2), and 【Chemistry 50】 wherein K is N or CH; (iii) R 31q is the following: 【Chemistry 51】 where R 35q is selected from H, —CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iv) R 32q , R 33q , and R 34q are each H; 13. The compound of claim 12, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

14. The compound or its salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative according to claim 12 or 13, wherein the compound is selected from the following: 【Chemistry 52】 【Chemistry 53】

15. A compound of formula (IIIr) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof: 【Chemical 54】 (In the formula: R 30r is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein said C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C 3 -C 6 cycloalkyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and said C 3 -C 9 heterocyclyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 9 -heterocyclyl, C 6 -C 12 aryl, -OH, -C═O, and halogen; R 31r is selected from H and C 1 -C 6 alkoxy; R 32r , R 33r , and R 34r are each independently selected from H and halogen; or A compound of formula (IIIs) or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof: 【Chemistry 55】 (In the formula: R 30s is selected from H and C 1 -C 6 alkoxy; R 31s is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein said C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C 3 -C 6 cycloalkyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and said C 3 -C 9 heterocyclyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 9 -heterocyclyl, C 6 -C 12 aryl, -OH, -C═O, and halogen; R 32s , R 33s , and R 34s are each independently selected from H and halogen; 2. The compound of claim 1, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

16. The compound is represented by formula (IIIr) and at least one of the following (i) to (iv) applies: (i) R 30r is the following: 【Chemistry 56】 (wherein L is N or CH) and 【Chemistry 57】 Selected from: (ii) R 30r is the following: 【Chemistry 58】 where R 35r is selected from H, —CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iii) R 31r is H; (iv) R 32r , R 33r , and R 34r are each H; or The compound is of formula (IIIs) and at least one of the following (i) to (iv) is true: (i) R 30s is H; (ii) R 31s is the following: 【Chemistry 59】 (wherein M is N or CH) and 【Chemistry 60】 Selected from: (iii) R 31s is the following: 【Chemistry 61】 where R 35s is selected from H, —CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iv) R 32s , R 33s , and R 34s are each H; 16. The compound of claim 15, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

17. The compound or its salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative according to claim 15 or 16, wherein the compound is selected from the following: 【Chemistry 62】 【Chemistry 63】 18. The compound of claim 1, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3. The compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3. the compound is an inhibitor of IRAK1 and IRAK4; or The compound is an inhibitor of IRAK1, IRAK4, and FLT3.

18. A compound according to any one of claims 1 to 17, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

19. The compound or its salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative according to claim 18, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3, and preferably, the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.

20. A composition comprising a compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof according to any one of claims 1 to 19, further comprising a compounding ingredient, adjuvant, or carrier.

21. A pharmaceutical composition for treating a disease or disorder in a subject, comprising a therapeutically effective amount of a compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof as described in any one of claims 1 to 19, or a composition as described in claim 20.

22. The pharmaceutical composition described in claim 21, for treating a disease or disorder responsive to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition.

23. A pharmaceutical composition described in any of claims 21 to 22, wherein the disease or disorder includes hematopoietic cancer.

24. The disease or disorder is (i) myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, marginal zone lymphoma, glioblastoma multiforme, 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 at least one cancer selected from the group consisting of glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer; or (ii) at least one inflammatory or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, and type 1 diabetes. Including, Preferably, the disease or disorder satisfies any of the following (i) to (iii): (i) The MDS is MDS having a splicing factor mutation, MDS having a mutation in isocitrate dehydrogenase 1, or MDS having a mutation in isocitrate dehydrogenase 2, and more preferably, the MDS having a splicing factor mutation includes MDS having a splicing factor mutation in U2AF1 or SF3B1; (ii) the AML is an AML with a splicing factor mutation, an AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or an AML that is not driven by FLT3 mutation but expresses IRAK4-Long, more preferably, the AML with a splicing factor mutation includes an AML with a splicing factor mutation in U2AF1 or SF3B1; (iii) the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL or the S219C MYD88 mutant (GCB) subtype of DLBCL; 24. A pharmaceutical composition according to any one of claims 21 to 23.

25. The pharmaceutical composition is selected from the group consisting of chemotherapeutic agents, BCL2 inhibitors, immunomodulatory agents, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetobotics), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, Plk inhibitors, MEK inhibitors, CDK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, smoothened receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors agents, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, AuraA inhibitors, Aurora kinase inhibitors, EGFR inhibitors, AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PD 25. The pharmaceutical composition of any of claims 21 to 24, in combination with one or more further therapeutic agents selected from a GFRA / B inhibitor, an AKT1, 2 and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a Menin-KMT2A / MLL inhibitor, and a multikinase inhibitor.

26. The pharmaceutical composition of claim 25, wherein the BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt thereof.

27. ​​A pharmaceutical composition described in any of claims 21 to 26, wherein the disease or disorder is a BCL2 inhibitor-resistant and / or FLT3 inhibitor-resistant disease or disorder.

28. The pharmaceutical composition of any of claims 21 to 27, wherein the disease or disorder is BCL2 inhibitor-resistant acute myeloid leukemia (AML), BCL2 inhibitor-resistant refractory acute myeloid leukemia (AML), BCL2 inhibitor-resistant relapsed acute myeloid leukemia (AML), venetoclax-resistant acute myeloid leukemia (AML), venetoclax-resistant refractory acute myeloid leukemia (AML), venetoclax-resistant relapsed acute myeloid leukemia (AML), FLT3 inhibitor-resistant acute myeloid leukemia (AML), FLT3 inhibitor-resistant refractory acute myeloid leukemia (AML), and / or FLT3 inhibitor-resistant relapsed acute myeloid leukemia (AML).

29. A compound according to any one of claims 1 to 19, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, or a composition according to claim 20, and 26. The pharmaceutical composition of claim 25, wherein the one or more additional therapeutic agents are administered together in a single dose or composition.

30. A compound according to any one of claims 1 to 19, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, or a composition according to claim 20, and 26. The pharmaceutical composition of claim 25, wherein the one or more additional therapeutic agents are administered separately as multiple doses or compositions.

31. A pharmaceutical composition described in any of claims 21 to 30, wherein the disease or disorder is a disease or disorder that is alleviated in the subject by inhibiting at least one of IRAK1, IRAK4, and FLT3.

Images