Polycyclic IRAK and FLT3 inhibitor compounds and uses thereof

Abstract

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

Description

[Technical Field]

[0001] The invention disclosed herein relates generally to compounds and compositions that are kinase inhibitors and their use in the treatment of diseases and disorders, including cancer.

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

[0003] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 482,736, filed February 1, 2023, which is incorporated herein by reference in its entirety. [Background technology]

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

[0005] MDS is a heterogeneous disease with few treatment options due to the lack of effective medications that can provide durable responses. Current treatment options for MDS are limited and include allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapy (Ebert, 2010). While 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). For progressive or high-risk MDS, patients may also receive immunosuppressive therapy, epigenetic modifiers, and / or chemotherapy (Greenberg, 2010). Despite recent advances, most MDS patients experience treatment-related toxicity or relapse (Sekeres, 2010a). Overall, the effectiveness of these treatments varies, and life expectancy is generally only slightly improved compared to supportive care. The complexity and heterogeneity of MDS and the lack of human xenograft models present difficult obstacles to the identification and validation of novel molecular targets for this disease.

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

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

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

[0009] Therefore, there is a need to develop treatments and methods that effectively treat MDS and / or AML. Additionally, in doing so, it is important to determine whether a patient is likely to respond to a particular treatment or treatment method. Certain embodiments of the present invention may address one or more of these problems. Summary of the Invention

[0010] In one embodiment, the present disclosure provides a compound of formula (I), (II), or (III): [ka] [ka] [ka] or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof, wherein A is selected from the group consisting of N and CR 5 D is selected from N and CR 4 E is selected from N and CR 3 At least one of A, D, and E is N, and R 1 , R 2 , R 3 , R 4 , and R 5 each independently represents H, deuterium, halogen, hydroxy, oxo, -CN, -C(=O)H, -C(=O)OH, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, or -C(=O)NR 31 R 32 , cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused ring heteroaryl, or -O-fused ring heteroaryl, wherein: R is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, -C(=O)H, -C(=O)OH, nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, -SOH, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)NH, -C(=O)N(CH), C-C alkyl, C-C perfluorinated alkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl;6 but, [ka] or one or more -NR 33 R 34 C-C cycloalkyl substituted with R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected from H, deuterium, halogen, hydroxy, oxo, -CN, -C(=O)H, -C(=O)OH, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl, wherein -C(=O)H, -C(=O)OH, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, -O- the heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused ring heteroaryl, or -O-fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, -C(=O)H, -C(=O)OH, nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, -SOH, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)NH, -C(=O)N(CH), C-C alkyl, C-C perfluorinated alkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 15 , R 16 , R17 , 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, deuterium, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused ring heteroaryl, or -O-fused ring heteroaryl, wherein -C(=O)H, -C(=O)OH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, the -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused ring heteroaryl, or -O-fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, -C(=O)H, -C(=O)OH, nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, -SOH, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)NH, -C(=O)N(CH), C-C alkyl, C-C perfluorinated alkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 31 and R 32are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more halogens; R 33 and R 34 are each independently selected from H and C1-C6 alkyl, and m, n, o, p, q, r, s, t, u, v, w, x are independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1 and where u+v+w+x is at least 1. In one embodiment, the compound of Formula (I) is a compound of Formula (Ib-5010-WO50): [ka] (Ib-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein V is N or CR 11 and W is N or CR 12 and X is N or CR 13 and [ka] teeth, [ka] and R 10b is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; and R 17bis halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), C3-C9 heterocyclyl, imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from —OH, C-C alkyl, and halogen; and R 11 , R 12 , and R 13 are each independently selected from H, C1-C6 alkoxy, and halogen; R 14a , R 14b , R 15a , R 15b , R 16a , R 16b , R 18a , and R 18b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms, and one of V, W, or X is N. In one embodiment, (i)-(v):(i) R 14b , R 15a , R 15b , R 16a , and R 16b is H and R 14a is F, (ii) R 11 , R 12 , and R 13 is H, if present, (iii) V is CR 11 where R 11 is F and W is CR 12 where R 12 is H and X is N; (iv) R 10b is selected from H and —OCH3; (v) R 17b but, [ka] In one embodiment, at least one of the following is applied: 17b but [ka] If R 10b is H and R 17b but [ka] If R 11 , R 12 , and R 13 and at least one of: is present and is selected from C1-C6 alkoxy and halogen. In one embodiment, the compound of formula (Ib-5010-WO50) is [ka] In one embodiment, the compound of formula (I) is selected from the compound of formula (Id-5010-WO50): [ka] (Id-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, wherein V is N or CR 11 and W is N or CR 12 and X is N or CR 13 and [ka] teeth, [ka] and R 10d is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18bwherein C-C alkyl and C-C alkoxy are each selected from —OH, deuterium, and halogen, and C-C cycloalkyl, wherein each —O—(C-C cycloalkyl) is optionally substituted with one or more substituents selected from C-C alkyl and halogen; and R 113d is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; wherein C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from —OH, C-C alkyl, and halogen; and R 11 , R 12 , and R 13 are each independently selected from H, C1-C6 alkoxy, and halogen; R 18a and R 18b are each independently selected from H, C-C alkyl, and C-C cycloalkyl, wherein each of the C-C alkyl and C-C cycloalkyl is optionally substituted with one or more halogens; and R 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms, and one of V, W, or X is N. In one embodiment, at least one of (i) to (vi) applies: (I) R 19a Each of R 19b , R 110a , R 110b , R 111a , R111b , R 112a , and R 112b is H, and (ii) R 19a Each of R 19b , R 110b , R 111a , R 111b , R 112a , and R 112b is H and R 110a is F, and (iii) R 11 , R 12 , and R 13 , if present, is H, and (iv) V is CR 11 where R 11 is F and W is CR 12 where R 12 is H, where X is N; (v) R 10d is selected from H and —OCH3, and (vi) R 113d but, [ka] In one embodiment, R 113d but [ka] If R 10d is H and R 113d but [ka] If R 11 , R 12 , and R 13 and at least one of: is present and is selected from C1-C6 alkoxy and halogen. In one embodiment, the compound of formula (Id-5010-WO50) is [ka] [ka] In one embodiment, the compound of formula (II) is selected from the compound of formula (IIa-5010-WO50): [ka] (IIa-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, wherein L is N or CR 21 and M is N or CR 22 and Q is N or CR 23 and [ka] teeth, [ka] and R 20a is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; wherein C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; and R 27a is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, spiro-fused cycloalkyl, -O-(C3-C6 cycloalkyl), C2-C6 heterocyclyl, imidazolyl, triazolyl, and -C(=O)NR 28a R 28b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; wherein C-C cycloalkyl, spiro-cycloalkyl, —O—(C-C cycloalkyl), C-C heterocyclyl are each optionally substituted with one or more substituents selected from —OH, C-C alkyl, and halogen; and R 21 , R 22 , and R23 are each independently selected from H, C1-C6 alkoxy, and halogen; R 24a , R 24b , R 25a , R 25b , R 26a , and R 26b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; R 28a and R 28b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens, and one of L, M, or Q is N. In one embodiment, at least one of (i) through (v) applies: (I) R 24b Each of R 25a , R 25b , R 26a , and R 26b is H and R 24a is F, and (ii) R 21 , R 22 , and R 23 , if present, is H, and (iii) L is CR 21 where R 21 is selected from F, Cl, and -OCH3, M is CR 22 where R 22 is H, Q is N, and (iv) R 20a is -OCH3, unsubstituted -O-(C3 cycloalkyl), and [ka] and (v) R 27a is unsubstituted C3-C6 cycloalkyl, [ka] In one embodiment, R 20a is -OCH3 and R 27aWhen R is an unsubstituted C3 cycloalkyl, 21 , R 22 , and R 23 and at least one of: is present and is selected from C1-C6 alkoxy and halogen. In one embodiment, the compound of formula (IIa-5010-WO50) is [ka] [ka] [ka] In one embodiment, the compound of formula (II) is selected from the compound of formula (IIb-5010-WO50): [ka] (IIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, wherein L is N or CR 21 and M is N or CR 22 and Q is N or CR 23 and [ka] teeth, [ka] and R 20b is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; wherein C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; and R27b is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, spiro-cycloalkyl, -O-(C3-C6 cycloalkyl), C2-C6 heterocyclyl, imidazolyl, triazolyl, and -C(=O)NR 28a R 28b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; wherein C-C cycloalkyl, spiro-cycloalkyl, —O—(C-C cycloalkyl), C-C heterocyclyl are each optionally substituted with one or more substituents selected from —OH, C-C alkyl, and halogen; and R 21 , R 22 , and R 23 are each independently selected from H, C1-C6 alkoxy, and halogen; R 29a , R 29b , R 210a , R 210b , R 211a , R 211b , R 212a , and R 212b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; R 28a and R 28b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens, and one of L, M, or Q is N. In one embodiment, at least one of (i) to (vi) applies: (I) R 29a Each of R 29b , R 210a , R 210b , R 211a , R 211b , R 212a , and R 212b is H, and (ii) R 29a Each of R 29b , R210b , R 211a , R 211b , R 212a , and R 212b is H and R 210a is F, and (iii) R 21 , R 22 , and R 23 is H, if present, and (iv) L is CR 21 where R 21 is selected from F, Cl, -OCH3, M is CR 22 where R 22 is H, Q is N, and (v) R 20b -OCH3, -OCD3, unsubstituted -O-(C3 cycloalkyl), and [ka] and (vi) R 27b is unsubstituted C3-C6 cycloalkyl, [ka] In one embodiment, R 20b is -OCH3 and R 27b When R is an unsubstituted C3 cycloalkyl, 21 , R 22 , and R 23 and at least one of: is present and is selected from C1-C6 alkoxy and halogen. In one embodiment, the compound of formula (IIb-5010-WO50) is [ka] [ka] [ka] [ka] [ka] [ka] In one embodiment, the compound of formula (III) is selected from the compound of formula (IIIa-5010-WO50): [ka] (IIIa-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, wherein R is N or CR 31 and T is N or CR 32 and U is N or CR 33 and [ka] teeth, [ka] and R 37a are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), C2-C6 heterocyclyl, imidazolyl, triazolyl, 2-pyrrolidinonyl, and -C(=O)NR 38a R 38b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; C-C cycloalkyl and —O—(C-C cycloalkyl), and C-C heterocyclyl are each optionally substituted with one or more substituents selected from —OH, C-C alkyl, and halogen; and R 31 , R 32 , and R 33 are each independently selected from H, C1-C6 alkoxy, and halogen; R 34a , R 34b , R 35a , R 35b , R 36a , R 36b , R 38a , and R 38bare each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R 38a and R 38b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens, and one of R, T, or U is N. In one embodiment, (i)-(iv): (I) R 34b , R 35a , R 35b , R 36a , and R 36b is H and R 34a is F, (ii) R 31 , R 32 , and R 33 is H, if present; (iii) R is CR31, where R 31 is F and T is CR32, where R 32 is H and U is N, and (Iv) R 37b but, [ka] In one embodiment, at least one of the following is applied: 37a teeth, [ka] In one embodiment, the compound of formula (IIIa-5010-WO50) is [ka] In one embodiment, the compound of formula (III) is a compound of formula (IIIb-5010-WO50): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein R is N or CR31 and T is N or CR 32 and U is N or CR 33 and [ka] teeth, [ka] and R 37b is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), C2-C6 heterocyclyl, imidazolyl, triazolyl, 2-pyrrolidinonyl, and -C(=O)NR 38a R 38b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; C-C cycloalkyl, —O—(C-C cycloalkyl), and C-C heterocyclyl are each optionally substituted with one or more substituents selected from —OH, C-C alkyl, and halogen; and R 31 , R 32 , and R 33 are each independently selected from H, C1-C6 alkoxy, and halogen; R 39a , R 39b , R 310a , R 310b , R 311a , R 311b , R 312a , and R 312b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R 38a and R 38bare each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens, and one of R, T, or U is N. In one embodiment, at least one of (i) through (v) applies: (i) R 39a , R 39b , R 310a , R 310b , R 311a , R 311b , R 312a , and R 312b is H; (ii) R 39a , R 39b , R 310b , R 311a , R 311b , R 312a , and R 312b is H and R 310a is F, (iii) R 31 , R 32 , and R 33 is H, if present; (iv) R is CR 31 where R 31 But, F, T, CR 32 , in the formula R 32 is H, and U is N, and (v) R 37b but, [ka] In one embodiment, R 37b but [ka] If R31, R32, and R 33 and at least one of: is present and is selected from C1-C6 alkoxy and halogen. In one embodiment, the compound of formula (IIIb-5010-WO50) is [ka] In one embodiment, (i) the compound of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), formula (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any one of the isomers thereof is an inhibitor of at least one of IRAK1, IRAK4, and FLT3, and (ii) the compound of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any one of the isomers thereof is an inhibitor of at least one of IRAK1, IRAK4, and FLT3. (iii) compounds of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), formula (IIIb-5010-WO50), or salts, esters, solvates, optical isomers, geometric isomers, or salts of any one of the isomers thereof, are inhibitors of IRAK1 and IRAK4, but are not inhibitors of FLT3;

[0011] In another aspect, the present disclosure provides a composition comprising a compound of any one of Formula (Ib-5010-WO50), Formula (Id-5010-WO50), Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), Formula (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any isomer thereof, wherein the composition further comprises a formulation component, adjuvant, or carrier.

[0012] In yet another aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound of Formula (Ib-5010-WO50), Formula (Id-5010-WO50), Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), or Formula (IIIb-5010-WO50), or a salt, ester, solvate thereof, The present invention relates to a method for treating a rheumatoid arthritis, the method comprising administering to a subject a composition comprising an optical isomer, a geometric isomer, or a salt of any one of isomers thereof, or a compound of Formula (Ib-5010-WO50), Formula (Id-5010-WO50), Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), or Formula (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any one of isomers thereof. In one embodiment, the disease or disorder is alleviated by inhibition of at least one of interleukin-1 receptor-associated kinase (IRAK) and fms-like tyrosine kinase 3 (FLT3). In one embodiment, the disease or disorder comprises hematopoietic cancer. In one embodiment, the hematopoietic cancer is selected from myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutations, follicular lymphoma, and marginal zone lymphoma. In one embodiment, the disease or disorder is selected from the following: BCL2 inhibitor-resistant acute myeloid leukemia (AML), BCL2 inhibitor-resistant refractory acute myeloid leukemia, BCL2 inhibitor-resistant relapsed acute myeloid leukemia, FLT3 inhibitor-resistant acute myeloid leukemia, FLT3 inhibitor-resistant refractory acute myeloid leukemia, or FLT3 inhibitor-resistant relapsed acute myeloid leukemia.In some embodiments, the disease or disorder comprises at least one cancer selected from bone marrow cancer, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer. 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, Crohn's disease, colitis, and atopic dermatitis.In one embodiment, the method includes the use of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetobolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody-drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK2 inhibitor ... / ERK inhibitors including MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura The present invention further comprises administering to the subject one or more additional therapies selected from an EGFR inhibitor, an Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT 1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a menin-KMT2A / MLL inhibitor, and a multikinase inhibitor. In one embodiment, the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof; the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them; the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitors BAY1251152 and atubeciclib, or a pharmaceutically acceptable salt of any one of them; or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), formula (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any of the isomers thereof, or a compound of formula (Ib-5010-WO50) ), a composition comprising a compound of Formula (Id-5010-WO50), Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), Formula (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any isomer thereof, and the one or more additional therapies are administered together in a single dose or composition.In one embodiment, a compound of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), formula (IIIb-5010-WO50), or any salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a compound of formula (Ib-5010-WO50). The compound of Formula (Id-5010-WO50), Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), Formula (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any of the isomers thereof, and the one or more additional therapies are administered separately in two or more doses or in two or more compositions. In one embodiment, the compound is a compound of any one of formula (Ib-5010-WO), formula (Id-5010-WO), formula (IIa-5010-WO), formula (IIb-5010-WO), formula (IIIa-5010-WO), formula (IIIb-5010-WO), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any one of the isomers thereof.

[0013] In another aspect, the disclosure provides a method of increasing survival in a subject diagnosed with or suspected of having acute myeloid leukemia (AML), the method comprising administering a therapeutically effective amount of a compound of Formula (Ib-5010-WO50), Formula (Id-5010-WO50), Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), Formula (IIIb-5010-WO50), or a salt or derivative of any thereof. The method comprises administering to the subject a composition comprising an ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a compound of Formula (Ib-5010-WO50), Formula (Id-5010-WO50), Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), Formula (IIIb-5010-WO50), or any salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, the survival of the subject is increased compared to a subject treated with a therapeutically effective amount of standard of care for AML. In one embodiment, the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is human. In one embodiment, the subject's survival is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with a therapeutically effective amount of standard of care for AML.In one embodiment, the method comprises administering to a subject a therapeutically effective amount of a compound of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), formula (IIIb-5010-WO50), or any salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (Id-5010-WO50), or any salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, 0), Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), Formula (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any of the isomers thereof, about every 6 hours, every 12 hours, every 18 hours, once daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once weekly.In one embodiment, the method includes the use of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetobolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody-drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK2 inhibitor ... / ERK inhibitors including MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura The present invention further comprises administering to the subject one or more additional therapies selected from an EGFR inhibitor, an Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT 1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a menin-KMT2A / MLL inhibitor, and a multikinase inhibitor. In one embodiment, the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them, the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitor BAY1251152 and atubeciclib, or a pharmaceutically acceptable salt of any one of them, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the AML is selected from the following: BCL2 inhibitor-resistant AML, BCL2 inhibitor-resistant refractory AML, BCL2 inhibitor-resistant relapsed AML, FLT3 inhibitor-resistant AML, FLT3 inhibitor-resistant refractory AML, or FLT3 inhibitor-resistant relapsed AML. In one embodiment, a compound of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), formula (IIIb-5010-WO50), or any salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or formula (Ib-5010-WO50) ), Formula (Id-5010-WO50), Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), Formula (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any of the isomers thereof, and the one or more additional therapies are administered together in a single dose or composition.In one embodiment, a compound of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), formula (IIIb-5010-WO50), or any salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a compound of formula (Ib-5010-WO50), formula ( The composition comprising a compound of Formula (IIa-5010-WO50), Formula (IIb-5010-WO50), Formula (IIIa-5010-WO50), Formula (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of any of the isomers thereof, and the one or more additional therapies are administered separately in two or more doses or in two or more compositions. [Brief explanation of the drawings]

[0014] [Figure 1] Figure 1 shows the relative concentrations (nM) of representative compounds of the present disclosure and gilteritinib ("Gil") required to fully potentiate (<20%) the 312.5 nM venetoclax Cell Titer Glo response in THP1 cells at 48 hours. Lower concentrations indicate a greater ability to synergize with venetoclax. [Figure 2] Figure 2 shows the relative concentrations (nM) of representative compounds of the present disclosure and gilteritinib (Gil) required to fully potentiate (<10%) the 62.5 nM venetoclax Cell Titer Glo response in MOLM14(D835Y) cells at 48 hours. Lower concentrations indicate a greater ability to synergize with venetoclax. [Figure 3] FIG. 3 provides the structures of the compounds studied in FIG. 4 and FIGS. 5A-5B. [Figure 4] FIG. 4 is a chart of survival of mice intravascularly implanted with AML cells comparing survival of Compound C (30 mg / kg) versus control, gilteritinib SOC (30 mg / kg), and CA-4948 (emavosertib, 30 mg / kg). [Figure 5]Figures 5A-5B are graphs showing leukemia grade at necropsy. When adjusted for survival, all treated animals show significant improvement compared to controls, except for F06, which had a decreased score compared to standard of care F02. Figure 5A: Leukemia grade at necropsy (statistical analysis used was mean with 95% confidence interval). Figure 5B: Survival-adjusted leukemia grade at necropsy (statistical analysis used was geometric mean with geometric SD). All compounds used in this study were administered at 30 mg / kg. Detailed Description of the Invention

[0015] The following applications are incorporated herein by reference in their entirety and for all purposes: International Publication No. WO 2018081738, Treatment of Diseases Associated with Activated Iris (filed October 30, 2017), U.S. Publication No. 2021 / 0292843, Treatment of Diseases Associated with Activated Iris (filed April 4, 2019), International Publication No. WO 2014190163, Combination Therapy for MDS (filed May 22, 2014), U.S. Patent No. 9,168,257, Combination Therapy for MDS (issued October 27, 2015), U.S. Patent No. 9,504,706, Combination Therapy for MDS (issued November 29, 2016), U.S. Patent No. 9,855,273, Combination Therapy for MDS (issued January 2, 2018), International Publication No. No. 2018038988, Methods for Treating Diseases, Compounds, Compositions, and Methods for Preparing Compounds (filed August 16, 2017); U.S. Patent No. 11,254,667, Substituted Imidazo[l,2-a]pyridines as IRAK 1 / 4 and FLT3 Inhibitors (issued February 2, 2022); U.S. Publication No. 2022 / 0213094, Substituted Imidazo[l,2-a]pyridines as IRAK 1 / 4 and FLT3 Inhibitors (filed January 4, 2022); U.S. Publication No. 2020 / 0199123, Substituted Imidazo[l,2-a]pyridines as IRAK 1 / 4 and FLT3 Inhibitors (filed February 28, 2020); U.S. Publication No. 2022 / 0235042, Substituted Imidazo[l,2-a]-pyridine (January 28, 2022), International Publication No. WO 2020252487, Rational therapeutic targeting of oncogenic immune signaling states in myeloid malignancies via the ubiquitin-conjugating enzyme UBE2N (filed June 15, 2020), International Publication No. WO 2022026935, Polycyclic IRAK and FLT3 inhibitor compounds and uses thereof (filed July 31, 2021), International Publication No. WO 2022140647, Polycyclic IRAK and FLT3 inhibitor compounds and uses thereof (December 23, 2021), International Publication No. WO No. 2023009833, Polycyclic IRAK and FLT3 Inhibitory Compounds and Uses Thereof (filed July 29, 2022), International Patent Application No. PCT / US2023 / 068520, Polycyclic IRAK and FLT3 Inhibitory Compounds and Uses Thereof (filed June 15, 2023), International Patent Application No. PCT / US2023 / 068897, Polycyclic IRAK and FLT3 Inhibitory Compounds and Uses Thereof (filed June 22, 2023), International Patent Application No. PCT / US2023 / 071435, Polycyclic IRAK and FLT3 Inhibitory Compounds and Uses Thereof (filed August 1, 2023), and International Patent Application No. PCT / US2023 / 034438, Polycyclic IRAK and FLT3 Inhibitory Compounds and Uses Thereof (filed October 4, 2023).

[0016] While embodiments embodying the general inventive concept may take a variety of forms, various embodiments will be described herein with the understanding that the disclosure is to be considered merely exemplary and that the general inventive concept is not intended to be limited to the disclosed embodiments.

[0017] Some embodiments of the present invention include compounds of the present invention (e.g., compounds of Formula (I)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising compounds of the present invention. Still other embodiments of the present invention include compositions for treating certain diseases, e.g., using compounds of the present invention. Some embodiments include methods of using compounds of the present invention (e.g., in compositions or pharmaceutical compositions) for administration and treatment. Further embodiments include methods for making compounds of the present invention. Still further embodiments include methods for determining whether a particular patient is likely to respond to such treatment with compounds and compositions of the present invention.

[0018] Unless otherwise noted, terms are understood according to conventional usage by those of ordinary skill in the art.

[0019] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0020] Where substituents are designated by their conventional chemical formula written from left to right, they equally encompass chemically identical substituents that would result from writing the structure from right to left, e.g., -CHO- is equivalent to -OCH-.

[0021] As used herein, with respect to compounds of Formula (I), (II), (III), etc., the term "attached" means a stable covalent bond, with certain preferred points of attachment being apparent to those skilled in the art.

[0022] As used herein (unless otherwise specified), the term "alkyl" refers to alkyl groups that may be fully saturated, monounsaturated, or polyunsaturated and have a specified number of carbon atoms (i.e., C-C 10means 1 to 10 carbons). For example, the terms "C1-C7 alkyl" or "C1-C4 alkyl" refer to a linear or branched saturated hydrocarbon group having 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7) or 1 to 4 (e.g., 1, 2, 3, or 4) carbon atoms, respectively. Examples of C1-C7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, and n-heptyl. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl.

[0023] As used herein (unless otherwise specified), the term "alkenyl" refers to a monovalent straight or branched hydrocarbon chain containing one or more (e.g., 1, 2, 3, or 4) double bonds. The double bond may occur at any stable point along the chain, and the carbon-carbon double bond may have either a cis or trans configuration. For example, this definition includes, but is not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, 1-pentenyl-3-cyclohexenyl, and the like. Similarly, "heteroalkenyl" refers to a heteroalkyl having one or more double bonds. Further examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0024] As used herein (unless otherwise specified), the term "alkynyl" means a monovalent straight or branched hydrocarbon chain that contains one or more (e.g., 1, 2, 3, or 4) triple bonds and may optionally contain one or more (e.g., 1, 2, 3, or 4) double bonds within the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0025] As used herein (unless otherwise specified), the term "alkoxy" means any of the above alkyl, alkenyl, or alkynyl groups attached to the remainder of the molecule by an oxygen atom (alkyl-O-). Examples of alkoxy groups include, but are not limited to, methoxy (sometimes designated as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy.

[0026] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, exemplified by, but not limited to, -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms.

[0027] As used herein (unless otherwise specified), the term "cycloalkyl" refers to a monovalent, monocyclic or bicyclic 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon group. The ring can be saturated or partially unsaturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyl (e.g., bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds). For monocyclic cycloalkyls, the ring is not aromatic. For bicyclic cycloalkyls, if one ring is aromatic, the other is not aromatic. For bicyclic cycloalkyls, one or both rings can be substituted.

[0028] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, stable linear or branched chains, or combinations thereof, which consist of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heteroatom(s) O, N, P, S, and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH3, and -CN. Up to two heteroatoms may be consecutive, such as -CH2-NH-OCH3.

[0029] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups, as used herein, include groups attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. Where "heteroalkyl" is mentioned followed by a specific heteroalkyl group, such as -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is mentioned for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, such as -NR'R''.

[0030] As used herein (unless otherwise specified), the term "halogen" or "halo" means monovalent Cl, F, Br, or I. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0031] As used herein (unless otherwise specified), the term "aryl" refers to a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic hydrocarbon group, and also refers to a polyvalent, unsaturated, aromatic, hydrocarbon substituent that may be fused together (i.e., fused-ring aryl) or covalently linked, single ring or multiple rings (preferably 1 to 3 rings). Fused-ring aryl refers to multiple rings fused together, where at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. For bicyclic aryls, one or both rings may be substituted.

[0032] As used herein (unless otherwise specified), the term "heteroaryl" refers to a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon group, in which 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic ring system is aromatic. The heteroaryl group (or ring) can contain 1 to 4 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, where at least one of the fused rings is a heteroaromatic ring). A 5,6-fused-ring heteroarylene refers to two rings fused together, one ring having 5 members and the other having 6 members, and at least one ring being a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 6 members, and at least one ring is a heteroaryl ring. Also, a 6,5-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Examples of heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisoxazolyl, 1H-pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl. For bicyclic heteroaryls, if one ring is aryl, the other is heteroaryl. For bicyclic heteroaryls, one or both rings can have one or more heteroatoms. For bicyclic heteroaryls, one or both rings can be substituted.

[0033] "Arylene" and "heteroarylene," alone or as part of another substituent, refer to divalent radicals derived from aryl and heteroaryl, respectively. Thus, the term "aryl" can refer to unsubstituted, monosubstituted, disubstituted, or trisubstituted monocyclic, polycyclic, biaryl, and heteroaromatic groups covalently attached at any ring position capable of forming a stable covalent bond, with certain preferred points of attachment apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl). Aryl substituents can be independently selected from halo, nitro, cyano, trihalomethyl, C 1-16 Alkyl, aryl C 1-16 Alkyl, C0- 16 Alkyloxy C0- 16 Alkyl, aryl C0- 16 Alkyloxy C0- 16 Alkyl, C0- 16 AlkylthioC0- 16 Alkyl, aryl C0- 16 AlkylthioC0- 16 Alkyl, C0- 16 Alkylamino C0- 16 Alkyl, aryl C0- 16 Alkylamino C0- 16 Alkyl, di(aryl C1- 16 Alkyl)aminoC0- 16 Alkyl, C1- 16 Alkylcarbonyl C0- 16 Alkyl, aryl C 1-16 Alkylcarbonyl C0- 16 Alkyl, C1- 16 Alkyl carboxy C0- 16 Alkyl, aryl C1- 16 Alkyl carboxy C0- 16 Alkyl, C 1-16 AlkylcarbonylaminoC0- 16 Alkyl, aryl C1- 16 AlkylcarbonylaminoC0- 16 Alkyl, -C0- 16 Alkyl COOR4, -C0- 16alkylCONR5R6, wherein R4, R5, and R6 are independently selected from the group consisting of hydrogen, C1-C 11 Alkyl, aryl C0-C 11 alkyl, or R5 and R6 together with the nitrogen to which they are attached form one C 1-16 Alkyl, aryl C0-C 16 Alkyl, or C0-Cl 16 With or without alkylaryl substituents, forming a ring system containing 3 to 8 carbon atoms. Aryl includes, but is not limited to, pyrazolyl and triazolyl.

[0034] For brevity, the term "aryl," when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the terms "arylalkyl," "aralkyl," and the like are intended to include radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like), and include alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like) or a sulfur atom. Thus, terms such as "arylalkyl" (e.g., (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represent an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.

[0035] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, may also be referred to as "heterocyclyl," and refer to cyclic versions of "alkyl" and "heteroalkyl," respectively, unless otherwise specified. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. As used herein (unless otherwise specified), the term "heterocycloalkyl" or "heterocyclyl" means a monovalent monocyclic or bicyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon ring in which 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic ring system is not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidine- Examples of heterocyclic heterocyclic groups include, but are not limited to, piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, or piperazin-4-yl), piperidinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, or piperazin-4-yl), and morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl). For bicyclic heterocyclyls, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), the other ring is not aromatic. For bicyclic heterocyclyls, one or both rings can have one or more heteroatoms.For a bicyclic heterocyclyl, either 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.

[0036] As used herein (unless otherwise specified), the term "heteroatom" means an atom selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0037] As used herein (unless otherwise specified), the term "hydroxy" or "hydroxyl" refers to the monovalent --OH group.

[0038] The term "acyl," unless otherwise indicated, means -C(O)R, in which R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0039] As used herein, the term "oxo" means an oxygen that is double bonded to a carbon atom.

[0040] 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").

[0041] The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge.

[0042] In the above definitions, the terms "alkyl" and "alkenyl" may be used interchangeably, as long as a stable chemical entity is formed, as will be apparent to one skilled in the art.

[0043] The term "linker" refers to an attachment group interposed between substituents. In some embodiments, the linker is an amide (-CONH-R n or -NHCO-R n ), thioamide (-CSNH-R n Or -NHCS-R n ), carboxyl (-CO2-R n 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.

[0044] 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.

[0045] As used herein (unless otherwise specified), the term "substituted" (e.g., as in substituted alkyl) means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from a specified selection. The replacement can occur at one or more positions. The term "optionally substituted" means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) can be, but need not be, replaced.

[0046] As used herein, "substituents" means non-hydrogen substituents that may be, and preferably are, groups selected from the following moieties: (A) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), CONH2, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) C-C alkyl, C-C heteroalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from the following: (i) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), CONH2, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) C-C alkyl, C-C heteroalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituted with at least one substituent selected from the following: (a) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), CONH2, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from the following: -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-S03H), CONH2, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

[0047] The terms "size-limited substituent" or "size-limited substituent group" as used herein mean, for example, a group selected from all of the substituents described above for substituents, wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 4- to 8-membered heterocycloalkyl.

[0048] As used herein, the terms "lower substituent" or "lower substituent group" refer, for example, to a group selected from all of the substituents described above for a substituent, wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C5-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5- to 7-membered heterocycloalkyl.

[0049] The term "about" when used in the context of a numerical value indicates a range of + / - 10% of that numerical value, unless expressly indicated otherwise.

[0050] Some compounds of the present invention may have one or more chiral centers, and may exist in optically active and racemic forms with respect to any of the one or more chiral centers, and may be isolated in such forms.Some compounds may exhibit polymorphism.The compounds of the present invention (e.g., Formula I) encompass any optically active racemate, stereoisomeric form, polymorph, or mixture thereof.If a chiral center does not provide an indication of its configuration (i.e., R or S) in the chemical structure, it should be considered to represent R, S, or racemate.

[0051] As used herein, the term "sample" encompasses samples obtained from a subject or patient. A sample can be of any biological tissue or fluid. Such samples include, but are not limited to, sputum, saliva, buccal samples, oral samples, blood, serum, mucus, plasma, urine, blood cells (e.g., white blood cells), circulating cells (e.g., stem cells or endothelial cells in blood), tissue, core needle or fine needle biopsy samples, cell-containing body fluids, suspended nucleic acids, urine, stool, ascites, and pleural fluid, tears, or cells therefrom. A sample can also include a section of tissue, such as a frozen or fixed section taken for histological purposes, or a microdissected cell or extracellular portion thereof. The sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch resection, or by any other surgical method resulting in biopsy or excised cellular material. Such a sample can contain cells obtained from a subject or patient. In some embodiments, the sample is a bodily fluid, for example, but not limited to, blood fluid, serum, mucus, plasma, lymph, ascites, gynecological tract, or urine, hi some embodiments, the sample can be a non-invasive sample, such as, for example, a saline swish, buccal scrape, buccal swab, or the like.

[0052] As used herein, blood can include, for example, plasma, serum, whole blood, blood lysate, and the like.

[0053] As used herein, the term "evaluating" includes any form of measurement, including determining whether an element is present. The terms "determining," "measuring," "evaluating," "assessing," "analyzing," and "assaying" may be used interchangeably and may include quantitative and / or qualitative measurements.

[0054] As used herein, the term "monitoring" with respect to a type of cancer refers to a method or process of determining the severity or extent of that type of cancer, or stratifying that type of cancer based on the risk and / or probability of death. In some embodiments, monitoring relates to a method or process of determining the therapeutic effectiveness of a treatment administered to a patient.

[0055] As used herein, "outcome" may refer to the outcome studied. In some embodiments, "outcome" may refer to survival / mortality over a given analysis period. For example, "outcome" may refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or more. In some embodiments, an increased risk of a poor outcome indicates that the therapy had poor efficacy, and a decreased risk of a poor outcome indicates that the therapy had good efficacy.

[0056] As used herein, the term "high-risk clinical trial" refers to one in which the investigational agent poses "more than minimal risk" (as defined by the terminology used by an Institutional Review Board or IRB). In some embodiments, a high-risk clinical trial is a clinical trial.

[0057] As used herein, the term "low-risk clinical trial" refers to one in which the test agent has "minimal risk" (as defined by the terminology used by the IRB). In some embodiments, a low-risk clinical trial is one that is not a clinical trial. In some embodiments, a low-risk clinical trial involves the use of monitors or clinical practice processes. In some embodiments, a low-risk clinical trial is an observational clinical trial.

[0058] As used herein, the terms "modulated" or "modulation," or "regulated" or "regulation," and "differentially regulated" can refer to both upregulation (i.e., activation or stimulation, e.g., by agonism or enhancement) and downregulation (i.e., inhibition or suppression, e.g., by antagonism, reduction, or inhibition), unless otherwise specified or apparent from the context of the particular use.

[0059] As used herein, the term "subject" refers to any suitable (e.g., treatable) member of the animal kingdom. In the methods, the subject is preferably a mammal. In the methods, the subject is preferably a human patient. In the methods, the subject may be a pediatric mammalian patient. In the methods, a pediatric patient is a mammalian (e.g., preferably human) patient under the age of 18, while an adult patient is 18 years of age or older.

[0060] As used herein, the term "treating" (and variations thereof, such as "treatment," "treating," "treat") should be considered in its broadest context unless otherwise specified and refers to obtaining a desired pharmacological and / or physiological effect. Specifically, for example, the term "treating" does not necessarily imply or may not require that an animal be treated until complete recovery. Thus, "treating" includes amelioration of symptoms, relief from symptoms or effects associated with a condition, reduction in the severity of a condition, or prevention of symptoms, prophylactic amelioration, or otherwise reducing the risk of developing a particular condition. In some aspects, "treating" does not require or include prevention. As used herein, reference to "treating" an animal includes, but is not limited to, prophylactic and therapeutic treatment. The effect may be prophylactic, in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic, in terms of a partial or complete cure of a disease and / or adverse effects resulting from a disease. As used herein, "treatment" encompasses any treatment of a disease in a subject, preferably a mammal (e.g., a human), and may include one or more of: (a) preventing the disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed with it; (b) inhibiting the disease, i.e., halting its development; and (c) relieving the disease, i.e., causing regression or elimination of the disease and / or alleviating one or more disease symptoms. In certain aspects of the method, such as for conditions or disorders characterized by dysregulated IRAK expression or a dysregulated (e.g., hyperactive) IRAK-mediated signaling pathway, treatment may be or may include reducing such expression or signaling. "Treatment" can also encompass the delivery of an agent or administration of a therapy to provide a pharmacological effect even in the absence of a disease or condition. Any of the compositions (e.g., pharmaceutical compositions) described herein can be used to treat a suitable subject.

[0061] A "therapeutically effective amount" refers to an amount effective to achieve a desired and / or beneficial effect. An effective amount can be administered in one or more administrations. In the methods, a therapeutically effective amount is an amount adequate to treat an indication. Treating an indication means achieving any desired effect, such as, for example, one or more of palliating, ameliorating, stabilizing, reversing, slowing, or delaying disease progression, improving quality of life, or extending lifespan. Such achievement can be measured by any suitable method, such as measuring tumor size or blood counts, or any other suitable measurement.

[0062] As used herein, the term "marker" or "biomarker" refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, etc., whose presence or concentration can be detected and correlated with a known condition, such as a disease state. It can also be used to refer to differentially expressed genes whose expression patterns can be utilized as part of a predictive, prognostic, or diagnostic process in healthy or disease states, or alternatively, can be used in methods to identify useful therapeutic or preventative therapies.

[0063] As used herein, an mRNA "isoform" is an alternative transcript of a particular mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, truncated, or aberrant mRNA, modified mRNA (e.g., containing any residue modifications, capping variants, polyadenylation variants, etc.), etc.

[0064] "Antibody" or "antibody peptide" refers to an intact antibody or a binding fragment thereof that competes with the intact antibody for specific binding; this definition also encompasses monoclonal and polyclonal antibodies. Binding fragments are produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies. An antibody other than a "bispecific" or "bifunctional" antibody is understood to have each of its binding sites identical. An antibody substantially inhibits the adhesion of a receptor to a counterreceptor when, for example, the excess antibody reduces the amount of receptor bound to the counterreceptor by at least about 20%, 40%, 60%, or 80%, more usually by more than about 85% (as measured in an in vitro competitive binding assay).

[0065] Embodiments of the invention described herein include compounds of the invention (e.g., compounds of Formula (I), such as compounds of Formula (II) and Formula (III)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising compounds of the invention. Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) for treating certain diseases, for example, using compounds of the invention. Some embodiments include methods of administering and using compounds of the invention (e.g., in compositions or pharmaceutical compositions) to treat (e.g., diseases such as cancer or blood disorders). Some embodiments include methods of determining whether a patient is suitable for or likely to respond favorably to a particular treatment. Further embodiments include methods for making compounds of the invention. Additional embodiments of the invention are also contemplated herein.

[0066] Compounds and compositions, including pharmaceutical compositions In one aspect, the present disclosure provides a compound of formula (I), (II), or (III): [ka] [ka] [ka] or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. In one embodiment, the compound is a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative of a compound of Formula (I), (II), or (III). In some embodiments, the compound is not an ester, is not a solvate, or is not a prodrug of a compound of Formula (I), (II), or (III).

[0067] In one embodiment, A in formula (I), (II), or (III) is selected from N and CR. In one embodiment, D in formula (I), (II), or (III) is selected from N and CR. 4 In one embodiment, E in formula (I), (II), or (III) is selected from N and CR 3 In one embodiment, one of A, D, or E is N. In another embodiment, A is selected from CR 5 and D is CR 4 and E is CR 3 is.

[0068] In an exemplary embodiment, R of formula (I), (II), or (III) 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C alkoxy, or -C(=O)NR 31 R 32, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused ring heteroaryl, or -O-fused ring heteroaryl; and The -O-fused ring heteroaryl or -O-fused ring heteroaryl is optionally substituted with one or more of deuterium, 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 perfluorinated alkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl.

[0069] In some embodiments of Formula (I), (II), or (III), R 1may be deuterium, 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, -O-cycloalkyl, spirofused cycloalkyl, -O-spirofused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl, and the amido, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirofused cycloalkyl, -O-spirofused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl R is optionally substituted with one or more of deuterium, 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 heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; 2is H, deuterium, halogen, hydroxy, oxo, -CN, amino, -O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl , fused ring heteroaryl, or -O-fused ring heteroaryl, wherein the amino, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirofused cycloalkyl, -O-spirofused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, - O-Heteroaryl, fused ring heteroaryl, or -O-fused ring heteroaryl is substituted with deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, optionally substituted with one or more of -CONHCH3, -CON(CH3), 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 5may be H, deuterium, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirofused cycloalkyl, -O-spirofused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl, wherein the methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirofused cycloalkyl, -O-spirofused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, The -O-aryl, heteroaryl, -O-heteroaryl, fused ring heteroaryl, or -O-fused ring heteroaryl is optionally substituted with one or more of deuterium, 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 haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl.

[0070] R of formula (I), (II), or (III) 6 teeth, [ka] and

[0071] R 7 , R 8 , R 9 , R 10 , R 11 , R12 , R 13 , R 14 can be H, deuterium, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl, wherein the methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl , -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused ring heteroaryl, or -O-fused ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, oxo, -C(=O)H, -C(=O)OH, nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, -SOH, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)NH, -C(=O)N(CH), C-C alkyl, C-C perfluorinated alkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; 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 30is H, deuterium, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused ring heteroaryl, or -O-fused ring heteroaryl, including methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spiro-fused cycloalkyl, -O-spiro-fused cycloalkyl, heterocyclyl, -O-heterocyclyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, Fused ring heteroaryl, or -O-fused ring heteroaryl, is selected from the group consisting of deuterium, halogen, hydroxy, oxo, -C(=O)H, -C(=O)OH, nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, -SO3H, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O) and m, n, o, p, q, r, s, t, u, v, w, and x can be 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1 and where u+v+w+x is at least 1.

[0072] In some embodiments, R of formula (I), (II), or (III) 1is H, deuterium, halogen, -CONH2, -CONHCH3, -CON(CH3)2, benzyl, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or -O-cycloalkyl, where C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or -O-cycloalkyl is optionally substituted with one or more halogen, deuterium, hydroxyl, C1-C7 alkyl, or C1-C7 haloalkyl. In some embodiments, R1 is H, Cl, -CONH2, -CONHCH3, methoxy, -OCD3, ethoxy, cyclopropyl, C1-C4 alkyl, -O-C3 cycloalkyl, where methoxy, ethoxy, cyclopropyl, C1-C4 alkyl, or -O-C3 cycloalkyl is optionally substituted with one or more F, -OH, methyl, or CF3. In some embodiments, R 1 is H. In some embodiments, R 1 is not H.

[0073] In some embodiments, R of formula (I), (II), or (III) 2 is H, deuterium, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, and wherein the O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 The alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more of deuterium, halogen, hydroxy, —CN, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused-ring aryl, fused-ring heteroaryl, pyrrolyl, piperidyl, piperazinyl, C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, R 2is H, halogen, hydroxy, O-aryl, amino, C-C alkyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, wherein the O-aryl, amino, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, R 2 is H, Cl, hydroxy, -NHCH, -N(CH), -OCH, -OCF, -OCHF, -OPh, -CF, -CHF, unsubstituted C-C alkyl, substituted amino, substituted C-C alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl. 2 is not H.

[0074] In some embodiments, R of formula (I), (II), or (III) 3is H, deuterium, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C1-C7 alkoxy is deuterium, halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), 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, —OCD, or methoxy. In some embodiments, R 3 is H. In some embodiments, R 3 is not H.

[0075] In some embodiments, R of formula (I), (II), or (III) 4is H, deuterium, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C1-C7 alkoxy is deuterium, halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), 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, —OCD, or methoxy. 4 is H. In some embodiments, R 4 is not H.

[0076] In some embodiments, R of formula (I), (II), or (III) 5 is H, deuterium, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, or C-C alkoxy, wherein the C-C alkyl or C-C alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, R5 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0077] In some embodiments, R of formula (I), (II), or (III) 4 is methyl or -CF3, and R 3 and R 5 At least one of is H or halogen.

[0078] In some embodiments of Formula (I), (II), or (III), there is a chiral center at the R6-attached carbon. In some embodiments, the chiral center is an R chiral center, an S chiral center, or a racemate. In certain embodiments, the chiral center is located at the following bond: [ka] As will be appreciated by those skilled in the art, where chiral centers are possible at other positions in compounds according to formula (I), (II), or (III), the linear bond shown may also be represented by [ka] It could be.

[0079] In some embodiments, R of formula (I), (II), or (III) 6 teeth, [ka] is.

[0080] In an exemplary embodiment, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently H, deuterium, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C 1 -C 7Alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, -C(=O)NR 31 R 32 , cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein the 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 deuterium, halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), nitro (—NO), -N and optionally substituted with one or more of H, -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. 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 one embodiment, 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 Each of, if present, is H.

[0081] In an exemplary embodiment, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, deuterium, 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 the methanoyl (-COH), carboxy (-COH), 2 H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is not limited to deuterium, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulphonyl, and optionally substituted with one or more of fluoro (-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. 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 30At least one of R is not H. In another 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 Each of, if present, is H.

[0082] In some embodiments, m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5; and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0083] In some embodiments, R of formula (I), (II), or (III) 6 teeth, [ka] is.

[0084] In some embodiments, R of formula (I), (II), or (III) 6 teeth, [ka] ss

[0085] In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14are independently selected from H, deuterium, 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 the 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 deuterium, 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, —CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl, with the proviso that R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 provided that at least one of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 Each of, when present, is H. In some embodiments, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, deuterium, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and the 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, deuterium, 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; is optionally substituted with one or more deuterium, 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, —CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl. In some embodiments, m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5; and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0086] In one embodiment, R 31 and R 32 each is independently selected from H, deuterium, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens.

[0087] In one embodiment, the compound of formula (I) is a compound of formula (I-5010), (II-5010), or (III-5010) [ka] [ka] [ka] and or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof, wherein A, D, E, R 1 , R 2 , and R 6 is as defined in formulas (I), (II), and (III).

[0088] In one embodiment, Formula (I), (II), or (III) is a compound of Formula (V), (VI), or (VII): [ka] [ka] [ka] or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof, During the ceremony, I is N or CR 51 and J is N or CR 52 and K is N or CR 53 and [ka] teeth, [ka] is selected from Each R 50 are independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, spirofused cycloalkyl, -O-(C3-C6 cycloalkyl), C3-C9 heteroaryl, C2-C9 heterocyclyl, and -C(=O)NR 552a R 552b wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogen; and C3-C6 cycloalkyl, spirofused cycloalkyl, and -O-(C3-C6 cycloalkyl), C2-C9 heterocyclyl are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl, and halogen; R 51 , R 52 , and R 53 are each independently selected from H, C1-C6 alkoxy, and halogen; R 54a , R 54b , R 55a , R 55b , R 56a , R 56b , R 57a , R 57b , R 58a , R 58b , R 59a , R 59b , R 550a , R 550b , R 551a , and R 551b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R 552a and R 552b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens; One of I, J, or K is N.

[0089] In one embodiment, R 54a , R 54b , R 55a , R 55b , R 56a , R 56b , R 57a , R 57b , R 58a , R 58b , R 59a , R 59b , R 550a , R 550b , R 551a , and R 551b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 54a , R 54b , R 55a , R 55b , R 56a , R 56b , R 57a , R 57b , R 58a , R 58b , R 59a , R 59b , R 550a , R 550b , R 551a , and R 551b Each of is H. Formula (Ia-5010-WO)

[0090] In one embodiment, the compound of formula (I) is a compound of formula (Ia-5010-WO): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, V is N or CR 11 and W is N or CR 12 and X is N or CR 13 and [ka] teeth, [ka] and R 10a is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 11 , R 12 , and R 13 are each independently selected from H, C1-C6 alkoxy, and halogen; R 14a , R 14b , R 15a , R 15b , R 16a , and R 16b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R 18a and R 18b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens; One of V, W, or X is N.

[0091] In one embodiment, R of formula (Ia-5010-WO) 14a , R 14b , R 15a , R 15b , R 16a , and R 16bis selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 15a , R 15b , R 16a , and R 16b is H and R 14a and / or R 14b is halogen. In one embodiment, R 15a , R 15b , R 16a , and R 16b is H and R 14a and / or R 14b is F. In one embodiment, R 14b , R 15a , R 15b , R 16a , and R 16b is H and R 14a is F.

[0092] In one embodiment, R of formula (Ia-5010-WO) 10a is unsubstituted C1-C6 alkoxy. In one embodiment, R 10a is -OCH3 and [ka] In one embodiment, R 10a is an unsubstituted —O—(C-C cycloalkyl). In one embodiment, R 10a is an unsubstituted —O—(C cycloalkyl). In another embodiment, R 10a is C1-C6 alkoxy substituted with one or more halogens. In one embodiment, R 10a teeth, [ka] is selected from.

[0093] In one embodiment, R of formula (Ia-5010-WO) 11 , R 12 , and R 13 is H, if present.

[0094] In one embodiment, the compound of formula (Ia-5010-WO) is a compound covered by the formula above and shown in Table 1 of the present application. Formula (Ib-5010-WO)

[0095] In another embodiment, the compound of formula (I) is a compound of formula (Ib-5010-WO): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, V is N or CR 11 and W is N or CR 12 and X is N or CR 13 and [ka] teeth, [ka] and R 10b is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 17b is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 11 , R 12 , and R 13 are each independently selected from H and halogen; R 14a , R 14b , R 15a , R 15b , R 16a , R 16b , R 18a , and R 18b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; One of V, W, or X is N.

[0096] In one embodiment, R of formula (Ib-5010-WO) 14a , R 14b , R 15a , R 15b , R 16a , and R 16b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 15a , R 15b , R 16a , and R 16b is H and R 14a and / or R 14b is halogen. In one embodiment, R 15a , R 15b , R 16a , and R 16b is H and R 14a and / or R 14b is F. In one embodiment, R 14b, R 15a , R 15b , R 16a , and R 16b is H and R 14a is F.

[0097] In one embodiment, R of formula (Ib-5010-WO) 10b is not H. In one embodiment, R 10b is unsubstituted C1-C6 alkoxy. In one embodiment, R 10b is -OCH3.

[0098] In one embodiment, R of Formula (Ib-5010-WO) is C-C alkyl substituted with one —OH and / or halogen. 17b teeth, [ka] is selected from.

[0099] In one embodiment, the compound of formula (Ib-5010-WO) is a compound covered by the formula above and shown in Table 1 of the present application. Formula (Ib-5010-WO50)

[0100] In another embodiment, the compound of formula (I) is a compound of formula (Ib-5010-WO50): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, V is N or CR 11 and W is N or CR 12 and X is N or CR 13 and [ka] teeth, [ka] and R 10b is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; and wherein C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 17b is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), C3-C9 heterocyclyl, imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from —OH, C-C alkyl, and halogen; R 11 , R 12 , and R 13 are each independently selected from H, C1-C6 alkoxy, and halogen; R 14a , R 14b , R 15a , R 15b , R 16a , R 16b , R 18a , and R 18b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; One of V, W, or X is N.

[0101] In one embodiment, R of formula (Ib-5010-WO50) 14a , R 14b , R 15a , R 15b , R 16a , and R 16b Each of R is H. In one embodiment, 14a , R 14b , R 15a , R 15b , R 16a , and R 16b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 15a , R 15b , R 16a , and R 16b is H and R 14a and / or R 14b is halogen. In one embodiment, R 15a , R 15b , R 16a , and R 16b is H and R 14a and / or R 14b is F. In one embodiment, R 14b , R 15a , R 15b , R 16a , and R 16b is H and R 14a is F.

[0102] In one embodiment, R of formula (Ib-5010-WO50) 10b is not H. In one embodiment, R 10b is unsubstituted C1-C6 alkoxy. In one embodiment, R 10b is -OCH3.

[0103] In one embodiment, R11, R12, and R13, when present in Formula (Ib-5010-WO50), are H. In another embodiment, V is CR 11 where R11 is F and W is CR 12 where R 12 is H and X is N.

[0104] In one embodiment, R of formula (Ib-5010-WO50) 17b is C1-C6 alkyl substituted with one -OH and / or halogen. In one embodiment, R 17b teeth, [ka] is selected from.

[0105] In one embodiment, the compound of formula (I) is a compound of formula (Ib-5010-WO50), provided that R 17b but [ka] If R 10b is H. In one embodiment, the compound of formula (I) is a compound of formula (Ib-5010-WO50), with the proviso that R 17b but [ka] If R 11 , R 12 , and R 13 is present and is selected from C1-C6 alkoxy and halogen.

[0106] In one embodiment, the compound of formula (Ib-5010-WO50) is [ka] is.

[0107] In one embodiment, the compound of formula (Ib-5010-WO50) is [ka] is selected from.

[0108] In one embodiment, the compound of formula (Ib-5010-WO50) is [ka] is selected from. Formula (Ic-5010-WO)

[0109] In another embodiment, the compound of formula (I) is a compound of formula (Ic-5010-WO): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, V is N or CR 11 and W is N or CR 12 and X is N or CR 13 and [ka] teeth, [ka] and R 10c is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 11 , R 12 , and R 13are each independently selected from H, C1-C6 alkoxy, and halogen; R 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R 18a and R 18b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens; One of V, W, or X is N.

[0110] In one embodiment, a compound of formula (Ic-5010-WO)R 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b Each of R is H. In another embodiment, one or more R 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 19a , R 19b , R 111a , R 111b , R 112a , and R 112b is H and R 110a and / or R 110b is halogen. In one embodiment, R19a , R 19b , R 111a , R 111b , R 112a , and R 112b is H and R 110a and / or R 110b is F. In one embodiment, R 19a , R 19b , R 110b , R 111a , R 111b , R 112a , and R 112b is H and R 110a is F.

[0111] In one embodiment, R of formula (Ic-5010-WO) 10c is unsubstituted C1-C6 alkoxy. In one embodiment, R 10c is -OCH3 and [ka] In one embodiment, R 10c is an unsubstituted —O—(C-C cycloalkyl). In one embodiment, R 10c is an unsubstituted —O—(C cycloalkyl). In another embodiment, R 10c is C1-C6 alkoxy substituted with one or more halogens. In one embodiment, R 10c teeth, [ka] is selected from.

[0112] In one embodiment, R of formula (Ic-5010-WO) 11 , R 12 , and R 13 is H, if present.

[0113] In one embodiment, the compound of formula (Ic-5010-WO) is a compound covered by the formula above and shown in Table 1 of the present application. Formula (Id-5010-WO)

[0114] In another embodiment, the compound of formula (I) is a compound of formula (Id-5010-WO): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, V is N or CR 11 and W is N or CR 12 and X is N or CR 13 and [ka] teeth, [ka] and R 10d is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 113d is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18bwherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 11 , R 12 , and R 13 are each independently selected from H and halogen; R 18a , R 18b , R 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; One of V, W, or X is N.

[0115] In one embodiment, R of formula (Id-5010-WO) 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b Each of R is H. In another embodiment, one or more R 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 19a , R 19b , R 111a , R 111b , R112a , and R 112b is H and R 110a and / or R 110b is halogen. In one embodiment, R 19a , R 19b , R 111a , R 111b , R 112a , and R 112b is H and R 110a and / or R 110b is F. In one embodiment, R 19a , R 19b , R 110b , R 111a , R 111b , R 112a , and R 112b is H and R 110a is F.

[0116] In one embodiment, R of formula (Id-5010-WO) 10d is H. In another embodiment, R 10d is the unsubstituted C 1- In one embodiment, R 10d is -OCH3.

[0117] In one embodiment, R of formula (Id-5010-WO) 113d is C1-C6 alkyl substituted with one -OH and / or halogen. In one embodiment, R 113d teeth, [ka] is selected from.

[0118] In one embodiment, the compound of formula (Id-5010-WO) is a compound covered by the formula above and shown in Table 1 of the present application. Formula (Id-5010-WO50)

[0119] In another embodiment, the compound of formula (I) is a compound of formula (Id-5010-WO50): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, V is N or CR 11 and W is N or CR 12 and X is N or CR 13 and [ka] teeth, [ka] and R 10d is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; and wherein C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 113d is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from —OH, C-C alkyl, and halogen; R 11 , R 12 , and R 13are each independently selected from H, C1-C6 alkoxy, and halogen; R 18a and R 18b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens; R 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; One of V, W, or X is N.

[0120] In one embodiment, R of formula (Id-5010-WO50) 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b Each of R is H. In another embodiment, one or more R 19a , R 19b , R 110a , R 110b , R 111a , R 111b , R 112a , and R 112b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 19a , R 19b , R 111a , R 111b , R 112a , and R 112b is H and R 110a and / or R 110b is halogen. In one embodiment, R19a , R 19b , R 111a , R 111b , R 112a , and R 112b is H and R 110a and / or R 110b is F. In one embodiment, R 19a , R 19b , R 110b , R 111a , R 111b , R 112a , and R 112b is H and R 110a is F.

[0121] In one embodiment, R of formula (Id-5010-WO50) 10d is H. In another embodiment, R 10d is unsubstituted C1-C6 alkoxy. In one embodiment, R 10d is -OCH3.

[0122] In one embodiment, R of formula (Id-5010-WO50) 11 , R 12 , and R 13 When present, V is H. In another embodiment, V is CR 11 where R 11 is F and W is CR 12 where R 12 is H and X is N.

[0123] In one embodiment, R of formula (Id-5010-WO50) 113d is C1-C6 alkyl substituted with one -OH and / or halogen. In one embodiment, R 113d teeth, [ka] is selected from.

[0124] In one embodiment, the compound of formula (I) is a compound of formula (Id-5010-WO50), provided that R 113d but [ka] If R 10d is H. In one embodiment, the compound of formula (I) is a compound of formula (Id-5010-WO50), with the proviso that R 113d but [ka] If R 11 , R 12 , and R 13 is present and is selected from C1-C6 alkoxy and halogen.

[0125] In one embodiment, the compound of (Id-5010-WO50) is not: [ka]

[0126] In one embodiment, the compound of formula (Id-5010-WO50) is [ka] [ka] is selected from.

[0127] In one embodiment, the compound of formula (Id-5010-WO50) is [ka] is selected from. Formula (IIa-5010-WO)

[0128] In one embodiment, the compound of formula (II) is a compound of formula (IIa-5010-WO): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, L is N or CR 21 and M is N or CR 22 and Q is N or CR 23 and [ka] teeth, [ka] R 20a is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 27a is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 21 , R 22 , and R 23 are each independently selected from H and halogen; R 24a , R24b , R 25a , R 25b , R 26a , R 26b , R 28a , and R 28b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; One of L, M, or Q is N.

[0129] In one embodiment, R of formula (IIa-5010-WO) 24a , R 24b , R 25a , R 25b , R 26a , and R 26b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 25a , R 25b , R 26a , and R 26b is H and R 24a and / or R 24b is halogen. In one embodiment, R 25a , R 25b , R 26a , and R 26b is H and R 24a and / or R 24b is F. In one embodiment, R 24b , R 25a , R 25b , R 26a , and R 26b is H and R 24a is F.

[0130] In one embodiment, R of formula (IIa-5010-WO) 20a is not H. In one embodiment, R 20a is unsubstituted C1-C6 alkoxy. In one embodiment, R 20a is -OCH3.

[0131] In one embodiment, R of formula (IIa-5010-WO) 27a is unsubstituted C-C cycloalkyl. In one embodiment, R 27a is an unsubstituted C cycloalkyl. In one embodiment, R 27a is C1-C6 alkyl substituted with one -OH and / or halogen. In one embodiment, R 27a teeth, [ka] is.

[0132] In one embodiment, the compound of formula (IIa-5010-WO) is a compound covered by the formula above and shown in Table 1 of the present application. Formula (IIa-5010-WO50)

[0133] In one embodiment, the compound of formula (II) is a compound of formula (IIa-5010-WO50): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, L is N or CR 21 and M is N or CR 22 and Q is N or CR 23 and [ka] teeth, [ka] and R 20a is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28bwherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; and wherein C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; Each R 27a are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, spirofused cycloalkyl, -O-(C3-C6 cycloalkyl), C2-C6 heterocyclyl, imidazolyl, triazolyl, and -C(=O)NR 28a R 28b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogen; and C-C cycloalkyl, spirocycloalkyl, -O-(C-C cycloalkyl), and C-C heterocyclyl are each optionally substituted with one or more substituents selected from -OH, C-C alkyl, and halogen; R 21 , R 22 , and R 23 are each independently selected from H, C1-C6 alkoxy, and halogen; R 24a , R 24b , R 25a , R 25b , R 26a , and R 26b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R 28a and R 28b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens; One of L, M, or Q is N.

[0134] In one embodiment, R of formula (IIa-5010-WO50) 24a , R 24b , R 25a , R 25b , R 26a , and R 26b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 25a , R 25b , R 26a , and R 26b is H and R 24a and / or R 24b is halogen. In one embodiment, R 25a , R 25b , R 26a , and R 26b is H and R 24a and / or R 24b is F. In one embodiment, R 24b , R 25a , R 25b , R 26a , and R 26b is H and R 24a is F.

[0135] In one embodiment, R of formula (IIa-5010-WO50) 20a is not H. In one embodiment, R 20a is unsubstituted C1-C6 alkoxy. In one embodiment, R 20a is —OCH3. In another embodiment, R 20a is C1-C6 alkoxy substituted with one or more halogens. In one embodiment, R 20a teeth, [ka] In other embodiments, R 20a is an unsubstituted —O—(C-C cycloalkyl). In one embodiment, R 20a is an unsubstituted —O—(C cycloalkyl).

[0136] One R of formula (IIa-5010-WO50) 21 , R 22 , and R 23 In another embodiment, L is CR 21 where R 21 is selected from F, Cl, and -OCH3, and M is CR 22 where R 22 is H and Q is N.

[0137] In one embodiment, R of formula (IIa-5010-WO50) 27a is unsubstituted C-C cycloalkyl. In one embodiment, R 27a is an unsubstituted C3 cycloalkyl or [ka] In another embodiment, R 27a is a C3-C6 cycloalkyl substituted with one or more -CH3 and / or F. In one embodiment, R 27a teeth, [ka] Selected from and [ka] . In one embodiment, R 27a is C1-C6 alkyl substituted with one or more -OH and / or one or more halogens. 27a teeth, [ka] In one embodiment, R 27a is a spiro-fused cycloalkyl. In one embodiment, R 27a teeth, [ka] In another embodiment, R 27ais an unsubstituted C2-C6 heterocyclyl. In one embodiment, R 27a is an unsubstituted C2-C6 heterocyclyl containing one oxygen atom, one nitrogen atom, or one oxygen atom and one nitrogen atom. 27a teeth, [ka] In one embodiment, R 27a teeth, [ka] In one embodiment, R 27a teeth, [ka] In another embodiment, R 27a is a C2-C6 heterocyclyl substituted with one or more F. In one embodiment, R 27a teeth, [ka] is.

[0138] In one embodiment, the compound of formula (II) is a compound of formula (IIa-5010-WO50), provided that R 20a is -OCH3 and R 27a When R is an unsubstituted C3 cycloalkyl, 21 , R 22 , and R 23 is present and is selected from C1-C6 alkoxy and halogen.

[0139] In one embodiment, the compound of formula (IIa-5010-WO50) is not: [ka]

[0140] In one embodiment, the compound of formula (IIa-5010-WO50) is [ka] [ka] is selected from.

[0141] In one embodiment, the compound of formula (IIa-5010-WO50) is [ka] [ka] is selected from. Formula (IIb-5010-WO)

[0142] In another embodiment, the compound of formula (II) is a compound of formula (IIb-5010-WO): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, L is N or CR 21 and M is N or CR 22 and Q is N or CR 23 and [ka] teeth, [ka] and R 20b is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28bwherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 27b is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 21 , R 22 , and R 23 are each independently selected from H and halogen; R 28a , R 28b , R 29a , R 29b , R 210a , R 210b , R 211a , R 211b , R 212a , and R 212b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; One of L, M, or Q is N.

[0143] In one embodiment, R of formula (IIb-5010-WO) 29a , R 29b , R 210a , R 210b , R 211a , R 211b , R 212a , and R212b Each of is H. In another embodiment, R 29a , R 29b , R 210a , R 210b , R 211a , R 211b , R 212a , and R 212b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 29a , R 29b , R 211a , R 211b , R 212a , and R 212b is H and R 210a and / or R 210b is halogen. In one embodiment, R 29a , R 29b , R 211a , R 211b , R 212a , and R 212b is H and R 210a and / or R 210b is F. In one embodiment, R 29a , R 29b , R 210b , R 211a , R 211b , R 212a , and R 212b is H and R 210a is F.

[0144] In one embodiment, R of formula (IIb-5010-WO) 20b is not H. In one embodiment, R 20b is unsubstituted C1-C6 alkoxy. In one embodiment, R 20b is -OCH3.

[0145] In one embodiment, R of formula (IIb-5010-WO) 27b is unsubstituted C-C cycloalkyl. In one embodiment, R 27b is an unsubstituted C cycloalkyl. In one embodiment, R 27bis C1-C6 alkyl substituted with one -OH and / or halogen. In one embodiment, R 27b teeth, [ka] is.

[0146] In one embodiment, the compound of formula (IIb-5010-WO) is a compound covered by the formula above and shown in Table 1 of the present application. Formula (IIb-5010-WO50)

[0147] In another embodiment, the compound of formula (II) is a compound of formula (IIb-5010-WO50): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, L is N or CR 21 and M is N or CR 22 and Q is N or CR 23 and [ka] teeth, [ka] and R 20b is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28bwherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; Each R 27b are independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, spirocycloalkyl, -O-(C3-C6 cycloalkyl), C2-C6 heterocyclyl, imidazolyl, triazolyl, and -C(=O)NR 28a R 28b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogen; and C-C cycloalkyl, spirocycloalkyl, -O-(C-C cycloalkyl), and C-C heterocyclyl are each optionally substituted with one or more substituents selected from -OH, C-C alkyl, and halogen; R 21 , R 22 , and R 23 are each independently selected from H, C1-C6 alkoxy, and halogen; R 29a , R 29b , R 210a , R 210b , R 211a , R 211b , R 212a , and R 212b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R 28a and R 28b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens; One of L, M, or Q is N.

[0148] In one embodiment, R of formula (IIb-5010-WO50) 29a , R 29b , R 210a , R 210b , R 211a , R 211b , R 212a , and R 212b Each of is H. In another embodiment, R 29a , R 29b , R 210a , R 210b , R 211a , R 211b , R 212a , and R 212b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 29a , R 29b , R 211a , R 211b , R 212a , and R 212b is H and R 210a and / or R 210b is halogen. In one embodiment, R 29a , R 29b , R 211a , R 211b , R 212a , and R 212b is H and R 210a and / or R 210b is F. In one embodiment, R 29a , R 29b , R 210b , R 211a , R 211b , R 212a , and R 212b is H and R 210a is F.

[0149] In one embodiment, R of formula (IIb-5010-WO50) 20b is not H. In one embodiment, R 20b is unsubstituted C1-C6 alkoxy. In one embodiment, R20b is —OCH. In one embodiment, R 20b is -OCD3. In another embodiment, R 20b teeth 、 is C1-C6 alkoxy substituted with one or more F. In one embodiment, R 20b teeth [ka] In one embodiment, R 20b is an unsubstituted —O—(C-C cycloalkyl). In one embodiment, R 20b is an unsubstituted —O—(C cycloalkyl).

[0150] In one embodiment, R of formula (IIb-5010-WO50) 21 , R 22 , and R 23 When present, L is H. In another embodiment, L is CR 21 where R 21 is selected from F, Cl, and -OCH3, and M is CR 22 where R 22 is H and Q is N,

[0151] In one embodiment, R of formula (IIb-5010-WO50) 27b is unsubstituted C-C cycloalkyl. In one embodiment, R 27b is an unsubstituted C3 cycloalkyl or [ka] In one embodiment, R 27b is C1-C6 alkyl substituted with one or more -OH and / or one or more halogens. 27b teeth, [ka] In another embodiment, R 27bis a C3-C6 cycloalkyl substituted with one or more -CH3, -OH, and / or F. In one embodiment, R 27b teeth [ka] In one embodiment, R 27b is a spiro-fused cycloalkyl. In one embodiment, R 27b teeth, [ka] In another embodiment, R 27b is an unsubstituted C2-C6 heterocyclyl. In one embodiment, R 27b is an unsubstituted C2-C6 heterocyclyl containing one oxygen atom, one nitrogen atom, or one oxygen atom and one nitrogen atom. 27b teeth, [ka] In one embodiment, R 27b teeth, [ka] In one embodiment, R 27b teeth, [ka] In another embodiment, R 27b is a C2-C6 heterocyclyl substituted with one or more F and / or -CH3. 27b teeth, [ka] In one embodiment, R 27b teeth, [ka] is.

[0152] In one embodiment, the compound of formula (II) is a compound of formula (IIb-5010-WO50), provided that R 20b is -OCH3 and R 27b When R is an unsubstituted C3 cycloalkyl, 21 , R 22 , and R 23 is present and is selected from C1-C6 alkoxy and halogen.

[0153] In one embodiment, the compound of formula (IIb-5010-WO50) is [ka] is.

[0154] In one embodiment, the compound of formula (IIb-5010-WO50) is: [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0155] In one embodiment, the compound of formula (IIb-5010-WO50) is: [ka] [ka] [ka] [ka] [ka] is selected from. Formula (IIIa-5010-WO)

[0156] In another embodiment, the compound of formula (III) is a compound of formula (IIIa-5010-WO): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R is N or CR 31 and T is N or CR 32 and U is N or CR 33 and [ka] teeth, [ka] and R 37a is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, 2-pyrrolidinonyl, and -C(=O)NR 38a R 38b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 31 , R 32 , and R 33 are each independently selected from H and halogen; R 34a , R 34b , R 35a , R 35b , R 36a , R 36b , R 38a , and R 38b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; One of R, T, or U is N.

[0157] In one embodiment, R of formula (IIIa-5010-WO) 34a , R 34b , R 35a , R 35b , R 36a , and R 36b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 35a , R 35b , R 36a , and R 36b is H and R 34a and / or R 34b is halogen. In one embodiment, R 35a , R 35b , R 36a , and R 36b is H and R 34a and / or R 34b is F. In one embodiment, R 34b , R 35a , R 35b , R 36a , and R 36b is H and R 34a is F.

[0158] In one embodiment, R of formula (IIIa-5010-WO) 37a is C1-C6 alkyl substituted with one -OH and / or halogen. In one embodiment, R 37a teeth, [ka] In one embodiment, R 37a is 2-pyrrolidinonyl. In one embodiment, R 37a teeth, [ka] is.

[0159] In one embodiment, the compound of formula (IIIa-5010-WO) is a compound covered by the formula above and shown in Table 1 of the present application. Formula (IIIa-5010-WO50)

[0160] In another embodiment, the compound of formula (III) is a compound of formula (IIIa-5010-WO50): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R is N or CR 31 and T is N or CR 32 and U is N or CR 33 and [ka] teeth, [ka] and Each R 37a are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), C2-C6 heterocyclyl, imidazolyl, triazolyl, 2-pyrrolidinonyl, and -C(=O)NR 38a R 38bwherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogen; and C-C cycloalkyl, -O-(C-C cycloalkyl), and C-C heterocyclyl are each optionally substituted with one or more substituents selected from -OH, C-C alkyl, and halogen; R 31 , R 32 , and R 33 are each independently selected from H, C1-C6 alkoxy, and halogen; R 34a , R 34b , R 35a , R 35b , R 36a , and R 36b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R 38a and R 38b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens; One of R, T, or U is N.

[0161] In one embodiment, R of formula (IIIa-5010-WO50) 31 , R 32 , and R 33 When present, R is H. In another embodiment, R is CR 31 where R 31 is F and T is CR 32 where R 32 is H and U is N.

[0162] In one embodiment, R of formula (IIIa-5010-WO50) 34a , R 34b , R 35a , R 35b, R 36a , and R 36b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 35a , R 35b , R 36a , and R 36b is H and R 34a and / or R 34b is halogen. In one embodiment, R 35a , R 35b , R 36a , and R 36b is H and R 34a and / or R 34b is F. In one embodiment, R 34b , R 35a , R 35b , R 36a , and R 36b is H and R 34a is F.

[0163] In one embodiment, R of formula (IIIa-5010-WO50) 37a is C1-C6 alkyl substituted with one or more -OH and / or one or more halogens. 37a teeth, [ka] is.

[0164] In one embodiment, the compound of formula (III) is a compound of formula (IIIa-5010-WO50), provided that R 37a teeth [ka] isn't it.

[0165] In one embodiment, the compound of formula (IIIa-5010-WO50) is: [ka]

[0166] In one embodiment, the compound of formula (IIIa-5010-WO50) is: [ka] Formula (IIIb-5010-WO)

[0167] In another embodiment, the compound of formula (III) is a compound of formula (IIIb-5010-WO): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R is N or CR 31 and T is N or CR 32 and U is N or CR 33 and [ka] teeth, [ka] and R 37b is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, 2-pyrrolidinonyl, and -C(=O)NR 38a R 38b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from —OH and halogen; and C-C cycloalkyl and —O—(C-C cycloalkyl) are each optionally substituted with one or more substituents selected from C-C alkyl and halogen; R 31 , R 32 , and R 33 are each independently selected from H and halogen; R 38a , R 38b , R 39a , R 39b , R 310a , R 310b , R 311a , R 311b , R 312a , and R 312b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; One of R, T, or U is N.

[0168] In one embodiment, R of formula (IIIb-5010-WO) 31 , R 32 , and R 33 When present, R is H. In another embodiment, R is CR 31 where R 31 is F and T is CR 32 where R 32 is H and U is N.

[0169] In one embodiment, R of formula (IIIb-5010-WO) 39a , R 39b , R 310a , R 310b , R 311a , R 311b , R 312a , and R 312b Each of is H. In another embodiment, R 39a , R 39b , R 310a , R 310b , R 311a , R 311b , R 312a , and R 312b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 39a , R 39b , R 311a , R 311b , R 312a, and R 312b is H and R 310a and / or R 310b is halogen. In one embodiment, R 39a , R 39b , R 311a , R 311b , R 312a , and R 312b is H and R 310a and / or R 310b is F. In one embodiment, R 39a , R 39b , R 310b , R 311a , R 311b , R 312a , and R 312b is H and R 310a is F.

[0170] In one embodiment, R of formula (IIIb-5010-WO) 37b is C1-C6 alkyl substituted with one -OH and / or halogen. In one embodiment, R 37b teeth, [ka] In one embodiment, R 37b is 2-pyrrolidinonyl. In one embodiment, R 37b teeth, [ka] is.

[0171] In one embodiment, the compound of formula (IIIb-5010-WO) is a compound covered by the formula above and shown in Table 1 of the present application. Formula (IIIb-5010-WO50)

[0172] In another embodiment, the compound of formula (III) is a compound of formula (IIIb-5010-WO50): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R is N or CR 31 and T is N or CR 32 and U is N or CR 33 and [ka] teeth, [ka] and Each R 37b are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), C2-C6 heterocyclyl, imidazolyl, triazolyl, 2-pyrrolidinonyl, and -C(=O)NR 38a R 38b wherein C-C alkyl and C-C alkoxy are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogen; and C-C cycloalkyl, -O-(C-C cycloalkyl), and C-C heterocyclyl are each optionally substituted with one or more substituents selected from -OH, C-C alkyl, and halogen; R 31 , R 32 , and R 33 are each independently selected from H, C1-C6 alkoxy, and halogen; R 39a , R 39b , R 310a , R 310b , R 311a , R 311b , R 312a , and R 312b are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein each of the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more halogen atoms; R38a and R 38b are each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more halogens; One of R, T, or U is N.

[0173] In one embodiment, R31, R 32 , and R 33 When present, R is H. In another embodiment, R is CR 31 where R 31 is F and T is CR 32 where R 32 is H and U is N.

[0174] In one embodiment, R of formula (IIIb-5010-WO50) 39a , R 39b , R 310a , R 310b , R 311a , R 311b , R 312a , and R 312b Each of is H. In another embodiment, R 39a , R 39b , R 310a , R 310b , R 311a , R 311b , R 312a , and R 312b is selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 39a , R 39b , R 311a , R 311b , R 312a , and R 312b is H and R 310a and / or R 310b is halogen. In one embodiment, R 39a , R 39b , R 311a , R 311b , R312a , and R 312b is H and R 310a and / or R 310b is F. In one embodiment, R 39a , R 39b , R 310b , R 311a , R 311b , R 312a , and R 312b is H and R 310a is F.

[0175] In one embodiment, R of formula (IIIb-5010-WO50) 37b is C1-C6 alkyl substituted with one -OH and / or halogen. In one embodiment, R 37b teeth, [ka] In one embodiment, R 37b is an unsubstituted C2-C6 heterocyclyl. In one embodiment, R 37b is an unsubstituted C heterocyclyl. In one embodiment, R 37b teeth, [ka] is.

[0176] In one embodiment, the compound of formula (III) is a compound of formula (IIIb-5010-WO50), provided that R 37b but [ka] If R 31 , R 32 , and R 33 is present and is selected from C1-C6 alkoxy and halogen.

[0177] In one embodiment, the compound of formula (IIIb-5010-WO50) is not: [ka]

[0178] In one embodiment, the compound of formula (IIIb-5010-WO50) is [ka] [ka] is selected from.

[0179] In one embodiment, the compound of formula (IIIb-5010-WO50) is [ka] is selected from.

[0180] In some embodiments, the compounds described herein may be in the form of salts, optical and geometric isomers, and salts of isomers. In other embodiments, the compounds may be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including, but not limited to, hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates. In some cases, for acidic compounds, salts may include metals, amines, or organic cations (e.g., quaternary ammonium). In still other embodiments, simple derivatives of compounds (e.g., ethers, esters, or amides) may be used that have desirable retention and release characteristics but are easily hydrolyzed by body pH, enzymes, or other suitable means.

[0181] In some embodiments, compounds of the present invention having chiral centers exist in and can be isolated in optically active and racemic forms. In other embodiments, compounds may exhibit polymorphism. Some embodiments of the present invention encompass any racemic, optically active, polymorphic, or stereoisomeric form of the compounds described herein, including isotopically and radiolabeled compounds, or mixtures thereof. See, e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be isolated by standard resolution techniques, including, for example, fractional crystallization, chiral chromatography, and the like. See, e.g., Eliel, EL & Wilen SH, 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. Preparation of optically active forms can be accomplished by any suitable method, including, but not limited to, resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0182] In some embodiments, the compounds disclosed herein have asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, and all isomeric forms and mixtures thereof are contemplated for use in the compounds and methods described herein. Compounds contemplated for use in the compounds and methods described herein do not include those known in the art to be too unstable to synthesize and / or isolate.

[0183] 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 ( 14C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope contemplated.

[0184] In some embodiments, metabolites of the compounds disclosed herein are useful in the methods disclosed herein.

[0185] In some embodiments, compounds contemplated herein may be provided in the form of a prodrug. The term "prodrug" refers to a compound that can be converted in vivo to a compound described herein (e.g., a biologically active compound). Prodrugs may be useful for a variety of reasons known in the art, including ease of administration, such as by enhancing oral bioavailability. Prodrugs may also have improved solubility in pharmaceutical compositions relative to the biologically active compound. One example, without limitation, of a prodrug is a compound that is administered as an ester (i.e., a "prodrug") to facilitate transport across cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the active carboxylic acid once inside the cell, where water solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in *Design of Prodrugs* (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference for the limited purpose of describing the procedures and preparation of suitable prodrug derivatives.

[0186] Certain compounds disclosed herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the contemplated compounds. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.

[0187] In certain embodiments, one or more compounds of the present invention (e.g., compounds of Formula (I), (II), (III), (V), (VI), (VII), (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIc-5010-WO), (IId ... 0-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)) may be part of the composition and may be at least about 0.0001%, at least The amount may be about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, or about 99.99% or less, 0.0001% to about 99%, 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75% (by weight of the total composition).

[0188] In some embodiments, one or more compounds of the present disclosure (e.g., compounds of Formula (I), (II), (III), (V), (VI), (VII), (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa- 5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)) is at least about 0.0001%, at least about 0.001% , at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, about 99.99% or less, 0.0001% to about 99%, 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75% (by weight of the total composition).

[0189] Processes for preparing compounds of formula (I, (II), or (III) In certain embodiments, a compound of Formula (I), (II), (III), (V), (VI), (VII), (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50) can be prepared including one or more steps described in the Examples of this disclosure. The synthetic routes shown and described in the Examples can be used to prepare, for example, the compounds herein described in the Tables, and structurally related compounds.

[0190] Pharmaceutical Compositions and Formulations Some embodiments of the present invention include compositions comprising one or more compounds of the present invention (e.g., compounds of Formula (I), (II), (III), (V), (VI), (VII), (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)). 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 may be represented by Formula (I), (II), (III), (V), (VI), (VII), (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50), including a compound set forth in the tables, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. In some embodiments, the compound is set forth in any of the tables herein.

[0191] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound disclosed herein contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfate, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0192] The compounds disclosed herein may exist as salts with pharmaceutically acceptable acids, etc. Thus, the compounds contemplated herein include such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts containing amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0193] 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.

[0194] Pharmaceutically acceptable salts of the above compounds in which a basic or acidic group is present in the structure are also included within the scope of the compounds contemplated herein. When acidic substituents such as -NHSOH, -COOH, and -P(O)(OH) are present, ammonium, sodium, potassium, calcium salts, and the like can be formed for use as dosage forms. Acidic salts such as amino or basic heteroaryl radicals or pyridyl, and hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like can be used as dosage forms.

[0195] In embodiments where R—COOH is present, pharmaceutically acceptable esters may also be used, such as methyl, ethyl, tert-butyl, pivaloyloxymethyl, etc., and esters known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0196] In some cases, pharmaceutical compositions are non-toxic, do not cause side effects, or both, while in some embodiments, there may be inherent side effects (e.g., they may be harmful to the patient or may be toxic or harmful to some extent in some patients).

[0197] In some embodiments, one or more compounds of the present invention (e.g., compounds of Formula (I, (II), (III), (V), (VI), (VII), (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO), (Id-5010-WO), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO), (IIb-5010-WO), (IIIa-5010-WO) ), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)) can be part of the pharmaceutical composition and may be at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 80%, at least about 90%, at least about 100%, at least about 15 ... The amount may be at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, about 99.99% or less, 0.001% to about 99%, 0.001% to about 50%, about 0.1% to about 99%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%. In some embodiments, the pharmaceutical composition is in a dosage form suitable for topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, dermal, nasal, vaginal, or ocular administration routes. In other embodiments, the pharmaceutical composition may be presented in a form suitable for parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. The pharmaceutical composition may be, for example, a tablet, capsule, pill, granule, suspension, emulsion, solution, gel (including hydrogel), paste, ointment, cream, plaster, drench, delivery device, suppository, enema, injectable, implant, spray, aerosol, or other suitable form.

[0198] In some embodiments, the compounds disclosed herein can be orally administered as tablets, aqueous or oily suspensions, drops, lozenges, powders, granules, emulsions, capsules, syrups, or elixirs. Compositions for oral use can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to produce pharmaceutically elegant and palatable preparations. Thus, pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein are also provided.

[0199] In some embodiments, tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate; (2) granulating and disintegrating agents such as corn starch or alginic acid; (3) binders such as starch, gelatin, or acacia; and (4) lubricants such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used.

[0200] For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powder, tablets, pills, capsules, cachets, suppositories and dispersible granules.Solid carriers can be one or more substances that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0201] For in vivo applications, the compounds disclosed herein, in the form of free compounds or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts, can be administered parenterally by injection or by gradual perfusion over time. Administration can be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavity, or transdermal. For in vitro studies, the compounds can be added or dissolved in an appropriate biologically acceptable buffer and added to cells or tissues.

[0202] In powders, the carrier is a finely divided solid in admixture with the finely divided active component. In tablets, the active component is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0203] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound containing an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier, thereby associating it with the carrier. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0204] For preparing suppositories, a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein as by stirring, etc. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0205] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0206] When parenteral application is required or desired, particularly suitable mixtures for the compounds disclosed herein are injectable sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. These suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles, carriers, and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables. Specifically, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, etc. Ampoules are convenient unit doses. The compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical mixtures suitable for use in the pharmaceutical compositions and methods disclosed herein include, for example, those described in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of both of which are incorporated herein by reference.

[0207] In some embodiments, preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol, and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water, alcohol, glycerol, and polyols. Intravenous vehicles include fluid and nutrient replenishers. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose, and sodium chloride. Intravenous vehicles for lactated Ringer's include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, growth factors, and inert gases and the like.

[0208] Preservatives include antibacterial agents, antioxidants, chelating agents, and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions and non-toxic excipients, including salts, preservatives, buffers, etc., as described, for example, in Remington's Pharmaceutical Sciences, 15th ed., Easton: Mack Publishing Co., pp. 1405-1412, 1461-1487 (1975) and The National Formulary XIV., 14th ed., Washington: American Pharmaceutical Association (1975), the contents of which are incorporated herein by reference. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine techniques in the art. See, for example, Goodman and Gilman (eds.), 1990, The Pharmacological Basis for Therapeutics (7th ed.).

[0209] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers and thickeners as needed.Aqueous suspensions suitable for oral use can be prepared by dispersing finely divided active ingredients in water using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.Aqueous suspensions usually contain the active substance mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients may be (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; (2) dispersing or wetting agents which may be (a) a naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, e.g., polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, e.g., heptadecaethyleneoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, e.g., polyoxyethylene sorbitol monooleate; or (e) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, e.g., polyoxyethylene sorbitan monooleate.

[0210] Also included are solid form preparations intended to be converted immediately before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0211] Pharmaceutical preparations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form may be a packaged preparation, the package containing discrete amounts of preparations such as packets of tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or drop itself, or the appropriate number of any of these in packaged form.

[0212] In some embodiments, the pharmaceutical composition may include one or more formulation ingredients. A "formulation ingredient" may be any suitable ingredient (e.g., appropriate for the drug, drug dosage, drug release timing, disease state, or delivery route), and may include water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water containing chloroform), sugar (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made therefrom), ethanol, glycerol, glycol (e.g., propylene glycol), acetone, ether, DMSO, surfactant (e.g., anionic surfactant, cationic surfactant, zwitterionic surfactant, or The additives include, but are not limited to, non-ionic surfactants (e.g., polysorbates), oils (e.g., animal oils, vegetable oils (e.g., coconut oil or peanut oil), or mineral oils), oil derivatives (e.g., ethyl oleate, glyceryl monostearate, or hydrogenated glycerides), excipients, preservatives (e.g., cysteine, methionine, antioxidants (e.g., vitamins (e.g., A, E, or C), selenium, retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens (e.g., methylparaben or propylparaben)), or combinations thereof.

[0213] In certain embodiments, pharmaceutical compositions can be formulated to release the active ingredient (e.g., one or more compounds of the invention, such as Formula (I)) substantially immediately upon administration, or at any substantially predetermined time or time after administration. Such formulations can include controlled-release formulations, such as, for example, various controlled-release compositions and coatings.

[0214] Other formulations (eg, formulations of pharmaceutical compositions) may, in certain embodiments, include incorporating the drug (or controlled release formulation) into a food, foodstuff, feed, or beverage.

[0215] Some compounds may have limited water solubility and therefore may require a surfactant or other suitable cosolvent in the composition. Such cosolvents include polysorbates 20, 60, and 80, Pluronic® F-68, F-84, and P-103, cyclodextrin, and polyoxyl 35 castor oil. Such cosolvents are typically used at levels of about 0.01% to about 2% by weight.

[0216] A viscosity greater than that of a simple aqueous solution may be desirable to reduce variability in dispensing of the formulation, to reduce physical separation of the formulation's suspension or emulsion components, and / or to otherwise improve the formulation. Examples of such viscosity-enhancing agents include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing. Such agents are typically used at levels of about 0.01% to about 2% by weight.

[0217] The compositions disclosed herein may additionally contain components to provide sustained release and / or comfort. Such components include high molecular weight anionic mucus-mimetic polymers, gelling polysaccharides, and micronized drug carrier substrates. These components are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes.

[0218] Various pharmaceutical compositions useful for ameliorating certain diseases and disorders are provided. In one embodiment, pharmaceutical compositions are prepared by formulating the compounds disclosed herein in the form of free compounds, either alone or together with other pharmaceutical agents, or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts suitable for administration to a subject using carriers, excipients, and additives or adjuvants. Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol, and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water, alcohol, glycerol, and polyols. Intravenous vehicles include fluid and nutrient replenishers.

[0219] Various pharmaceutical compositions useful for ameliorating certain diseases and disorders are provided. In one embodiment, pharmaceutical compositions are prepared by formulating the compounds disclosed herein in the form of free compounds, either alone or together with other pharmaceutical agents, or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts suitable for administration to a subject using carriers, excipients, and additives or adjuvants. Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol, and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water, alcohol, glycerol, and polyols. Intravenous vehicles include fluid and nutrient replenishers.

[0220] Methods for treating and preventing diseases In addition to their ability to inhibit IRAK, IRAK inhibitors have been demonstrated to have selectivity over multiple kinases. In some embodiments, the compounds described herein have inhibitory activity against one or more kinases, such as interleukin-1 receptor-associated kinase (IRAK) and FMS-like tyrosine kinase 3 (FLT3). The inhibitory effect on one or more kinases, such as IRAK and FLT3, may enable the use of the compounds of the present invention (e.g., Formula (I)) to treat and / or prevent diseases in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cows, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans), including, but not limited to, hematopoietic cancers (e.g., disorders of hematopoietic stem cells in the bone marrow or disorders related to the myeloid lineage), MDS, AML, myeloproliferative disorders, and diseases (e.g., hematopoietic cancers) associated with mutations in IRAK1, IRAK4, and / or FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3-internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations).

[0221] In some embodiments, compounds of the present invention can inhibit the activity of one or more of FLT3, a FLT3 mutation (e.g., a FLT3 juxtamembrane region mutation, a FLT3 kinase domain mutation, a FLT3 point mutation, a FLT3 internal tandem duplication mutation, a FLT3-ITD mutation, a D835Y FLT3 mutation, a D835V FLT3 mutation, a F691L FLT3 mutation, or a R834Q FLT3 mutation), IRAK4 (interleukin-1 receptor-associated kinase 4), an isoform of IRAK4, a mutation of IRAK4, IRAK1 (interleukin-1 receptor-associated kinase 1), an isoform of IRAK1, and / or a mutation of IRAK1. In some embodiments, compounds of the present invention can inhibit the activity of one or both of FLT3 and FLT3 mutations (e.g., FLT3 juxtamembrane region mutations, FLT3 kinase domain mutations, FLT3 point mutations, FLT3 internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and optionally inhibit one or more of IRAK4, an isoform of IRAK4, a mutation of IRAK4, IRAK1, an isoform of IRAK1, or a mutation of IRAK1. In some embodiments, compounds of the present invention can inhibit the activity of one or both of FLT3 and FLT3 mutations (e.g., FLT3 juxtamembrane region mutations, FLT3 kinase domain mutations, FLT3 point mutations, FLT3 internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and optionally inhibit one or both of IRAK4 and IRAK1, or isoforms or mutations thereof. In some embodiments, compounds of the present invention can inhibit FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In one embodiment, compounds of the present invention are pan-FLT3 inhibitors. In one embodiment, compounds of the present invention are IRAK1, IRAK4, and pan-FLT3 inhibitors.

[0222] In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3 with an activity of 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 even greater. In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3 with an activity of 0.1 nM to 1 nM, e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 nM. In some embodiments, the compounds described herein exhibit inhibitory activity against IRAK and / or FLT-3 with an activity 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 in a variety of ways known in the art. Unless otherwise indicated, such terms, as used herein, are used in their customary sense (i.e., IC) to achieve half-maximal inhibition. 50 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 in a variety of ways known in the art. Unless otherwise indicated, such terms, as used herein, refer to IC in their customary sense (i.e., the concentration to achieve half-maximal inhibition). 50 Refers to...

[0223] In some embodiments, hematopoietic cancers that may be treated in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using the compounds of the invention (e.g., Formula (I)) include, but are not limited to, hematopoietic cancers and cancers of the myeloid lineage of blood cells, cancers at high risk of developing due to other blood disorders, cancers at high risk of developing due to chemical exposure (e.g., anti-cancer therapy or occupational chemical exposure), ionizing radiation (e.g., anti-cancer therapy), cancers progressing from myelodysplastic syndromes, cancers progressing from myeloproliferative disorders, and cancers of B cells.

[0224] In some embodiments, hematopoietic cancers that may be treated include, but are not limited to, MDS, AML, lymphoma, leukemia, myeloid cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., ABC DLBCL with a MYD88 mutation (e.g., L265P)), follicular lymphoma, or marginal zone lymphoma, or a combination thereof.

[0225] In some embodiments, cancers characterized by dysregulated IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling may be treated, including, but not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer, and the like, and combinations thereof.

[0226] In some embodiments, compounds of the present invention can be used to inhibit targets in the context of additional conditions characterized by overactive IRAK1 and / or IRAK4. According to certain aspects of the present invention, compounds of the present invention can be used to inhibit overactive IRAK1 and / or IRAK4 under conditions such as inflammatory and autoimmune diseases, which are characterized by overactive IRAK1 and / or IRAK4. In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling can be treated, including, but not limited to, chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, and the like, and combinations thereof.

[0227] In certain embodiments, MDS that may be treated in a subject (e.g., mammals, pigs, dogs, birds (e.g., chickens), cows, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the invention (e.g., Formula (I)) include MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations, refractory cytopenias with single lineage dysplasia (e.g., refractory cytopenias with single lineage dysplasia), and refractory cytopenias with single lineage dysplasia (e.g., refractory cytopenias with single lineage dysplasia). These conditions include, but are not limited to, refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ringed sideroblasts, and animals with pathological changes not limited to erythroid cells such as prominent proleukocyte and proplatelet (megakaryocyte) dysplasia), refractory anemia with excess blasts I and II, 5q-syndrome, megakaryocytic dysplasia with fibrosis, and refractory cytopenia in children. In some embodiments, MDS that may be treated include, but are not limited to, inherited MDS, MDS at high risk due to genetic predisposition, MDS at high risk due to other blood disorders, MDS at high risk due to chemical exposure, MDS at high risk due to ionizing radiation, MDS at high risk due to cancer treatment (e.g., radiation in combination with radiomimetic alkylating agents such as busulfan, nitrosoureas, or procarbazine (with a 5-7 year latency period), or DNA topoisomerase inhibitors), MDS progressing from acquired aplastic anemia and Fanconi anemia after immunosuppressive treatment, MDS at high risk due to splicing factor mutations, MDS at high risk due to isocitrate dehydrogenase 1 mutations, and MDS at high risk due to isocitrate dehydrogenase 2 mutations. Animals that may be treated include, but are not limited to, mammals, rodents, primates, monkeys (e.g., macaques, rhesus monkeys, pig-tailed monkeys), humans, dogs, cats, pigs, birds (e.g., chickens), cows, mice, rabbits, and rats. In the methods, the term "subject" can refer to both human and non-human subjects.In some cases, the subject is in need of treatment (eg, by exhibiting symptoms of disease or MDS, or by having low blood counts).

[0228] 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 invention (e.g., Formula (I)) include, but are not limited to, MDS that can be treated by inhibiting one or more of FLT3 (e.g., using an FLT3 inhibitor), FLT3 mutation (e.g., using an inhibitor of a FLT3 mutant), IRAK4 (e.g., using an IRAK4 inhibitor), IRAK4 mutation (e.g., using an inhibitor of an IRAK4 mutant), IRAK1 (e.g., using an IRAK1 inhibitor), and / or IRAK1 mutation (e.g., using an inhibitor of an IRAK1 mutant). In certain embodiments, MDS that can be treated include, but are not limited to, MDS that can be treated by inhibiting IRAK4 (or a mutation thereof), MDS that can be treated by inhibiting IRAK1 (or a mutation thereof), or MDS that can be treated by inhibiting IRAK4 (or a mutation thereof) and IRAK1 (or a mutation thereof). In some embodiments, MDS that can be treated include, but are not limited to, MDS that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for tumors that have FLT3 mutations that can be, or become, resistant to FLT3 inhibitors due to, for example, adaptive resistance mechanisms driven by IRAK.In some embodiments, MDS that may be treated is characterized by MDS with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or MDS that is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 Mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in Myeloid Malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entireties)).

[0229] In some embodiments, AML that may be treated in a subject (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the invention (e.g., Formula (I)) includes inherited AML, AML at high risk of development due to genetic predisposition, AML with one or more recurrent genetic abnormalities (e.g., AML with inversion or translocation, e.g., MLLT3 / MLL (“MLL”) with a translocation between chromosomes 9 and 11, AML with a translocation between chromosomes 8 and 21, and AML with a translocation between chromosomes 9 and 21). L, AML with translocation or inversion of chromosome 16, AML with translocation between chromosomes 9 and 11, APL with translocation between chromosomes 15 and 17 (M3), AML with translocation between chromosomes 6 and 9, AML with translocation or inversion of chromosome 3, etc.), AML with translocation between chromosomes 1 and 22 (megakaryoblastic), AML with myelodysplasia-related changes, AML related to previous chemotherapy or radiation (e.g., alkylating agent-associated AML, topoisomerase II inhibitor-associated AML, etc.), AML not elsewhere classified (see above). Not falling within the above categories (similar to the FAB classification), e.g., minimally differentiated AML (M0), AML with minimal maturation (M1), AML with maturation (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroleukemia (M6), acute megakaryoblastic leukemia (M7), acute basophilic leukemia, acute panmyelosis with fibrosis, etc.), myeloid sarcoma (also known as granulocytic sarcoma, chloroma, or extramedullary myeloblastoma), undifferentiated and mixed acute leukemia (also known as mixed phenotype acute leukemia), AML at high risk of development due to other blood disorders, and AML due to exposure to chemicals. AML with high risk of progression, AML with high risk of development due to ionizing radiation, AML progressing from myelodysplastic syndrome, AML progressing from myeloproliferative disorder, AML with high risk due to FLT3 mutation, AML with high risk due to FLT3 mutation in the juxtamembrane region of FLT3, AML with high risk due to FLT3 mutation of internal tandem duplication in the juxtamembrane region of FLT3, AML with high risk due to FLT3 mutation in the kinase domain of FLT3, AML with high risk due to FLT3 mutation D835Y, AML with high risk due to FLT3 mutation D835V,These include, but are not limited to, high-risk AML due to the FLT3 mutation F691L and high-risk AML due to the FLT3 mutation R834Q. In some embodiments, AML that can be treated includes AML by inhibiting one or more of FLT3 (e.g., using an FLT3 inhibitor), FLT3 mutation (e.g., using an inhibitor of an FLT3 mutant), IRAK4 (e.g., using an IRAK4 inhibitor), IRAK4 mutation (e.g., using an inhibitor of an IRAK4 mutant), IRAK1 (e.g., using an IRAK1 inhibitor), and / or IRAK1 mutation (e.g., using an inhibitor of an IRAK1 mutant). In certain embodiments, AML that can be treated includes, but is not limited to, AML that can be treated by inhibiting IRAK4 (or a mutation thereof), MDS that can be treated by inhibiting IRAK1 (or a mutation thereof), or AML that can be treated by inhibiting IRAK4 (or a mutation thereof) and IRAK1 (or a mutation thereof). In some embodiments, AML that may be treated includes, but is not limited to, AML that may be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that may be, or may become, resistant to FLT3 inhibitors due to, for example, adaptive resistance mechanisms driven by IRAK. In some embodiments, AML that may be treated is characterized as AML with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or AML that is not driven by FLT3 mutations but expresses IRAK4-Long based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g.,As described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 Mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in Myeloid Malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entirety).

[0230] In some embodiments, hematopoietic cancers that may be treated in a subject (e.g., mammal, pig, dog, bird (e.g., chicken), cow, cat, primate, rodent, monkey, rabbit, mouse, rat, and human) using a compound of the present invention (e.g., Formula (I)) include, but are not limited to, hematopoietic cancers (e.g., MDS, AML, DLBCL, etc., as described above) that may be treated by inhibiting (e.g., reducing the activity or expression of) one or more of FLT3 (e.g., using an FLT3 inhibitor), a mutation of FLT3 (e.g., using an inhibitor of a mutant FLT3), IRAK4 (e.g., using an IRAK4 inhibitor), an isoform of IRAK4, a mutation of IRAK4 (e.g., using an inhibitor of a mutant IRAK4), IRAK1 (e.g., using an IRAK1 inhibitor), an isoform of IRAK1, or a mutation of IRAK1 (e.g., using an inhibitor of a mutant IRAK1). In certain embodiments, hematopoietic cancers that may be treated include, but are not limited to, cancers that may be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof) and IRAK4 (or mutations thereof), or by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof) and IRAK1 (or mutations thereof), or by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof), IRAK4 (or isoforms or mutations thereof), and IRAK1 (or isoforms or mutations thereof). In some embodiments, hematopoietic cancers that may be treated include, but are not limited to, hematopoietic cancers that may be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that may be, or may become, resistant to FLT3 inhibitors due to, for example, adaptive resistance mechanisms driven by IRAK.In some embodiments, hematopoietic cancers that may be treated are characterized by hematopoietic cancers with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or hematopoietic cancers that are not driven by FLT3 mutations but express IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 Mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in Myeloid Malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entireties)).

[0231] In some embodiments, cancers that may be treated include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer, which may be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1, and combinations thereof. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that may be, or may become, resistant to FLT3 inhibitors due to, for example, adaptive resistance mechanisms driven by IRAK. In some embodiments, cancers that may be treated are characterized by cancers with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or cancers that are not driven by FLT3 mutations but express IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 Mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in Myeloid Malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entireties)).

[0232] In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling that can be treated include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, and the like, and combinations thereof, which can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In one embodiment, the inflammatory disease that can be treated is Crohn's disease or colitis. In one embodiment, the inflammatory disease that can be treated is atopic dermatitis. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 treats inflammatory and autoimmune diseases with FLT3 mutations that may be resistant or become resistant to FLT3 inhibitors, e.g., due to adaptive resistance mechanisms driven by IRAK. In some embodiments, inflammatory and autoimmune diseases that may be treated are characterized by inflammatory and autoimmune diseases having enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or inflammatory and autoimmune diseases that are not driven by FLT3 mutations but express IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692 and Smith, MA, et al. (2019). "U2AF1 Mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in Myeloid Malignancies." Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5 (both of which are incorporated by reference in their entireties)).

[0233] In relation to the treatment of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2), treatment can include, but is not limited to, prophylactic and therapeutic treatments. Thus, treatments include preventing MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS), reducing the risk of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS), improving or alleviating the symptoms of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS), inducing a physical response to MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS), and improving or alleviating the symptoms of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS). inhibiting the onset or progression of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); inhibiting or preventing the onset of symptoms associated with MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); reducing the severity of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); causing regression of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) or one or more symptoms associated with MDS (e.g., increased blood counts);These effects may include, but are not limited to, causing remission of MDS (e.g., MDS with a splicing factor mutation, MDS with a isocitrate dehydrogenase 1 mutation, or MDS with a isocitrate dehydrogenase 2 mutation) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations), preventing the recurrence of MDS (e.g., MDS with a splicing factor mutation, MDS with a isocitrate dehydrogenase 1 mutation, or MDS with a isocitrate dehydrogenase 2 mutation), or preventing the recurrence of MDS (e.g., MDS with a splicing factor mutation, MDS with a isocitrate dehydrogenase 1 mutation, or MDS with a isocitrate dehydrogenase 2 mutation) in animals or humans with intrinsic or acquired resistance to other MDS therapies. In some embodiments, treating does not include prophylactic treatment of MDS (e.g., preventing or ameliorating future MDS).

[0234] In relation to the treatment of hematopoietic cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow carcinoma, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation (e.g., ABC DLBCL with MYD88 mutation L265P), follicular lymphoma, or marginal zone lymphoma, and combinations thereof), treatment can include, but is not limited to, prophylactic and therapeutic treatments. Thus, treatment includes preventing cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, 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), and treating cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof). reducing the risk of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, 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); ameliorating or alleviating symptoms of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); inhibiting the onset or progression of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, 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 or preventing the onset of symptoms associated with cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, 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); inhibiting or preventing the onset of symptoms associated with cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, 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); reducing the severity of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof), causing regression of one or more symptoms associated with cancer (e.g., reduction in tumor size), and inducing remission of cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof), by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations). inducing remission of acute myeloid leukemia by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations); inducing remission of cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); inducing remission of acute myeloid leukemia by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations);Examples of the therapeutic effects of the present invention may include, but are not limited to, preventing the recurrence of cancer (such as acute myeloid leukemia, lymphoma, leukemia, myeloid cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof) in animals with intrinsic or acquired resistance to other cancer therapies (e.g., from some FLT3 inhibitors or from MLL), or preventing the recurrence of acute myeloid leukemia in animals with intrinsic or acquired resistance to other cancer therapies (e.g., from some FLT3 inhibitors or from MLL). In some embodiments, treating does not include prophylactic treatment of cancer (e.g., preventing or ameliorating future cancer).

[0235] Treatment of a subject can be carried out using any suitable administration method (such as those disclosed herein) and using any suitable amount of a compound of the invention (e.g., Formula (I)). In some embodiments, the method of treatment includes treating an animal or human for MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2). In some embodiments, the method of treatment includes treating an animal or human for a hematopoietic cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.). Other embodiments include following one or more of: having a blood disorder, having a myelodysplastic syndrome, having a myeloproliferative disorder, developing a chemical exposure, exposure to ionizing radiation, or treatment for a hematopoietic cancer (e.g., chemotherapy, ionizing radiation, or both). Some embodiments of the present invention include methods for treating a subject (e.g., an animal such as a human or a primate) with a composition (e.g., a pharmaceutical composition) comprising a compound of the present invention (e.g., Formula (I)), which comprises one or more administrations of one or more such compositions, which, if there are two or more administrations, may be the same or different.

[0236] In some embodiments, the method of treatment comprises administering to a subject an effective amount of a composition comprising a compound of the present invention (e.g., Formula (I), (II), (III), (V), (VI), (VII), (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)). As used herein, the term "effective amount" refers to a dose or series of doses sufficient to affect therapy in a subject (e.g., for treating MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations), or for treating a hematopoietic cancer, such as, but not limited to, acute myeloid leukemia, lymphoma, leukemia, myeloid carcinoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutations, follicular lymphoma, or marginal zone lymphoma, and combinations thereof). In some embodiments, an effective amount can encompass a therapeutically effective amount disclosed herein. In certain embodiments, the effective amount can vary depending on the subject and the particular treatment being affected. The exact amount required may vary from subject to subject, depending, for example, on the age and general condition of the subject, the particular adjuvant (if any) used, the administration protocol, etc. Thus, the effective amount may vary, for example, based on the particular circumstances, and an appropriate effective amount may be determined in each particular case. An effective amount may include, for example, any of the dosages or composition amounts disclosed herein.In some embodiments, an effective amount of at least one compound of the present invention (which may be administered to a subject, such as a mammal, primate, monkey, or human) may 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 dosage may 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 invention (e.g., Formula (I), including, but not limited to, compounds 1-77, 209-214, and 1a-115a as listed in Tables 1, 6, and 49) (which may be administered to a subject, such as a mammal, rodent, mouse, rabbit, cat, pig, or dog) is about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight. , about 0.1 to about 10 mg / kg body weight, about 0.5 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 invention (which may be administered to an animal, such as a mammal, primate, monkey, or human) may be an amount of 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 dosage may be about 20 mg / kg human body weight or about 100 mg / kg human body weight. In some cases, an effective amount of at least one compound of the present invention (which may be administered to an animal such as a mammal, rodent, mouse, rabbit, cat, pig, or dog) may be an amount of 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.

[0237] In some embodiments, treatment may also include one or more of surgical intervention, chemotherapy, radiation therapy, hormone therapy, immunotherapy, and adjuvant systemic therapy. Adjuvants may include, but are not limited to, chemotherapy (e.g., temozolomide), radiation therapy, antiangiogenic therapy (e.g., bevacizumab), and hormone therapy such as administration of LHRH agonists, antiestrogens such as tamoxifen, high-dose progestogens, aromatase inhibitors, and / or adrenalectomy. Chemotherapy may be used as a single agent or in combination with known or new therapies.

[0238] In some embodiments, administration of at least one compound of the present invention (e.g., Formula (I)) to a subject is an adjuvant cancer therapy or part of an adjuvant cancer therapy. Adjuvant therapy includes the treatment of cancers disclosed herein, including but not limited to tumors, by the mechanisms disclosed herein. Corresponding primary therapy may include, but is not limited to, surgery, chemotherapy, or radiation therapy. In some cases, adjuvant therapy may be a combination of a chemokine receptor antagonist with a conventional chemotoxic agent or with immunotherapy, which may enhance treatment specificity for cancer and limit additional systemic side effects. In yet other embodiments, a compound of the present invention (e.g., Formula (I)) may be used as an adjuvant with other chemotherapeutic agents. The use of a compound of the present invention (e.g., Formula (I)) may, in some cases, reduce the duration of the dose of both the drug and the drug combination, reducing side effects.

[0239] In some embodiments, administration to a subject may reduce the incidence of one or more symptoms associated with MDS / AML / certain types of hematopoietic cancer, hi some embodiments, administration may reduce bone marrow failure, immune dysfunction, transformation to overt leukemia, or a combination thereof in the subject compared to a subject who does not receive the composition.

[0240] In some embodiments, the method may reduce a marker of viability of MDS cells or cancer cells in the subject. In one aspect, the method may reduce a marker of viability of MDS, AML, and / or cancer cells. The marker may be selected from survival over time, proliferation, growth, migration, colony formation, chromosome assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or a combination thereof.

[0241] Combination therapy In one embodiment, a compound of Formula (I) is administered with one or more therapeutic agents. Exemplary therapeutic agents include, but are not limited to, CDK inhibitors, BCL2 inhibitors, PTEFb inhibitors, DNA polymerase inhibitors, cytidine deaminase inhibitors, DNA methyltransferase (DNMT) inhibitors, immunomodulatory imides, cereblon modulators, purine nucleoside antimetabolites, type II topoisomerase inhibitors, DNA intercalators, hedgehog antagonists, IDH2 inhibitors, IDH1 inhibitors, ribonucleotide reductase inhibitors, adenosine deaminase inhibitors, Mek1 / 2 inhibitors, ERK1 / 2 inhibitors, AKT inhibitors, PTPN11 inhibitors, SHP2 inhibitors, glucocorticoid steroids, menin inhibitors, MDM2 inhibitors, BTK inhibitors, and mutated / inactivated p53 reactivators.

[0242] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a salt thereof. In one embodiment, the therapeutic agent comprises a DNA polymerase inhibitor. In one embodiment, the DNA polymerase inhibitor is cytidine. In one embodiment, the therapeutic agent comprises a cytidine deaminase inhibitor. In one embodiment, the cytidine deaminase inhibitor is zebularine. In one embodiment, the therapeutic agent comprises a DNMT inhibitor. In one embodiment, the DNMT inhibitor is zebularine, decitabine, or 5-azacytidine. In one embodiment, the therapeutic agent comprises an immunomodulatory imide (cereblon-modulating agent). In one embodiment, the immunomodulatory imide (cereblon-modulating agent) is lenalidomide. In one embodiment, the therapeutic agent comprises a purine nucleoside antimetabolite. In one embodiment, the purine nucleoside antimetabolite is clofarabine. In one embodiment, the therapeutic agent comprises a type II topoisomerase inhibitor / DNA intercalator. In one embodiment, the type II topoisomerase inhibitor / DNA intercalator is vosaroxin. In one embodiment, the therapeutic agent comprises a hedgehog antagonist. In one embodiment, the hedgehog antagonist is glasdegib. In one embodiment, the therapeutic agent comprises an IDH1 inhibitor. In one embodiment, the IDH1 inhibitor is ivosidenib. In one embodiment, the therapeutic agent comprises an IDH2 inhibitor. In one embodiment, the IDH2 inhibitor is enasidenib. In one embodiment, the therapeutic agent comprises a ribonucleotide reductase inhibitor. In one embodiment, the ribonucleotide reductase inhibitor is gemcitabine. In one embodiment, the therapeutic agent comprises an adenosine deaminase inhibitor. In one embodiment, the adenosine deaminase inhibitor is cladribine. In one embodiment, the therapeutic agent comprises a Mek1 / 2 inhibitor. In one embodiment, the Mek1 / 2 inhibitor is trametinib. In one embodiment, the therapeutic agent comprises an ERK1 / 2 inhibitor. In one embodiment, the ERK1 / 2 inhibitor is ulixertinib. In one embodiment, the therapeutic agent comprises an AKT inhibitor. In one embodiment, the AKT inhibitor is capivasertib (AZD5363). In one embodiment, the therapeutic agent comprises a PTPN11 / SHP2 inhibitor.In one embodiment, the PTPN11 / SHP2 inhibitor is TNO-155. In one embodiment, the therapeutic agent comprises a glucocorticoid steroid. In one embodiment, the glucocorticoid steroid is prednisolone. In one embodiment, the therapeutic agent comprises a menin inhibitor. In one embodiment, the menin inhibitor is SNDX-5613. In one embodiment, the therapeutic agent comprises an MDM2 inhibitor. In one embodiment, the MDM2 inhibitor is nabtemadrine (AMG 232, KRT-232). In one embodiment, the therapeutic agent comprises a BTK inhibitor. In one embodiment, the BTK inhibitor is selected from ibrutinib, acalabrutinib, and zanubrutinib. In one embodiment, the therapeutic agent comprises a mutated / inactivated p53 reactivator. In one embodiment, the mutated / inactivated p53 reactivator is eprenetapopt (APR-246).

[0243] In one embodiment, the therapeutic agent comprises a CDK inhibitor. The CDK inhibitor can be any CDK inhibitor known to those skilled in the art. In one embodiment, the CDK inhibitor is a CKD1, CKD2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13 inhibitor, or a combination thereof.

[0244] In one embodiment, the CDK inhibitor comprises an inhibitor described in one of the following patents or patent applications: US 20210332071, US 20210330653, WO 2021214253, WO 2021178595, WO 2021207632, US 8685660, US 20200361906, US 10695346, US 11142507, WO 2021198439, WO 2021201170, US 8153632, US 11013743, US 11135198, US 20210299111, WO 2021190637, WO 2021188855, WO 2021188849, US 20210292299, US 11124836, US 10961527, US 20210284629, US 20210283265, WO 2021183994, WO 2021181233, US 11116755, WO 2021176045, WO 2021177816, WO 2021176049, WO 2021176349, US 20210275522, US 20210275491, US 20210277037, US 11111250, WO 2021142448, WO 2021172359, WO 2021174195, US 20210260209, US 20210261609, US 20210261636, US 20210261546, WO 2021168341, US 11014911, US 9932344, US 8415355, US 11091485, US 11091490, US 20210246422, US 20210246138, US 20210244715, US 11083722, US 11083728, US 20210238226, US 20190142835, WO 2021155006, WO 2021152107, WO 2021155192, US 10294234, US 11077156, WO 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2002100401, US 6486166, WO 2002072085, US 6462069, US 6451618, US 6420345, WO 2002051849, US 6413974, US 6414013, US 6407103, WO 2001083716, US 5672508, US 6291504, WO 2001038532, W.O. 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R. et al., Pharmacology & Therapeutics,2017,173:83-105, Chou, J. et al., Cancer Discovery,2020,10:351-370, Galbraith, MDetal., Transcription, 2019, 10(2):118-136; Goel, B. et al., Current Topics in Medicinal Chemistry, 2020, 20:1535-1563; Heptinstall, A.B. et al., Future Medicinal Chemistry, 2018, 10(11):1369-1388 (each of which is incorporated by reference in its entirety).

[0245] In one embodiment, the CDK inhibitor is a CDK9 inhibitor. In one embodiment, the CDK9 inhibitor is atubeciclib (BAY-1143572) or BAY-1251152 (VIP152). In one embodiment, BAY-1251152 (VIP152) is a selective CDK9 inhibitor, while atubeciclib (BAY-1143572) is a CDK9 / PTEFb inhibitor. In one embodiment, the CDK inhibitor is a CDK4 / 6 inhibitor. In one embodiment, the CDK4 / 6 inhibitor is palbociclib. In one embodiment, the CDK inhibitor is a CDK7 inhibitor. In one embodiment, the CDK7 inhibitor is THZ1.

[0246] Exemplary CDK inhibitors include, but are not limited to, Compound 21 (PMID 27326333), CYC065, YKL-1-116, i-CDK9, JH-VII-49, JH-XI-10-02, SEL120-34A, MM-D37K, PF-06873600, BEY-1007, BEY-1107, vilociclib (XZP-3297), FCN-437, TP-1287, BEBT-209, TQB-3616, AMG-925 (FLX -925), CS3002, HS-10342, Terameprocol (EM-1421), NU-6102, CGP-60474, BMS-265246, NU-6027, Purvalanol A, Purvalanol B, RGB-286147, Indirubin, 7-hydroxystaurosporine, BS-194, PHA-690509, Cdk4 / 6 inhibitor IV, FCN437c, [ka]

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[0247] [ka] (Wherein, Ar is [ka] ),

[0248] [ka] wherein X is N, Y is —C(═O)H, and Ar is [ka] X is N, Y is —CHOH, and Ar is [ka] or X is CH, Y is —CHOH, and Ar is [ka] ), [ka] wherein X is NH or O; [ka] wherein X is NH or O; [ka] (Wherein R1 is [ka] ), [ka] wherein R is H or -CH3; [ka] wherein R is -CH3, X is F, R is H, and X is F, or R is -CH3, and X is Cl; [ka] wherein R is tetrahydro-pyran-4-yl and R' is H, or R is -CHCH and R' is -OCH, or R is isopropyl and R' is H, or R is -CHCH and R' is F, [ka] wherein R is t-butylcarboxyl and n is 1, or R is H and n is 2; [ka] wherein X is NH or O; [ka] wherein R is H and R' is F, or R is F and R' is F, or R is H and R' is H, [ka] wherein R is -OCH3 and R' is F, or R is F and R' is SF5, or R is -OCH3 and R' is -SF5, [ka] wherein R is F and R' is -CH3, or R is -SF5 and R' is H; [ka] wherein R is —CF and R′ is —CH, or R is H and R′ is cyclopropyl; [ka] wherein R is 3-fluoroailin-1yl and R' is F, or R is phenyl and R' is -CH; [ka] wherein R is H or F, and alkyl is —CH or —CHCH, [ka] wherein R is 3-fluorophenyl or morpholin-4-yl; [ka] wherein R is cyclopropan-1-ol-1-yl, X is Cl, and n is 1, or R is tetrahydrofuran-3-yl, X is Cl, and n is 1, or R is -CH3, X is F, and n is 2, or R is cyclopropan-1-1-yl, X is F, and n is 1, or oxatan-3-yl, X is -CH3, and n is 1, [ka] wherein R is 1,2-oxazol-3yl or 3,4-difluorobenzene-1yl, [ka] wherein R is H, C(=O)NHCH3, -SO2NH2, SO2CH3, or 2,3-dihydroxpropan-1yl; [ka] wherein R is H, CH, 2-aminoethyan-1yl, 3-aminopropan-1yl, or 2,3-dihydroxpropan-1yl; [ka] wherein R is H or -CH3; [ka] wherein R is H, C(=O)NHCH3, or -SO2CH3; [ka] wherein R is 3-fluorobenzyl or 3-fluoropyridin-3yl, [ka] wherein aryl is 4-fluorophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 4-methylphenyl, 2-ethylphenyl, or 3-pyridyl, and R is H, cyclopropyl, cyclopentyl, or cycloheptyl; [ka] wherein R is 2-phenylethan-1yl or (furan-2-yl)methyl; [ka] wherein R is H or —C(═O)CHOH, [ka] wherein R is —NHC(═O)CH or —NHSOCH, [ka] wherein R is H or isobutyl; [ka] wherein R is H and R' is -CH3, or R is -CN and R' is H; [ka] wherein R is 3,4-dimethyl-1H-pyrazol-4-yl and R' is -CH3, or R is piperazin-1yl and R' is H, [ka] wherein R is 2,6-dichlorophenyl, 2,3,4,5,6-tetrafluorophenyl, or 3-fluorophenyl; [ka] wherein R is —CHNCH or H, [ka] wherein R is —CHN(CH) or H; [ka] wherein R is H, —SO2CH3, —CH2C(═O)N(CH3)2, 4-carboxylic acid-cyclobutan-1yl, or (2(hydroxymethy)pyrrolidin-1-yl)-2-one-ethan-1yl, R′ is H or F, and R″ is H or —CH2CH3, [ka] (wherein R1 is -OH, R2 is H, R3 is H, and R4 is H (meridianin A), R1 is -OH, R2 is H, R3 is Br, and R4 is H (meridianin B), R1 is H, R2 is Br, R3 is H, and R4 is H (meridianin C), R1 is H, R2 is H, R3 is Br, and R4 is H (meridianin D), or R1 is -OH, R2 is H, R3 is H, and R4 is Br (meridianin E)), HH, and [ka] wherein R is piperidin-3yl, pyrrolidin-3yl, or morpholin-2yl.

[0249] In one embodiment, the therapeutic agents comprise a BCL2 inhibitor and a DNMT inhibitor. In one embodiment, the therapeutic agents comprise venetoclax, or a salt thereof, and 5-azacytidine, or a salt thereof.

[0250] In some embodiments, the treatments disclosed herein may include the use of other drugs (e.g., antibiotics) or therapies to treat diseases, such as MDS / AML / certain types of hematopoietic cancer. For example, antibiotics can be used to treat infections and can be used in combination with the compounds of the present invention to treat diseases (e.g., infections). In other embodiments, intravenous immunoglobulin (IVIG) therapy can be used as part of a treatment regimen (i.e., in addition to administering the compounds of the present invention). For example, treatment regimens for various types of cancer may involve one or more elements selected from chemotherapy, targeted therapy, alternative therapy, immunotherapy, etc.

[0251] Thus, in some embodiments, the compounds and / or compositions described herein may be used in combination with one or more BCL2 inhibitors, BTK inhibitors, chemotherapy, targeted therapy, replacement therapy, immunotherapy, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (anti-metabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or the like, or one or more combinations thereof, in one or more administrations to a subject, and the compositions, if there are two or more administrations, may be the same or different. In some embodiments, when there is more than one administration, at least one composition used in at least one administration is different from the composition in at least one other administration. In one embodiment, a composition comprising a compound of Formula (I), (II), or (III) is administered to a subject separately from a composition comprising a therapeutic agent described elsewhere herein.

[0252] Specifically, IRAK inhibitors have been demonstrated to have synergistic effects when administered in combination with apoptosis regulators / inhibitors, such as BCL2 inhibitors. As described in U.S. Patent Publication No. 2020 / 0199123 (incorporated herein by reference in its entirety), exemplary apoptosis / BCL2 inhibitors have been shown to have synergistic effects when used in combination with exemplary IRAK inhibitors in multiple AML cell lines. Venetoclax was used as a representative apoptosis / BCL2 inhibitor.

[0253] When the concentration of an exemplary IRAK inhibitor was combined with venetoclax, the efficacy of venetoclax increased by approximately 50-fold, an unexpectedly high level. According to certain aspects of the present invention, this synergistic combination allows for increased efficacy of venetoclax at lower doses, avoiding at least some of the toxicity observed in clinical trials. According to certain aspects, the extent of the interaction depends on the dose ratio combination used, with lower concentrations of the exemplary IRAK inhibitor providing a greater shift in the venetoclax IC50. This unexpected and dramatic shift in the venetoclax IC50 is substantially greater than an additive response, demonstrating the unexpected synergistic interaction of the two drugs, even in cell lines that do not express activating FLT3 mutants.

[0254] Accordingly, the present invention encompasses methods for treating a disease or disorder responsive to inhibition of IRAK, the methods comprising administering to a subject a composition comprising an IRAK inhibitor compound, and some embodiments of the methods may further involve administering an apoptosis-modulating agent. The apoptosis-modulating agent may comprise a BTK inhibitor and / or a BCL2 inhibitor. The BTK inhibitor and BCL2 inhibitor may, for example, be those known in the art. In some embodiments, the method may comprise administering to the subject an apoptosis-modulating agent. In some embodiments, the apoptosis-modulating agent may comprise a BCL2 inhibitor selected from ABT-263 (navitoclax), ABT-737, ABT-199 (venetoclax), GDC-0199, GX15-070 (obatoclax) (all available from Abbott Laboratories), HA14-1, S1,2-methoxyantimycin A3, gossypol, AT-101, apogossypol, WEHI-539, A-1155463, BXI-61, BXI-72, TW37, MIM1, UMI-77, and the like, and combinations thereof. One of skill in the art will appreciate that there are many known BCL2 inhibitors that may be used in accordance with the present invention. In some embodiments, the BCL2 inhibitor comprises venetoclax.

[0255] 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.

[0256] In some embodiments, the IRAK inhibitor compound is selected from compounds 1-77, 209-214, 1a-115a, or a salt, isomer, derivative, or analog thereof, and the BCL2 inhibitor is venetoclax, or a salt, isomer, derivative, or analog thereof.

[0257] In some embodiments, the method may further involve administering to the subject an immunomodulatory agent. The immunomodulatory agent may include, for example, lenalidomide (Revlimid, Celgene Corporation). In some embodiments, the method may involve administering an epigenetic modulating agent. The epigenetic modulating agent may include, for example, a hypomethylating agent such as azacitidine, decitabine, or a combination thereof.

[0258] In some embodiments, the compounds and / or compositions described herein may be used with or in combination with one or more BTK inhibitors, such as, for example, ibrutinib, or salts, isomers, derivatives, or analogs thereof, in one or more administrations to a subject.

[0259] For example, the compounds and / or compositions described herein may be used in combination with DNA methyltransferase inhibitors / hypomethylating agents such as, for example, azacitidine, decitabine, cytarabine (ara-C, cytosine arabinoside), and / or guadecitabine; anthracyclines such as, for example, daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a fixed 5:1 molar ratio combination of cytarabine and daunorubicin); histone deacetylase (HDAC) inhibitors such as, for example, vorinostat, panobinostat, valproic acid, and / or pracinostat; purine nucleoside analogs (anti-metabolites) such as, for example, fludarabine, cladribine, and / or clofarabine; Perspectives, 2019, 35:160-166 (incorporated herein by reference), AGI-6780, BAY1436032, FT-2102, IDH305, AGI-5198, ML309 (AGI-5027), GSK 321, and DC_H31, and / or enasidenib (idohifa; for further information, see Dugan, J. et al., Expert Review of Clinical isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, such as, for example, CD33 (e.g., Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin), and / or antibody-drug conjugates, such as anti-CD45 (e.g., I131-apamistamab), for example, anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123×CD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab, for further information see Salman, DA et al., Blood, 2019, 134:569 (incorporated herein by reference); Plk inhibitors such as, for example, volasertib and / or rigosertib; MEK inhibitors such as, for example, trametinib, cobimetinib, selumetinib, pimasertib, and / or refametinib; CDK inhibitors such as, for example, albociclib, atubeciclib, palbociclib, ribociclib, and / or zotiraclib; CDK9 inhibitors such as, for example, alvocidib, Bay 1143572, dinaciclib (SCH 727965), SNS-032 (BMS-387032), TG02, CDKI-73 (LS-007), LY2857785, and / or voruciclib (for more information on CDK9 inhibitors, see Boffo, S. et al. al., Journal of Experimental & Clinical Cancer Research, 2018, 37:36 (incorporated herein by reference); CDK8 inhibitors such as SEL120; retinoic acid receptor agonists such as ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist), tamibarotene, adapalene, bexarotene; APR-246 (eprenetapopt, for further information see Ceder, S. et al. al., EMBOMol. Med., 2021, 13:e10852 (incorporated herein by reference)), TP53 activators (including non-functional mutant TP53 activators) such as APR-548, RETRA, and / or PC14586; CELMoDs such as lenalidomide, pomalidomide, CC-92480, CC-90009, avadomide, and / or iveldomide; smoothened receptor antagonists such as glasdegib; ERK inhibitors such as ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, e.g., ulixertinib (for further information, see Sullivan, RJ et al., Cancer Discovery, 2018 8:185-195 (incorporated herein by reference), SCH772984, ravoxertinib, MK-8353, PD98059, and / or VTX-11e; PI3K inhibitors such as, for example, copanlisib, gedatolisib, pictilisib, fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); for example, onatasertib, sirolimus, temsirolimus, bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, mTOR inhibitors, such as riboflavin (AP-23573), everolimus, and / or bistusertib (AZD2014); steroid or glucocorticoid receptor modulators, such as agonists including prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or antagonists including mifepristone, myricholant, and / or onapristone, and / or another binding ligand including vamorolone (VBP15); and / or EZH2 inhibitors, such as tazemetostat, may be used in one or more doses. In some embodiments, the compounds and pharmaceutical compositions containing them, when used in combination with EZH2 inhibitors, may be used in the prevention of secondary malignancies.

[0260] In one embodiment, the compounds and / or compositions described herein are selected from the group consisting of hedgehog (Hh) inhibitors such as, for example, daurismo (glasdegib maleate; for more information, see Wolska-Washer, A. et al., Future Oncology, 2019, 15:3219-3232, incorporated herein by reference), vismodegib, erismodegib, elibage, sonidegib, odomzo, slidegib, exerex, and / or taladegib; BCL-2 inhibitors such as venetoclax (vencrexita), navitoclax, WEHI-539, and / or A-1331852; decitabine (for more information, see Stresemann, C. International Journal of Cancer, 2008, 123:8-13 (incorporated herein by reference)) or cytarabine (for further information, see Lowenberg, B. et al., N. Engl. J. Med., 2011, 364:1027-1036 (incorporated herein by reference)); topoisomerase I inhibitors such as topotecan and / or irinotecan; topoisomerase II inhibitors such as mitoxantrone, doxorubicin, and / or daunorubicin; bestatin (ubenimex, for further information, see Hitzerd, S. M. et al., Amino Acids, 2009, 123:8-13 (incorporated herein by reference)); Acids, 2014, 46:793-808 (incorporated herein by reference)), ubenimex, and / or aminopeptidase / leukotriene A4 hydrolase inhibitors such as tosedostat; Xospata (gilteritinib, for more information see Dhillon, S., Drugs, 2019, 79:331-339 (incorporated herein by reference)) and / or FLT3 / Axl / ALK inhibitors such as ASP2215; Ridapt (midostaurin, for more information see Sheridan, C., Nature Biotechnology, 2017, 35:696-698 (incorporated herein by reference)); Syk inhibitors such as fostamatinib (R788), entospletinib (GS-9973, for further information see Walker, A. R. et al., Blood, 2016, 128:2831 (incorporated herein by reference)), celdulatinib (PRT062070), and / or TAK-659; E-selectin inhibitors such as uproleselan (for further information see Barbier, V. et al., Nature Commun., 2020, 11:2042); pevonedistat (for further information see Swords, R. T. et al., British J. Haematology, 2015, 169: NEDD8 activators such as idasanutlin (for further information see Lehmann, C. et al., Journal of Hematology & Oncology, 2016, 9:50, which is incorporated herein by reference); MDM2 inhibitors such as AMG-232 and / or CGM-097; PLK1 inhibitors such as onvansertib, BI2536, and / or volasertib (for further information see Van den Bossche, J. et al., Medicinal Research Reviews, 2016, 36:749-786, which is incorporated herein by reference); alisertib (MLN8237, for further information see Goldberg, S. et al.,, Leukemia Research Reports, 2014, 3:58-61 (incorporated herein by reference); Aura inhibitors such as MLN8054, TAS-119, and / or erbumine (LY3295668); Aurora kinase inhibitors such as alisertib, danusertib, balacertinib, and / or ilorasertib; EGFR inhibitors such as erlotinib, dacomitinib, and / or valitinib; ilorasertib (ABT-348; for more information, see Garcia-Manero, G. et al., Investigational New Drugs, 2015, 33:870-880 (incorporated herein by reference); Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors such as uprosertib (for further information, see Darici, S. et al., J. Clin. Med., 2020, 9:2934 (incorporated herein by reference)); afuresertib (GSK2110183), CCT128930, milansertib (ARQ AKT1, 2, and / or 3 inhibitors such as capivasertib (AZD5363), GSK690693, ipatasertib (GDC-0068), BAY1125976, and / or oridonin (NSC-250682); ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors such as dasatinib; tipifarnib (for more information, see Epling-Burnette, P.K. et al., Expert Opinion on Investigational Drugs, 2010, 19:689-698 (incorporated herein by reference)), farnesyltransferase inhibitors such as lonafarnib, manumycin A, gingerol, gliotoxin, and / or alpha-hydroxyfarnesyl phosphate; BRAF / MAP2K1 / MAP2K2 inhibitors such as trametinib; Ko-539 and / or SNDX-5613 (for more information on Ko-539 and / or SNDX-5613, see Gundry, MC et al., Cancer Cell, 2020, 37:267-269 (incorporated herein by reference); antimetabolites such as cytarabine, floxuridine, 5-fluorouracil, prexasertib, raltitrexed, and / or methotrexate; and / or multikinase inhibitors such as dasatinib.

[0261] In one embodiment, the compounds and / or compositions described herein are used in one or more doses with or in combination with lenalidomide, a highly effective treatment for myelodysplastic syndrome (MDS) associated with deletion of chromosome 5q (del(5q)). Lenalidomide induces ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4CRBN), resulting in CK1α degradation. CK1α is encoded by a gene within the common deletion region for del(5q) MDS, and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for lenalidomide's therapeutic window in del(5q) MDS. In one embodiment, the compounds and / or compositions described herein are used in one or more doses with or in combination with cytarabine (ara-C, cytosine arabinoside), which has been used for over 30 years to treat acute myeloid leukemia (AML). It was first used in remission induction therapy at a dose of 100-200 mg per square meter of body surface area. From approximately 1975 to 1985, investigators began evaluating the use of high-dose cytarabine therapy, administered at a dose of 3000 mg per square meter twice daily for six days. In single-arm studies, high response rates were observed among patients with relapse, and promising results were reported for patients with a new diagnosis of AML. However, more recent studies have demonstrated that induction therapy with lower doses of cytarabine already produces maximal anti-leukemia effects for all response endpoints, suggesting a plateau in the dose-response relationship above this dose level, and thus suggesting that high doses of cytarabine produce excessive toxic effects without therapeutic benefit. In one embodiment, the compounds and / or compositions described herein are used in one or more doses with or in combination with a hypomethylating agent, such as azacitidine, decitabine, and / or vencrexitabine. DNA methylation is the modification of DNA nucleotides by the addition of methyl groups. Hypomethylating agents (or demethylating agents) are drugs that inhibit DNA methylation.Because DNA methylation affects cellular function throughout successive generations of cells without altering the underlying DNA sequence, hypomethylating agents are considered a type of epigenetic therapy. Currently available hypomethylating agents block the activity of DNA methyltransferase (DNA methyltransferase inhibitors / DNMT inhibitors). Two members of this class, azacitidine and decitabine, have been approved by the FDA for use in myelodysplastic syndromes in the United States. Azacitidine, marketed as Vidaza, is primarily used to treat myelodysplastic syndromes and was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2004. In two randomized controlled trials comparing azacitidine with supportive care, 16% of subjects with myelodysplastic syndromes randomized to receive azacitidine had complete or partial normalization of blood counts and bone marrow morphology compared with zero subjects receiving supportive care, and approximately two-thirds of patients who required blood transfusions no longer required transfusions after receiving azacitidine. Azacitidine can also be used as a hypomethylating agent to treat acute myeloid leukemia. Decitabine has shown significant clinical benefit in the treatment of myelodysplastic syndromes (MDS) by depleting DNA methyltransferase enzymes and inducing DNA demethylation and epigenetic reprogramming in vitro. Vencrexitabine is a selective small molecule inhibitor of the anti-apoptotic protein BCL-2. Overexpression of BCL-2 in cancer cells is associated with tumor cell survival and resistance to chemotherapy. Therefore, BCL-2 inhibitors, such as Vencrexitab, promote apoptosis by directly binding to BCL-2 protein, displacing pro-apoptotic proteins, and inducing mitochondrial outer membrane permeabilization and caspase activation. In one embodiment, the compounds and / or compositions described herein are used in one or more doses with or in combination with an anti-CD47 monoclonal antibody, such as magrolimab.Monoclonal antibodies against CD47 are designed to interfere with the recognition of CD47 by the SIRPα receptor on macrophages, thus blocking the "don't eat me" signal used by cancer cells to avoid being ingested by macrophages. Magrolimab is a first-in-class investigational monoclonal antibody against CD47 and macrophage checkpoint inhibitor being developed for several hematological and solid tumor malignancies, including MDS. Magrolimab has been granted Fast Track Designation by the FDA for the treatment of MDS, AML, diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. In one embodiment, the compounds and / or compositions described herein are used in one or more doses with or in combination with a SYK inhibitor, such as entospletinib. Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase expressed primarily in cells of the hematopoietic lineage. Constitutive activation of SYK has been reported in AML, and targeted inhibition of SYK has been shown to induce differentiation in vitro and demonstrate anti-leukemic activity in AML mouse models. SYK has also been shown to directly phosphorylate the FLT3 receptor, regulating its activation and potentially promoting its role in leukemogenesis. Entospletinib is an orally bioavailable, selective inhibitor of SYK that has been shown to be clinically active in B-cell malignancies. In one embodiment, the compounds and / or compositions described herein are used in one or more doses with or in combination with an E-selectin inhibitor, such as uproleserin. E-selectin directly induces signaling pathways that promote the survival and regeneration of malignant cells. Using an acute AML mouse model, it has been shown that AML blast cells release inflammatory mediators that upregulate E-selectin expression in the endothelial niche. Altered cell surface glycosylation associated with tumorigenesis enhances AML blast binding to E-selectin, allowing for enhanced pro-survival signaling through the AKT / NF-κB pathway.In vivo AML blasts with the highest E-selectin binding capacity are 12-fold more likely to survive chemotherapy, a major contributor to disease relapse. Therapeutic blockade of E-selectin using the small molecule mimetic ulprolactin effectively inhibits this niche-mediated pro-survival signaling, suppresses AML blast regeneration, and strongly synergizes with chemotherapy, doubling mouse survival compared to chemotherapy alone. In one embodiment, the compounds and / or compositions described herein are used in one or more doses with or in combination with a CDK9 inhibitor, such as alvocidib. The cyclin-dependent kinase 9 (CDK9) pathway is dysregulated in AML, and therefore targeting this pathway is an attractive approach for treating AML. Inhibition of CDK9 leads to downregulation of cell survival genes controlled by super-enhancers, such as MCL-1, MYC, and cyclin D1. Because CDK9 inhibitors are nonselective, predictive biomarkers are now being utilized that can help identify patients most likely to respond to CDK9 inhibitors with the goal of improving efficacy and safety. Alvocidib is a multiserine-threonine cyclin-dependent kinase inhibitor with demonstrable in vitro and clinical activity in AML when combined in a timed sequential chemotherapy regimen. In one embodiment, the compounds and / or compositions described herein are used in one or more doses with or in combination with a menin-KMT2A (MLL) inhibitor, such as Ko-539 and / or SNDX-5613. When overexpressed in murine hematopoietic progenitor cells, meningioma-1 (MN1) causes aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A-rearranged (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Menin (Men1) is also important for the self-renewal of MN1-driven AML through the maintenance of distinct gene expression programs. Genetic inactivation of Men1 resulted in a reduction in the number of functional leukemia-initiating cells.Pharmacological inhibition of KMT2A-menin interaction has been shown to reduce colony-forming activity, induce a differentiation program in MN1-driven murine leukemia, and reduce leukemia burden in human AML xenografts. These results identify menin inhibition as a promising therapeutic strategy in MN1-driven leukemia. While a Phase 2 clinical trial of SNDX-5613 is recruiting patients according to disease and molecular genetics (MLLr AML, NPM1c AML, or MLLr acute lymphoblastic leukemia), KO-539 is recruiting patients for a Phase 1 study of relapsed / refractory AML. Both compounds have demonstrated excellent pharmacokinetic properties and low toxicity profiles in preclinical studies. In one embodiment, the compounds and / or compositions described herein are used in one or more doses with or in combination with a non-functional mutant TP53 reactivator, such as eprenetapopt (APR-246). TP53 gene mutations are detected in approximately 10% to 20% of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and in 30% to 40% of patients with therapy-related disease. Treatment outcomes for patients with TP53 mutations are poor with available therapies. Hypomethylating agents (HMAs), such as azacitidine and decitabine, produce statistically similar complete remission (CR) rates of approximately 15% to 20% in patients with either TP53-mutated or wild-type MDS. However, remissions in TP53-mutated patients are short, with median overall survival (OS) ranging from 5 to 12 months, reflecting the significant unmet medical need for targeted therapies for patients with TP53-mutated MDS and AML. Eprenetapopt (APR-246) targets the mutant p53 protein and is converted to methylenequinuclidinone (MQ), which disrupts cellular antioxidant balance. APR-246 is currently being tested in a Phase III clinical trial in myelodysplastic syndromes (MDS).

[0262] In some embodiments, one or more therapeutic agents may be in the form of salts, optical and geometric isomers, and salts of isomers. In other embodiments, the therapeutic agent may be in various forms, such as an uncharged molecule, a component of a molecular complex, or a non-irritating pharmacologically acceptable salt, including, but not limited to, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some cases, for acidic compounds, salts may include metal, amine, or organic cations (e.g., quaternary ammonium). In still other embodiments, simple derivatives (e.g., ethers, esters, or amides) of the therapeutic agent may be used that have desirable retention and release characteristics but are easily hydrolyzed by body pH, enzymes, or other suitable means.

[0263] In some embodiments, therapeutic agents have chiral centers and exist in and can be isolated in optically active and racemic forms. In other embodiments, therapeutic agents may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of the compounds described herein, including isotopically and radiolabeled compounds. See, e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be isolated by standard resolution techniques, including, for example, fractional crystallization, chiral chromatography, and the like. See, e.g., Eliel, EL & Wilen SH, 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. Preparation of optically active forms can be accomplished by any suitable method, including, but not limited to, resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0264] In some embodiments, therapeutic agents possess asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, and all isomeric forms, as well as mixtures thereof, are contemplated for use in the compounds and methods described herein. Compounds contemplated for use in the compounds and methods described herein do not include those known in the art to be too unstable to synthesize and / or isolate.

[0265] The therapeutic agents disclosed herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope contemplated.

[0266] In some embodiments, metabolic products of the therapeutic agents disclosed herein are useful in the methods disclosed herein.

[0267] In some embodiments, therapeutic agents contemplated herein may be provided in the form of a prodrug. The term "prodrug" refers to a compound that can be converted in vivo to a compound described herein (e.g., a biologically active compound). Prodrugs may be useful for a variety of reasons known in the art, including ease of administration, such as by enhancing oral bioavailability. Prodrugs may also have improved solubility in pharmaceutical compositions relative to the biologically active compound. One example, without limitation, of a prodrug is a compound that is administered as an ester (i.e., a "prodrug") to facilitate transport across cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the active carboxylic acid once inside the cell, where water solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in *Design of Prodrugs* (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference for the limited purpose of describing the procedures and preparation of suitable prodrug derivatives.

[0268] Certain therapeutic agents disclosed herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the contemplated compounds. Certain therapeutic agents of the present disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.

[0269] Additional therapies are described below and are contemplated in combination therapy in the context of the present invention. Chemotherapy / targeted therapy / alternative therapy

[0270] Cancer is generally treated with chemotherapy and / or targeted therapy and / or alternative therapies. Chemotherapy works by indiscriminately targeting healthy cells and rapidly dividing cells, including tumor cells, whereas targeted cancer therapies work by interfering with specific molecules or molecular targets involved in the growth and progression of cancer. Targeted therapies generally target only cancer cells, with minimal damage to normal cells. Chemotherapy and targeted therapies that are approved and / or in clinical trials are known to those skilled in the art. Any such compounds may be utilized in the practice of the present invention.

[0271] 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 Aroma. Syn (exemestane), Alanon (nelarabine), Arzera (ofatumumab injection), Avastin (bevacizumab), Beleodac (belinostat injection), Bexar (tositumomab), BiCNU (carmustine), Blenoxane (bleomycin), Bilincyto (blinatumomab injection), Bosulif (bosutinib), Busulfex injection (busulfan injection), Campas (alemtuzumab), Camptosar (irinotecan), Caprelsa (vandetanib), Casodex (bicalutamide), CeeNU (lomustine), CeeNU Dose Pack (lomustine), Cervizin (daunorubicin), Chloral (clofarabine injection), Cometrik (cabozantinib), Cosmegen (dactinomycin), Cotellic (cobimetinib), Cyramza (ramucirumab injection), cytosarU (cytarabine), Cytoxan (cytoxan), Cytoxan injection (cyclophosphamide injection), Dacogen (decitabine), Daunoxome (daunorubicin lipid complex injection), Decadron (dexamethasone), Depocyt (cytarabine lipid complex injection), Dexamethasone Intensor (dexamethasone), Dexpac Taper Pack (dexamethasone), Docephres (docetaxel), Doxil (doxorubicin lipid complex injection), Droxia (hydroxyurea), DTIC (dacarbazine), Eligard (leuprolide), Elence (Elence (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Elspar (asparaginase), Emcyte (estramustine), Erbitux (cetuximab), Elibege (vismodegib),Erwinase (asparaginase from Erwinia chrysanthemi), Ethiol (amifostine), Etopofos (etoposide injection), Eurexin (flutamide), Fairston (toremifene), Farydak (panobinostat), Faslodex (fulvestrant), Femara (letrozole), Farmagon (degarelix injection), Fludara (fludarabine), Folex (methotrexate injection), Folotin (pralatrexate injection), FUDR (FUDR (floxuridine)), Gazyva ( Obinutuzumab injection), Gemzar (gemcitabine), Giotrif (afatinib), Glivec (imatinib mesylate), Gliadel wafer (carmustine wafer), Halaven (eribulin injection), Herceptin (trastuzumab), Hexalen (altretamine), Hycamtin (topotecan), Hycamtin (topotecan), Hydrea (hydroxyurea), Ibrance (palbociclib), Iclusig (ponatinib), Idamycin PFS (idarubicin), Ifex (ifox) Sufamide, Imbruvica (ibrutinib), Inlyta (axitinib), IntronA alpha b (interferon alpha-2a), Iressa (gefitinib), Istodax (romidepsin injection), Ixempra (ixabepilone injection), Jakafi (ruxolitinib), Jevtana (cabazitaxel injection), Kadcyla (ado-trastuzumab emtansine), Keytruda (pembrolizumab injection), Kyprolis (carfilzomib), Lenvima (lenvatinib), Leukelan (clear venom), Lorambucil), Leukine (sargramostim), Leustatin (cladribine), Lonsurf (trifluridine and tipiracil), Lupron (leuprolide), Lupron Depot (leuprolide), Lupron Depot PED (leuprolide), Lynparza (olaparib), Risodren (mitotane), Marquibokit (vincristine lipid complex injection), Matulane (procarbazine), Megase (megestrol), Mekinist (trametinib; for more information, see Borthakur, G. et al., Blood, 2012, 120:677, which is incorporated herein by reference),Methnex (Mesna), Methnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mastergen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin). For more information, see Norsworthy, KJet al., Oncologist, 2018, 23:1103-1108 (incorporated herein by reference), Navelbine (vinorelbine), Neosarl Injection (cyclophosphamide injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (sorafenib), Nilandrone (nilandrone (nilutamide)), Nipent (pentostatin), Nolvadex (tamoxifen), Novantrone (mitoxantrone; for more information, see Fox, EJ, Neurology, 2004, 28 (12 Suppl 6):S15-8 (incorporated herein by reference), Odomzo (sonidegib), Oncaspar (peguaspargase), Oncovin (vincristine), Ontak (denileukin diftitox), Onxol (paclitaxel injection), Opdivo (nivolumab injection), Panretin (alitretinoin), Paraplatin (carboplatin), Perjeta (pertuzumab injection), Pla Tininol (cisplatin), Platinol (cisplatin injection), Platinol AQ (cisplatin), Platinol AQ (cisplatin injection), Pomalyst (pomalidomide), Prednisone Intensor (prednisone), Proleukin (aldesleukin), Purinetol (mercaptopurine), Liclast (zoledronic acid), Revlimid (lenalidomide, for more information see Kronke, J. et al., Nature, 2015, 523:183-188 (incorporated herein by reference)), Actimid (pomalidomide), Rheumatrex (methotrexate), Rituxan (rituximab), Roferon A alpha a (interferon alpha-2a), Rubex (doxorubicin), Sandostatin (octreotide),Sandostatin LAR Depot (octreotide), Soltamox (tamoxifen), Sprycel (dasatinib; for more information, see Duong, V. Het al., Leukemia Research, 2013, 37:300-304, incorporated herein by reference), Stelapred (prednisone), Stelapred DS (prednisone), Stivarga (regorafenib), Suprelin LA (histrelin implant), Sutent (sunitinib), Silatron (peginterferon alfa-2b injection (Silatron)), Silvant (siltuximab injection), Synribo (omacetamol) Injection), Tabloid (thioguanine), Taflinar (dabrafenib), Tarceva (erlotinib), Targretin Capsules (bexarotene), Tasigna (dacarbazine), Taxol (paclitaxel injection), Taxotere (docetaxel), Temodar (temozolomide), Temodar (temozolomide injection), Tepadina (thiotepa), Thalomid (thalidomide), TheraCys BCG (BCG), Thioprex (thiotepa), TICE BCG (BCG), Toposar (etoposide injection), Torisel (temsirolimus), Treanda (bendamustine hydrochloride), Trelstar (triptorelin injection), Trexar (methotrexate), Trisenox (arsenic trioxide), Tykerb (lapatinib), Unituxin (dinutuximab injection), Valstar (valrubicin intravesical), Vantas (histrelin implant), Vectibix (panitumumab), Balban (vinblastine), Belcad (bortezomib), Bepecid (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 (Ziv-aflibercept injection), Zanosar (streptozocin), Zelboraf (vemurafenib),These include Zevalin (ibritumomab tiuxetan), Zoladex (goserelin), Zolinza (vorinostat), Zometa (zoledronic acid), Zoltrex (everolimus), Zydelig (idelalisib), Zykadia (ceritinib), Zytiga (abiraterone), and their analogs and derivatives. For example, approved targeted therapies include ado-trastuzumab emtansine (Kadcyla), afatinib (Giotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campus), axitinib (Inlyta), bosutinib (Bosulif), brentuximab vedotin (Adcetris), cabozantinib (Cabometyx [tablets], Cometrix [capsules]), canakinumab (Ilaris), Carfilzomib (Kyprolis), ceritinib (Zykadia), cetuximab (Erbitux), cobimetinib (Cotellic), crizotinib (Xalkori), dabrafenib (Tafinlar), daratumumab (Darazalex), dasatinib (Sprycel), denosumab (Zygeva), dinutuximab (Unituxin), elotuzumab (Empliciti), erlotinib (Tarceva; for more information, see Boehrer, S. et al. al., Blood, 2008, 111:2170-2180 (incorporated herein by reference)), everolimus (Afinitor), gefitinib (Iressa), ibritumomab tiuxetan (Zevalin), ibrutinib (Imbruvica), idelalisib (Zydelig), imatinib (Gleevec), ipilimumab (Yervoy), ixazomib (Ninlaro), lapatinib (Tykerb), lenvatinib (Lenvima), necitumumab (Portraza), nilotinib (Tasigna), nivolumab ( Opdivo), obinutuzumab (Gazyva), ofatumumab (Arzera, HuMax-CD20), olaparib (Lynparza), osimertinib (Tagrisso), palbociclib (Ibrance), panitumumab (Vectibix), panobinostat (Farydak), pazopanib (Votrient), pembrolizumab (Keytruda), pertuzumab (Perjeta), ponatinib (Iclusig), ramucirumab (Cyramza), rapamycin, regorafenib (Stivarga), rituximab (Rituxan,MabThera), romidepsin (Istodax), ruxolitinib (Jakafi), siltuximab (Sylvanto), sipuleucel-T (Provenge), sirolimus, sonidegib (Odomzo), sorafenib (Nexavar), sunitinib, tamoxifen, temsirolimus (Torisel), tocilizumab (Actemra), tofacitinib (Xeljanz), tositumomab (Bexar), trametinib, (Mekinist), trastuzumab (Herceptin), vandetanib (Caprelsa), vemurafenib (Zelboraf), venetoclax (Venclexta), vismodegib (Elivege), vorinostat (Zolinza), ziv-aflibercept (Zaltrap), and the like, and analogs and derivatives thereof. In one embodiment, the approved chemotherapy is an anthracycline, such as doxorubicin, daunarubicin, epirubicin, and / or idarubicin. In one embodiment, the approved chemotherapy is selected from azacitidine (for further information, see Keating, GM, Drugs, 2012, 72:1111-1136, incorporated herein by reference), vencrexitab (for further information, see Raedler, LA, Journal of Hematology Oncology Pharmacy, 2017, 7:53-55, incorporated herein by reference).

[0272] Those skilled in the art can determine appropriate chemotherapy and / or targeted therapy and / or alternative therapy options, including approved treatments and treatments in clinical trials or otherwise under development. Some targeted therapies are also immunotherapies. Any relevant chemotherapy, targeted therapy, and alternative therapy treatment strategies can be utilized in the practice of the present invention, alone or in combination with one or more additional cancer therapies.

[0273] immunotherapy In some embodiments, immunotherapies include cell-based immunotherapies, such as those involving cells that influence the immune response (e.g., lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTLs), antibodies and antibody derivatives, such as monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemically labeled antibodies, etc.), immune checkpoint inhibitors, vaccines (e.g., cancer vaccines (e.g., tumor cell vaccines), and the like). These include immunotherapy using immunomodulators (e.g., interleukins, antigen vaccines, dendritic cell vaccines, vector-based vaccines, etc., e.g., oncophage, sipuleucel-T, etc.), immunomodulators (e.g., interleukins, cytokines, chemokines, etc.), local immunotherapy (e.g., imiquimod, etc.), injectable immunotherapy, adoptive cell transfer, oncolytic virus therapy (e.g., talimogene laherparepvec (T-VEC), etc.), immunosuppressive drugs, helminth therapy, and other non-specific immunotherapies. Immune checkpoint inhibitor immunotherapy is an immunotherapy that inhibits PD-1, PD-L1, and CTLA- 4. Immune checkpoint inhibitor immunotherapies include ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), and the like. Non-specific immunotherapies include cytokines, interleukins, interferons, and the like. In some embodiments, the immunotherapy assigned or administered to a subject is an interleukin, and / or interferon (IFN), and / or denileukin. This may include administration of one or more suitable antibody-based reagents such as diftitox, and / or an antibody-based reagent selected from the group consisting of ado-trastuzumab emtansine, alemtuzumab, atezolizumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, catumaxomab, gemtuzumab, ibritumomab tiuxetan, iripimumab, natalizumab, nimotuzumab, nivolumab, fatumumab, panitumumab, pembrolizumab, rituximab, tositumomab, trastuzumab, bivatuxin, and the like.In some embodiments, the immunotherapy assigned or administered to the subject may include indoleamine 2,3-dioxygenase (IDO) inhibitors, adoptive T cell therapy, viral therapy (T-VEC), and / or any other immunotherapy whose efficacy broadly depends on anti-tumor immunity.

[0274] Those skilled in the art will be able to determine appropriate immunotherapeutic options, including approved treatments and treatments in clinical trials or otherwise under development. Any relevant immunotherapeutic treatment strategy, alone or in combination with one or more additional cancer therapies, may be utilized in the practice of the present invention.

[0275] Other cancer treatments In addition to chemotherapy, targeted therapy, alternative therapy, and immunotherapy, cancer may additionally be treated by other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplantation, precision medicine, etc. Such treatments and the compounds and compositions utilized therein are known to those skilled in the art. Any such treatment strategy may be utilized in the practice of the present invention.

[0276] Alternative treatment strategies have also been used for various types of cancer. Such treatments may be used alone or in combination with any other treatment modality. These include exercise, massage, relaxation techniques, yoga, acupuncture, aromatherapy, hypnosis, music therapy, dietary changes, nutritional and dietary supplements, and the like, and such treatments are known to those skilled in the art. Any such treatment strategy may be utilized in the practice of the present invention, alone or in combination with one or more additional cancer therapies.

[0277] Dosage and route of administration Other embodiments of the present invention may include methods of administering to or treating animals, which may involve treatment with an amount of at least one compound of the present invention (e.g., Formula (I)) effective to treat a disease, condition, or disorder that the organism has, is suspected of having, or is susceptible to having, or to cause a desired physiological effect. In some embodiments, the composition or pharmaceutical composition is administered to an animal (such as 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. and at least one compound of the present invention (e.g., Formula (I), (II), (III), (V), (VI), (VII), (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)) may be administered to a subject. For some conditions, the dosage may be about 0.5 mg / kg human body weight or about 6.5 mg / kg human body weight.In some cases, a subject (e.g., a mammal, mouse, rabbit, cat, pig, or dog) may 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 skill in the art will recognize that many concentrations are possible for use in the methods of the present invention. Additionally, using, in part, the guidance provided herein, any number of concentrations can be adjusted and tested to find one that achieves the desired results in a given situation. In some embodiments, the dose or therapeutically effective dose of a compound disclosed herein is sufficient to achieve a plasma concentration of the compound or its active metabolite within the ranges described herein, e.g., 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, preferably about 1-10 nM, 10-100 nM, or 0.1-1 μM. Without wishing to be bound by any theory, it is believed that such compounds are indicated for the treatment or management of hematopoietic cancers, such as MDS and / or AML and / or DLBCL, as described herein.

[0278] In other embodiments, the compounds and / or pharmaceutical compositions of the present invention (e.g., compounds of Formula (I), (II), or (III), and pharmaceutical compositions comprising same) may be administered in combination with one or more other therapeutic agents for a given disease, condition, or disorder.

[0279] The compounds and pharmaceutical compositions are preferably prepared and administered in dosage units.Solid dosage units are tablets, capsules, and suppositories.For the treatment of a subject, different daily doses can be used depending on the activity of the compound, the method of administration, the nature and severity of the disease or disorder, and the age and weight of the subject.

[0280] However, under certain circumstances, higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out both by single administration in the form of individual dose units or several smaller dose units, and by multiple administration of subdivided doses at specific intervals.

[0281] The compounds and pharmaceutical compositions contemplated herein can be administered locally or systemically at therapeutically effective doses.The effective amount for this use will naturally depend on the severity of disease or disorder, and the subject's weight and general condition.Typically, the dosage used in vitro can provide useful guidance for the amount useful for in situ administration of pharmaceutical compositions, and animal models can be used to determine the effective dosage for the treatment of specific disorders.

[0282] Various considerations are described, for example, in Langer, 1990, Science, 249: 1527; Goodman and Gilman's (eds.), 1990, ibid. (each of which is incorporated herein by reference and for all purposes). A dosage for parenteral administration of an active pharmaceutical agent can be converted to a corresponding dosage for oral administration by multiplying the parenteral dosage by the appropriate conversion factor. For general use, a parenteral dosage in mg / mL x 1.8 is equivalent to the corresponding oral dosage in milligrams (mg). For oncology use, a parenteral dosage in mg / mL x 1.6 is equivalent to the corresponding oral dosage in mg. The average adult body weight is approximately 70 kg. See, for example, Miller-Keane, 1992, Encyclopedia & Dictionary of Medicine, Nursing & Allied Health, 5th Ed. (WB Saunders Co.), pp. 1708 and 1651.

[0283] However, it will be understood that the specific dose level for any 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, drug combination, and the severity of the particular disease being treated.

[0284] In some embodiments, compounds and / or pharmaceutical compositions may include a unit dose of one or more compounds of the present invention (e.g., compounds of Formula (I), (II), or (III), and pharmaceutical compositions comprising same) in combination with a pharmaceutically acceptable carrier, and may, in addition, include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients. In certain embodiments, the carrier, vehicle, or excipient may facilitate improved administration, delivery, and / or storage of the composition. In other embodiments, the one or more carriers include, but are not limited to, saline solutions, such as normal saline, Ringer's solution, PBS (phosphate buffered saline), and mixtures of various salts, typically including potassium and phosphate salts, with or without sugar additives such as glucose. Carriers may include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the body fluids of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. In other embodiments, the one or more excipients may 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, may also be added to the compositions. Oral formulations may include commonly used excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.

[0285] The quantity of active ingredient in a unit dose 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 according to the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0286] The compounds of the invention (eg, compounds according to Formula (I), (II), or (III)) can be administered to a subject by any number of suitable routes of administration or formulations. The compounds of the present invention (e.g., of Formula (I), (II), (III), (V), (VI), (VII), (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)) can also be used to treat subjects for a variety of diseases. 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.

[0287] The route of administration of the compounds of the present invention (e.g., Formula (I)) may be any suitable route. The route of administration may be, but is not limited to, oral, parenteral, cutaneous, nasal, rectal, vaginal, and ocular. In other embodiments, the route of administration may be parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular. The choice of administration route may depend on the identity of the compound (e.g., the physical and chemical properties of the compound), as well as the age and weight of the animal, the particular disease (e.g., cancer or MDS), and the severity of the disease (e.g., the stage or severity of cancer or MDS). Of course, a combination of administration routes may be administered as desired.

[0288] Some embodiments of the present invention include methods for providing a subject with a composition (e.g., a pharmaceutical composition) comprising one or more compounds of the invention (e.g., Formula (I)) described herein, which comprises one or more administrations of one or more such compositions, which, if two or more administrations are present, may be the same or different.

[0289] How to increase a subject's survivability In yet another aspect, the present disclosure provides a method of increasing survival in a subject diagnosed with or suspected of having acute myeloid leukemia (AML), the method comprising administering to a subject a compound of Formula (I), (II), (III), (V), (VI), or (VII) (Formulas (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO) , (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)) or a salt thereof, an ester and the like. The compounds of formula (I), (II), (III), (V), (VI), or (VII) (formula (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIb-5010-WO), (IIc-5010-WO), (IId-5010-WO), (IIa ... The method comprises administering to the subject a therapeutically effective amount of a composition comprising a compound of formula (Ia-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, the survival of the subject is increased compared to a subject treated with a therapeutically effective amount of a standard of care for AML. In one embodiment, the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof.

[0290] In one embodiment, the method includes administering to the subject a compound of Formula (I), (II), (III), (V), (VI), or (VII) (Formula (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa ... (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO), or (IIIb-5010-WO) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a compound of formula (I), (II), (III), (V), (VI), or (VII) Compounds of formula (including compounds of formula Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010 The present invention relates to a method for treating a subject's rheumatoid arthritis, the method comprising administering a therapeutically effective amount of a composition comprising a compound of formula (IIIa-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, about every 6 hours, every 12 hours, every 18 hours, once daily, every other day, every third day, every fourth day, every fifth day, every sixth day, or once weekly. In one embodiment, the administration includes parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. In one embodiment, the compound is administered to a 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, a lower dose of a compound of Formula (I), (II), (III), (V), (VI), or (VII) (Formula (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO), (Id-5010-WO), (IIa-5010-WO), (IIb-5010-WO) ), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a compound of formula (I), (II), (II A compound of formula I), (V), (VI), or (VII) (including compounds of formula (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (II A composition comprising compound 51, including the compounds of formula (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO), or (IIIb-5010-WO), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, improves survival in a subject compared to a standard of care dose. In one embodiment, the method comprises administering to a subject a therapeutically effective amount of compound 51, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In another embodiment, the method comprises administering to a subject a composition comprising a therapeutically effective amount of compound 51, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.

[0291] In one embodiment, the AML includes AML with splicing factor mutations, AML with enhanced IRAK4-Long expression and / or activity compared to IRAK4-Short, and / or AML that is not driven by FLT3 mutations but expresses IRAK4-Long.

[0292] In one embodiment, the method includes the use of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetobolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody-drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK2 inhibitor ... / ERK inhibitors including MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura The method further comprises administering to the subject one or more additional therapies selected from an EGFR inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT 1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a menin-KMT2A / MLL inhibitor, and a multikinase inhibitor.

[0293] In one embodiment, the AML is responsive to at least one of a BCL2 inhibitor, a BTK inhibitor, a CDK inhibitor, and a DNA methyltransferase inhibitor, or the AML is sensitive to an anti-inflammatory glucocorticoid, hi one embodiment, the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.

[0294] In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, the AML is resistant to a BCL2 inhibitor. In one embodiment, the AML is resistant to venetoclax. In one embodiment, the AML is BCL2 inhibitor-resistant refractory AML. In one embodiment, the AML is venetoclax-resistant refractory AML. In one embodiment, the AML is BCL2 inhibitor-resistant relapsed AML. In one embodiment, the AML is venetoclax-resistant relapsed AML.

[0295] In one embodiment, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof. In one embodiment, the AML is resistant to a BTK inhibitor. In one embodiment, the AML is resistant to ibrutinib.

[0296] In one embodiment, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them. In one embodiment, the AML is sensitive to anti-inflammatory glucocorticoids. In one embodiment, the AML is dexamethasone-, methylprednisolone-, or prednisolone-resistant.

[0297] In one embodiment, the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitors BAY1251152 and atubeciclib, or a pharmaceutically acceptable salt of any one of them. In one embodiment, the AML is resistant to a CDK inhibitor. In one embodiment, the AML is resistant to palbociclib, THZ1, BAY 12511152, or atubeciclib.

[0298] In one embodiment, the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the AML is DNA methyltransferase inhibitor-resistant. In one embodiment, the AML is azacitidine-resistant.

[0299] In one embodiment, the AML is resistant to a BCL2 inhibitor and a DNA methyltransferase inhibitor. In one embodiment, the AML is resistant to venetoclax and azacitidine. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.

[0300] In one embodiment, the AML is FLT3 inhibitor-resistant. In one embodiment, the AML is FLT3 inhibitor-resistant refractory AML. In one embodiment, the AML is FLT3 inhibitor-resistant relapsed AML.

[0301] In one embodiment, a compound of Formula (I), (II), (III), (V), (VI), or (VII) (Formula (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO), (Id-5010-WO), (IIa-5010-WO), (IIb-5010-WO), (IIa -5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a compound of formula (I), (II), (III), (V ), (VI), or (VII) compounds of formula (including compounds of formula (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-50 The one or more additional therapies are administered together in a single dose or composition, comprising a compound of formula (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO), or (IIIb-5010-WO), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.In another embodiment, a compound of Formula (I), (II), (III), (V), (VI), or (VII) (Formula (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO), (Id-5010-WO), (IIa-5010-WO), (IIb-5010-WO), (IIa- 5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a compound of formula (I), (II), (III), (V), (V I), or (VII) (including compounds of formula (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO), (IIb-5010-WO), (IIa-5010-WO50), (IIb-5010-WO50), 0), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50), or (IIIb-5010-WO50)), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered separately in two or more doses or in two or more compositions.

[0302] In one embodiment, viability is increased by inhibiting at least one of IRAK1, IRAK4, and FLT3 in a subject. In one embodiment, viability is increased by inhibiting at least two of IRAK1, IRAK4, and FLT3 in a subject. In one embodiment, viability is increased by inhibiting IRAK1 and IRAK4 in a subject. In one embodiment, viability is increased by inhibiting IRAK1, IRAK4, and FLT3 in a subject. In one embodiment, FLT3 is selected from at least one of WT FLT3, activated FLT3, and mutant FLT3. In one embodiment, the mutant FLT3 is D835Y mutant FLT3 or F691L mutant FLT3.

[0303] In one embodiment, the subject is a human. In one embodiment, the survival of the human subject is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a human subject treated with a therapeutically effective amount of standard of care for AML.

[0304] In another embodiment, the subject is a non-human mammal engrafted with AML cells. In one embodiment, the subject is a mouse engrafted with AML cells. In one embodiment, the AML cells are MOLM14-FLT3-ITD(D835Y) cells. In one embodiment, the survival of the mouse subject is increased by about 1 day, about 2 days, about 5 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 65 days, about 70 days, about 75 days, about 80 days, about 85 days, or about 90 days compared to a mouse subject treated with a therapeutically effective amount of a standard of care for AML.

[0305] toxicity The ratio between toxic and therapeutic effects for a particular compound is its therapeutic index, LD 50 (lethal dose of compound in 50% of the population) and ED 50Therapeutic indices may 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 range of dosages for use in humans. The dosage of such compounds is determined to be the ED with little or no toxicity. 50 It is preferred that the plasma concentration range is within the range including the range of 0.01 to 0.01. The dosage can 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 physician in consideration of the patient's condition and the particular method in which the compound is used. For in vitr...

Claims

1. A compound of formula (I), (II), or (III): 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof, During the ceremony, A is N and CR ５ is selected from D is N and CR ４ is selected from E is N and CR ３ is selected from At least one of A, D, and E is N; R １ , R ２ , R ３ , R ４ , and R ５ are each independently H, deuterium, halogen, hydroxy, oxo, —CN, —C(═O)H, —C(═O)OH, C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ Alkoxy, —C(═O)NR ３１ R ３２ , cycloalkyl, —O-cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein —C(═O)H, —C(═O)OH, C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ Alkoxy, cycloalkyl, -O-cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl may be substituted with deuterium, halogen, hydroxy, oxo, -C(=O)H, -C(=O)OH, nitro (-NO ２ ), -NH ２ , -N(CH ３ ) ２ , cyano (-CN), ethynyl (-CCH), propynyl, -SO ３ H, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —C(═O)-morpholin-4-yl, —C(═O)NH ２ , -C(=O)N(CH ３ ) ２ , C １ -C ７ Alkyl, C １ -C ７ Perfluorinated alkyl, C １ -C ７ Alkoxy, C １ -C ７ C substituted with haloalkoxy or cycloalkyl １ -C ７ optionally substituted with one or more of alkyl; R ６ but, 【Chemistry 4】 or one or more -NR ３３ R ３４ C substituted with ３ -C ６ is cycloalkyl, R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , and R １４ are each independently H, deuterium, halogen, hydroxy, oxo, —CN, —C(═O)H, —C(═O)OH, C １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein: １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ the 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 H, deuterium, 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, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein: １ -C ７ Alkyl, C ２ -C ７ Alkenyl, C ２ -C ７ Alkynyl, C １ -C ７ the alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; R ３１ and R ３２ are each independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl, wherein C １ -C ６ Alkyl and C ３ -C ６ cycloalkyl is optionally substituted with one or more halogens; R ３３ and R ３４ are each independently H and C １ -C ６ alkyl, 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; or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

2. 2. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (Ib-5010-WO50): 【Transformation 5】 (Ib-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, V is N or CR １１ and W is N or CR １２ and X is N or CR １３ and 【Transformation 6】 teeth, 【Transformation 7】 and R １０ｂ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl, —O—(C ３ -C ６ cycloalkyl), imidazolyl, triazolyl, and —C(═O)NR １８ａ R １８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, 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 １７ｂ is a halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl, —O—(C ３ -C ６ cycloalkyl), C ３ -C ９ Heterocyclyl, imidazolyl, triazolyl, and —C(═O)NR １８ａ R １８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; ３ -C ６ Cycloalkyl and —O—(C ３ -C ６ cycloalkyl) are each —OH, C １ -C ６ optionally substituted with one or more substituents selected from alkyl and halogen; R １１、 R １２ , and R １３ are each independently H, C １ -C ６ alkoxy, and halogen; R １４ａ , R １４ｂ , R １５ａ , R １５ｂ , R １６ａ , R １６ｂ , R １８ａ , and R １８ｂ are each independently H, halogen, —OH, C １ -C ６ Alkyl, and C １ -C ６ alkoxy, wherein C １ -C ６ Alkyl and C １ -C ６ each alkoxy is optionally substituted with one or more halogen atoms; A compound wherein one of V, W, or X is N.

3. The compound of claim 2, comprising (i) to (v): (i) R １４ｂ , R １５ａ , R １５ｂ , R １６ａ , and R １６ｂ is H, and R １４ａ But F, (ii) R １１ , R １２ , and R １３ is H, if present; (iii) V is CR １１ wherein R １１ is F and W is CR １２ wherein R １２ is H and X is N; (iv) R １０ｂ is H and -OCH ３ and (v) R １７ｂ but, 【Transformation 8】 The compound to which at least one of the following is applied:

4. 4. A compound according to claim 2 or 3, R １７ｂ but 【Chemistry 9】 If R １０ｂ is H, R １７ｂ but 【Chemistry 10】 If R １１ , R １２ , and R １３ and at least one of C １ -C ６ A compound selected from alkoxy and halogen.

5. The compound according to any one of claims 2 to 4, wherein the compound of formula (Ib-5010-WO50) is 【Chemistry 11】 A compound selected from:

6. 2. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (Id-5010-WO50) 【Chemistry 12】 or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, V is N or CR １１ and W is N or CR １２ and X is N or CR １３ and 【Chemistry 13】 teeth, 【Chemistry 14】 and R １０ｄ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl, —O—(C ３ -C ６ cycloalkyl), imidazolyl, triazolyl, and —C(═O)NR １８ａ R １８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, 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 １１３ｄ is a halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl, —O—(C ３ -C ６ cycloalkyl), imidazolyl, triazolyl, and —C(═O)NR １８ａ R １８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; ３ -C ６ Cycloalkyl and —O—(C ３ -C ６ cycloalkyl) are each —OH, C １ -C ６ optionally substituted with one or more substituents selected from alkyl and halogen; R １１ , R １２ , and R １３ are each independently H, C １ -C ６ alkoxy, and halogen; R １８ａ and R １８ｂ are each independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl, wherein C １ -C ６ Alkyl and C ３ -C ６ each cycloalkyl is optionally substituted with one or more halogens; R １９ａ , R １９ｂ , R １１０ａ , R １１０ｂ , R １１１ａ , R １１１ｂ , R １１２ａ , and R １１２ｂ are each independently H, halogen, —OH, C １ -C ６ Alkyl, and C １ -C ６ alkoxy, wherein C １ -C ６ Alkyl and C １ -C ６ each alkoxy is optionally substituted with one or more halogen atoms; A compound wherein one of V, W, or X is N.

7. 10. The compound of claim 6, comprising (i) to (vi): (i) R １９ａ , R １９ｂ , R １１０ａ , R １１０ｂ , R １１１ａ , R １１１ｂ , R １１２ａ , and R １１２ｂ each of which is H; (ii) R １９ａ , R １９ｂ , R １１０ｂ , R １１１ａ , R １１１ｂ , R １１２ａ , and R １１２ｂ is H, and R １１０ａ But F, (iii) R １１ , R １２ , and R １３ is H, if present; (iv) V is CR １１ wherein R １１ is F and W is CR １２ wherein R １２ is H and X is N; (v) R １０ｄ is H and -OCH ３ and (vi)R １１３ｄ が、 【Chemistry 15】 The compound to which at least one of the following is applied:

8. 8. A compound according to claim 6 or 7, R １１３ｄ but 【Chemistry 16】 If R １０ｄ is H, R １１３ｄ but 【Chemistry 17】 If R １１ , R １２ , and R １３ and at least one of C １ -C ６ A compound selected from alkoxy and halogen.

9. The compound according to any one of claims 6 to 8, wherein the compound of formula (Id-5010-WO50) is [Chemistry 18] 【Chemistry 19】 A compound selected from:

10. 2. The compound according to claim 1, wherein the compound of formula (II) is a compound of formula (IIa-5010-WO50): 【Chemistry 20】 or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, L is N or CR ２１ and M is N or CR ２２ and Q is N or CR ２３ and 【Chemistry 21】 teeth, 【Chemistry 22】 and R ２０ａ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl, —O—(C ３ -C ６ cycloalkyl), imidazolyl, triazolyl, and —C(═O)NR ２８ａ R ２８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, 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; Each R ２７ａ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, spiro-fused cycloalkyl, —O—(C ３ -C ６ cycloalkyl), C ２ -C ６ Heterocyclyl, imidazolyl, triazolyl, and —C(═O)NR ２８ａ R ２８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; ３ -C ６ Cycloalkyl, spirocycloalkyl, —O—(C3-C6 cycloalkyl), and C ２ -C ６ Heterocyclyl is each —OH, C １ -C ６ optionally substituted with one or more substituents selected from alkyl and halogen; R ２１ , R ２２ , and R ２３ are each independently H, C １ -C ６ alkoxy, and halogen; R ２４ａ , R ２４ｂ , R ２５ａ , R ２５ｂ , R ２６ａ , and R ２６ｂ are each independently H, halogen, —OH, C １ -C ６ Alkyl, and C １ -C ６ alkoxy, wherein C １ -C ６ Alkyl and C １ -C ６ each alkoxy is optionally substituted with one or more halogen atoms; R ２８ａ and R ２８ｂ are each independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl, wherein C １ -C ６ Alkyl and C ３ -C ６ each cycloalkyl is optionally substituted with one or more halogens; The compound wherein one of L, M, or Q is N.

11. The compound of claim 10, comprising (i) to (v): (i) R ２４ｂ , R ２５ａ , R ２５ｂ , R ２６ａ , and R ２６ｂ is H, and R ２４ａ But F, (ii) R ２１ , R ２２ , and R ２３ is H, if present; (iii) L is CR ２１ wherein R ２１ is F, Cl, and —OCH ３ and M is selected from CR ２２ wherein R ２２ is H and Q is N; (iv) R ２０ａ But, -OCH ３ , unsubstituted -O-(C ３ cycloalkyl), and 【Chemistry 23】 Selected from: (v) R ２７ａ is unsubstituted C ３ -C ６ cycloalkyl, 【Chemistry 24】 The compound to which at least one of the following is applied:

12. 12. A compound according to claim 10 or 11, R ２０ａ Ga-OCH ３ and R ２７ａ is unsubstituted C ３ When R is cycloalkyl, ２１ , R ２２ , and R ２３ and at least one of C １ -C ６ A compound selected from alkoxy and halogen.

13. The compound according to any one of claims 10 to 12, wherein the compound (IIa-5010-WO50) is 【Chemistry 25-1】 【Chemistry 25-2】 A compound selected from:

14. 2. The compound according to claim 1, wherein the compound of formula (II) is a compound of formula (IIb-5010-WO50): 【Chemistry 26】 or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, L is N or CR ２１ and M is N or CR ２２ and Q is N or CR ２３ and 【Chemistry 27】 teeth, 【Chemistry 28】 and R ２０ｂ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl, —O—(C ３ -C ６ cycloalkyl), imidazolyl, triazolyl, and —C(═O)NR ２８ａ R ２８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, 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 ２７ｂ is a halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, spirocycloalkyl, —O—(C ３ -C ６ cycloalkyl), C ２ -C ６ Heterocyclyl, imidazolyl, triazolyl, and —C(═O)NR ２８ａ R ２８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; ３ -C ６ Cycloalkyl, spirocycloalkyl, —O—(C ３ -C ６ cycloalkyl), and C ２ -C ６ Heterocyclyl is each —OH, C １ -C ６ optionally substituted with one or more substituents selected from alkyl and halogen; R ２１ , R ２２ , and R ２３ are each independently H, C １ -C ６ alkoxy, and halogen; R ２９ａ , R ２９ｂ , R ２１０ａ , R ２１０ｂ , R ２１１ａ , R ２１１ｂ , R ２１２ａ , and R ２１２ｂ are each independently H, halogen, —OH, C １ -C ６ Alkyl, and C １ -C ６ alkoxy, wherein C １ -C ６ Alkyl and C １ -C ６ each alkoxy is optionally substituted with one or more halogen atoms; R ２８ａ and R ２８ｂ are each independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl, wherein C １ -C ６ Alkyl and C ３ -C ６ each cycloalkyl is optionally substituted with one or more halogens; The compound wherein one of L, M, or Q is N.

15. 15. The compound of claim 14, comprising (i) to (vi): (i) R ２９ａ , R ２９ｂ , R ２１０ａ , R ２１０ｂ , R ２１１ａ , R ２１１ｂ , R ２１２ａ , and R ２１２ｂ each of which is H; (ii) R ２９ａ , R ２９ｂ , R ２１０ｂ , R ２１１ａ , R ２１１ｂ , R ２１２ａ , and R ２１２ｂ is H, and R ２１０ａ But F, (iii) R ２１ , R ２２ , and R ２３ is H, if present; (iv) L is CR ２１ wherein R ２１ is F, Cl, and -OCH ３ and M is selected from CR ２２ wherein R ２２ is H and Q is N; (v) R ２０ｂ But, -OCH ３ , -OCD ３ , unsubstituted -O-(C ３ cycloalkyl) 、 and 【Chemistry 29】 Selected from: (vi) R ２７ｂ is unsubstituted C ３ -C ６ cycloalkyl, 【Transformation 30】 The compound to which at least one of the following is applied:

16. 16. A compound according to claim 14 or 15, R ２０ｂ Ga-OCH ３ and R ２７ｂ is unsubstituted C ３ When R is cycloalkyl, ２１ , R ２２ , and R ２３ and at least one of C １ -C ６ A compound selected from alkoxy and halogen.

17. The compound according to any one of claims 14 to 16, wherein the compound of formula (IIb-5010-WO50) is 【Chemistry 31-1】 【Chemistry 31-2】 【Chemistry 31-3】 【Chemistry 31-4】 【Chemistry 31-5】 【change】 【Chemistry 31-6】 A compound selected from:

18. 2. The compound according to claim 1, wherein the compound of formula (III) is a compound of formula (IIIa-5010-WO50): 【Chemistry 32】 or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R is N or CR ３１ and T is N or CR ３２ and U is N or CR ３３ and 【Transformation 33】 teeth, 【Transformation 34】 and Each R ３７ａ are independently halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl, —O—(C ３ -C ６ cycloalkyl), C ２ -C ６ Heterocyclyl, imidazolyl, triazolyl, 2-pyrrolidinonyl, and —C(═O)NR ３８ａ R ３８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; ３ -C ６ Cycloalkyl and —O—(C ３ -C ６ cycloalkyl), and C ２ -C ６ Heterocyclyl is each —OH, C １ -C ６ optionally substituted with one or more substituents selected from alkyl and halogen; R ３１ , R ３２ , and R ３３ are each independently H, C １ -C ６ alkoxy, and halogen; R ３４ａ , R ３４ｂ , R ３５ａ , R ３５ｂ , R ３６ａ , and R ３６ｂ are each independently H, halogen, —OH, C １ -C ６ Alkyl, and C １ -C ６ alkoxy, wherein C １ -C ６ Alkyl and C １ -C ６ each alkoxy is optionally substituted with one or more halogen atoms; R ３８ａ and R ３８ｂ are each independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl, wherein C １ -C ６ Alkyl and C ３ -C ６ each cycloalkyl is optionally substituted with one or more halogens; The compound wherein one of R, T, or U is N.

19. 19. The compound of claim 18, comprising (i) to (iv): (i) R ３４ｂ , R ３５ａ , R ３５ｂ , R ３６ａ , and R ３６ｂ is H, and R ３４ａ But F, (ii) R ３１ , R ３２ , and R ３３ is H, if present; (iii) R is CR ３１ wherein R ３１ is F and T is CR ３２ wherein R ３２ is H and U is N, and (iv) R ３７ａ but, 【Chemistry 35】 The compound to which at least one of the following is applied:

20. 20. The compound of claim 18 or 19, wherein R ３７ａ but, 【Transformation 36】 Not a compound.

21. 21. The compound according to any one of claims 18 to 20, wherein the compound of formula (IIIa-5010-WO50) is: 【Chemistry 37】

22. 2. The compound of claim 1, wherein the compound of formula (III) is a compound of formula IIIb-5010-WO50): 【Transformation 38】 or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony, R is N or CR ３１ and T is N or CR ３２ and U is N or CR ３３ and 【Chemistry 39】 teeth, 【Chemistry 40】 and R ３７ｂ is a halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl, —O—(C ３ -C ６ cycloalkyl), C ２ -C ６ Heterocyclyl, imidazolyl, triazolyl, 2-pyrrolidinonyl, and —C(═O)NR ３８ａ R ３８ｂ wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy is optionally substituted with one or more substituents selected from —OH, deuterium, and halogen; ３ -C ６ cycloalkyl, —O—(C ３ -C ６ cycloalkyl), and C ２ -C ６ Heterocyclyl is each —OH, C １ -C ６ optionally substituted with one or more substituents selected from alkyl and halogen; R ３１ , R ３２ , and R ３３ are each independently H, C １ -C ６ alkoxy, and halogen; R ３９ａ , R ３９ｂ , R ３１０ａ , R ３１０ｂ , R ３１１ａ , R ３１１ｂ , R ３１２ａ , and R ３１２ｂ are each independently H, halogen, —OH, C １ -C ６ Alkyl, and C １ -C ６ alkoxy, wherein C １ -C ６ Alkyl and C １ -C ６ each alkoxy is optionally substituted with one or more halogen atoms; R ３８ａ and R ３８ｂ are each independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl, wherein C １ -C ６ Alkyl and C ３ -C ６ each cycloalkyl is optionally substituted with one or more halogens; The compound wherein one of R, T, or U is N.

23. 23. The compound of claim 22, comprising (i) to (v): (i) R ３９ａ , R ３９ｂ , R ３１０ａ , R ３１０ｂ , R ３１１ａ , R ３１１ｂ , R ３１２ａ , and R ３１２ｂ each of which is H; (ii) R ３９ａ , R ３９ｂ , R ３１０ｂ , R ３１１ａ , R ３１１ｂ , R ３１２ａ , and R ３１２ｂ is H, and R ３１０ａ But F, (iii) R ３１ , R ３２ , and R ３３ is H, if present; (iv) R is CR ３１ wherein R ３１ is F and T is CR ３２ wherein R ３２ is H and U is N, (v) R ３７ｂ but, 【Chemistry 41】 The compound to which at least one of the following is applied:

24. 24. A compound according to claim 22 or 23, R ３７ｂ but 【Chemistry 42】 When R ３１ , R ３２ , and R ３３ and at least one of C １ -C ６ A compound selected from alkoxy and halogen.

25. The compound according to any one of claims 22 to 24, wherein the compound of formula (IIIb-5010-WO50) is 【Chemistry 43】 A compound selected from:

26. A compound according to any one of claims 1 to 25, (i) the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3; (ii) the compound is an inhibitor of IRAK1 and IRAK4, but is not an inhibitor of FLT3; or (iii) A compound which is an inhibitor of each of IRAK1, IRAK4, and FLT3.

27. 27. A composition comprising a compound according to any one of claims 1 to 26 and a formulation component, adjuvant, or carrier.

28. 28. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 26 or a composition of claim 27.

29. 29. The method of claim 28, wherein the disease or disorder is alleviated by inhibition of at least one of interleukin-1 receptor-associated kinase (IRAK) and fms-like tyrosine kinase 3 (FLT3).

30. 30. The method of claim 28 or 29, wherein the disease or disorder comprises a hematopoietic cancer.

31. 31. The method of claim 30, wherein the hematopoietic tumor is selected from myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, and marginal zone lymphoma.

32. 32. The method of claim 30 or 31, wherein the disease or disorder is: BCL2 inhibitor-resistant acute myeloid leukemia (AML), BCL2 inhibitor-resistant refractory acute myeloid leukemia, BCL2 inhibitor-resistant relapsed acute myeloid leukemia, FLT3 inhibitor-resistant acute myeloid leukemia, FLT3 inhibitor-resistant refractory acute myeloid leukemia, or FLT3 inhibitor-resistant relapsed acute myeloid leukemia.

33. 30. The method of claim 28 or 29, wherein the disease or disorder comprises at least one cancer selected from bone marrow cancer, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, abdominal cancer, and uterine cancer.

34. 30. The method of claim 28 or 29, wherein the disease or disorder comprises at least one inflammatory or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, Crohn's disease, and colitis, and atopic dermatitis.

35. 35. The method of any one of claims 28 to 34, wherein the therapeutic agent 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 (antimetabolites), 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 steroids, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura and administering to the subject one or more additional therapies selected from an A inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an Aurora B / 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.

36. 36. The method of claim 35, wherein the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.

37. 37. The method of claim 36, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them, the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitors BAY1251152 and atubeciclib, or a pharmaceutically acceptable salt of any one of them, or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.

38. 36. The method of claim 35, wherein the compound of any one of claims 1 to 26 or the composition of claim 27 and the one or more additional therapies are administered together in one administration or one composition.

39. 36. The method of claim 35, wherein the compound of any one of claims 1-26 or the composition of claim 27 and the one or more additional therapies are administered separately in two or more doses or two or more compositions.

40. 40. The method according to any one of claims 28 to 39, wherein the compound is a compound of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), formula (IIIb-5010-WO50), or any salt, ester, solvate, optical isomer, geometric isomer, or salt of said isomer.

41. 28. A method of increasing survival in a subject diagnosed with or suspected of having acute myeloid leukemia (AML), comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 26 or a composition of claim 27.

42. 42. The method of claim 41, wherein the survival of the subject is increased compared to a subject treated with a therapeutically effective amount of a standard of care for AML.

43. 43. The method of claim 42, wherein the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof.

44. The method of any one of claims 41 to 43, wherein the subject is a human.

45. 45. The method of claim 44, wherein the survival of the subject is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with a therapeutically effective amount of the standard of care for AML.

46. 46. ​​The method of any one of claims 41-45, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-26 or a composition of any one of claims 27-30 about every 6 hours, every 12 hours, every 18 hours, once daily, every other day, every third day, every fourth day, every fifth day, every sixth day, or once weekly.

47. 47. The method of any one of claims 41 to 46, wherein the therapeutic agent 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 (antimetabolites), 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 steroids, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura and administering to the subject one or more additional therapies selected from an A inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an Aurora B / 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.

48. 48. The method of claim 47, wherein the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.

49. 49. The method of claim 48, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them, the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitor BAY1251152 and atubeciclib, or a pharmaceutically acceptable salt of any one of them, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.

50. 50. The method of any one of claims 41 to 49, wherein the AML comprises: BCL2 inhibitor-resistant AML, BCL2 inhibitor-resistant refractory AML, BCL2 inhibitor-resistant relapsed AML, FLT3 inhibitor-resistant AML, FLT3 inhibitor-resistant refractory AML, or FLT3 inhibitor-resistant relapsed AML.

51. 48. The method of claim 47, wherein the compound of any one of claims 1 to 26 or the composition of claim 27 and the one or more additional therapies are administered together in one administration or one composition.

52. 48. The method of claim 47, wherein the compound of any one of claims 1 to 26 or the composition of claim 27 and the one or more additional therapies are administered separately in two or more doses or two or more compositions.

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