POLYCYCLIC IRAK AND flt3 INHIBITORING COMPOUNDS AND USES THEREOF

Abstract

Some embodiments of the invention include compounds of the invention (e.g., compounds of Formula (I), (II), or (III)) and compositions (e.g., pharmaceutical compositions) that inhibit IRAK and / or FLT3 and can be used to treat, for example, certain diseases. Some embodiments include methods of administering and treating (e.g., diseases, such as hematopoietic cancer, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), using a compound of the invention (e.g., in a composition or in a pharmaceutical composition). Additional embodiments provide disease treatment using the IRAK and / or FLT3 inhibiting compounds of the invention in combination with other therapies, such as cancer therapies.

Description

Technical Field

[0001] The invention disclosed herein relates in general to compounds and compositions as kinase inhibitors and their use in treating diseases and conditions, including cancer.

[0002] Government rights

[0003] This invention was developed under a collaborative research and development agreement with the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. The U.S. government holds certain rights to this invention.

[0004] Cross-references to related applications

[0005] 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

[0006] Myelodysplastic syndromes (MDS) are a malignant, potentially fatal blood disorder caused by defective hematopoietic stem cells / progenitor cells. It is predisposed to acute myeloid leukemia (AML) (Corey et al., 2007; Nimer, 2008) and typically progresses to chemotherapy-resistant secondary acute myeloid leukemia (sAML). Most patients with MDS die from bone marrow failure, immune dysfunction, and / or transformation into overt leukemia.

[0007] MDS is a heterogeneous disease with few treatment options due to the lack of effective drugs that provide a durable response. Current treatment options for MDS are limited but include allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapies (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 transfusions to manage disease complications. Unfortunately, even after HSC transplantation, MDS clones can persist in the bone marrow, and the disease always progresses (Tehranchi et al., 2010). For advanced or high-risk MDS, patients may also receive immunosuppressive therapy, epigenetic modifying agents, and / or chemotherapy (Greenberg, 2010). Despite recent advances, most MDS patients experience treatment-related toxicities or relapse (Sekeres, 2010a). Overall, the efficacy of these treatments is variable, and life expectancy is typically only slightly improved compared to supportive care. The complexity and heterogeneity of MDS, as well as the lack of human xenotransplantation models, are obstacles to identifying and evaluating new molecular targets for this disease.

[0008] Approximately 30% of MDS patients also develop aggressive AML due to additional mutations acquired in defective hematopoietic stem / progenitor cells (HSPCs) (Greenberg et al., 1997). AML is a cancer of myeloid blood cells characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. Although AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, its incidence is expected to increase with an aging population. Several risk factors and chromosomal abnormalities have been identified, but the specific causes remain unclear. As an acute leukemia, AML progresses rapidly and is often fatal within weeks or months if left untreated. AML caused by MDS has a worse prognosis compared to other types of AML.

[0009] Several compounds are known to treat blood disorders and cancers (e.g., MDS, AML), but with limited efficacy. While some known compounds, such as quizartinib, gilteritinib, and crenolanib, can be used to treat AML, some treatments fail to achieve complete or partial remission. For example, in some cases, treatment can lead to adaptive resistance or selective mutations that make the tumor resistant to inhibitors, particularly with quizartinib, where repeated administration can lead to desensitization to tumor cell proliferation inhibition (Melgar et al., 2019).

[0010] In the treatment of MDS and / or AML, it is important to develop therapies that can inhibit adaptive tolerance mechanisms to improve survival in the context of AML and MDS. There is also an unmet need for AML drugs that improve overall survival, shorten hospital stays and readmission rates, overcome acquired resistance to other treatments, and improve the success rate of hematopoietic stem cell transplantation. Additionally, there is a need for drugs to treat MDS that can slow the rate of transformation to AML and reduce transfusion dependence.

[0011] Therefore, it is necessary to develop effective treatments and methods for MDS and / or AML. Furthermore, in doing so, it is important to determine whether a patient is likely to respond to a particular treatment or therapy. Certain embodiments of the present invention can address one or more of these problems. Summary of the Invention

[0012] In one embodiment, this disclosure provides compounds of formula (I), (II), or (III):

[0013]

[0014] Or its salts, esters, solvates, optical isomers, geometric isomers, isomer salts, prodrugs, or derivatives, wherein: A is selected from 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; R 1 R 2 R 3 R 4 and R 5 Each is independently selected from H, deuterium, halogen, hydroxyl group, oxo group, -CN, -C(=O)H, -C(=O)OH, C 17 Alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, -C(=O)NR 31 R 32 Cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, 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, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl or -O-fused-ring heteroaryl are optionally one or more of the following. Substitution: deuterium, halogen, hydroxyl, oxo, -C(=O)H, -C(=O)OH, nitro (-NO2), -NH2, -N(CH3)2], cyano (-CN), ethynyl (-CCH), propynyl, -SO3H, cycloalkyl, heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)NH2, -C(=O)N(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy or C1-C7 alkyl substituted with cycloalkyl; R 6 for Or by one or more -NR 33 R 34 Substituted C3-C6 cycloalkyl; R 7 R 8 R 9 R 10 R 11 R 12 R 13 and R 14Each is independently selected from H, deuterium, halogen, hydroxyl, oxo group, -CN, -C(=O)H, -C(=O)OH, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, 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, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl The heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl may optionally be substituted with one or more of the following: deuterium, halogen, hydroxyl, oxo group, -C(=O)H, -C(=O)OH, nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, -SO3H, cycloalkyl, heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)NH2, -C(=O)N(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl; 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 30Independently selected from H, deuterium, halogen, hydroxyl, oxo group, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, 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, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl The alkyl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl may optionally be substituted with one or more of the following: deuterium, halogen, hydroxyl, oxo, -C(=O)H, -C(=O)OH, nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl-SO3H, cycloalkyl, heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)NH2, -C(=O)N(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl; R 31 and R 32 Each is 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 Each is independently selected from H and C1-C6 alkyl groups; and m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5, wherein q+r+s+t is at least 1, and wherein u+v+w+x is at least 1. In one embodiment, the compound of formula (I) is a compound of formula (Ib-5010-WO50): (Ib-5010-WO50)

[0015] Or its salts, esters, solvates, optical isomers, geometric isomers, or isomer salts; wherein: V is N or CR 11 W is N or CR 12 X is N or CR 13 ; for R 10b Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens; R 17b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C3-C9 heterocyclic groups, imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens.

[0016] R 11 R 12 and R 13 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 14a R 14b R 15a R 15b R 16a R 16b R 18a and R 18b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and one of V, W, or X is N. In one embodiment, at least one of (i) to (v) is applicable: (i) R 14b R 15a R 15b R 16a and R 16b Each of them is H, and R 14a For F; (ii)R 11 R 12 and R 13 If it exists, it is H; (iii) V is CR 11 , where R 11 F is F, W is CR 12 , where R 12 H is H, and X is N; (iv) R 10b Selected from H and -OCH3; and (v)R 17b Selected from In one embodiment, when R 17b for At that time, R10b For H; and when R 17b for At that time, R 11 R 12 and R 13 At least one of the following is present and is selected from C1-C6 alkoxy groups and halogens. In one embodiment, the compound of formula (Ib-5010-WO50) is selected from: In some embodiments, the compound of formula (I) is a compound of formula (Id-5010-WO50): (Id-5010-WO50), or its salt, ester, solvate, optical isomer, geometric isomer, or isomer salt; wherein: V is N or CR 11 W is N or CR 12 X is N or CR 13 ; for R 10d Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and the C3-C6 cycloalkyl group is wherein the -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl groups and halogens; R 113d Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from –OH, C1-C6 alkyl, and halogens; R 11 R 12 and R 13 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 18a and R 18b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; R 19a R 19b R 110a R 110b R111a R 111b R 112a and R 112b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and one of V, W, or X is N. In one embodiment, at least one of (i) to (vi) is applicable: (i) R 19a R 19b R 110a R 110b R 111a R 111b R 112a and R 112b Each of them is H; (ii)R 19a R 19b R 110b R 111a R 111b R 112a and R 112b Each of them is H and R 110a For F; (iii)R 11 R 12 and R 13 If it exists, it is H; (iv) V is CR 11 , where R 11 F is F, W is CR 12 , where R 12 Let H be a variable and X be a variable N; (v)R 10d Selected from H and -OCH3; and (vi)R 113d Selected from In one embodiment, when R 113d for At that time, R 10d Let H be the value of R; and R be the value of R. 113d for At that time, R 11 R 12 and R 13 At least one of the following is present and is selected from C1-C6 alkoxy groups and halogens. In one embodiment, the compound of formula (Id-5010-WO50) is selected from... In one embodiment, the compound of formula (II) is a compound of formula (IIa-5010-WO50): (IIa-5010-WO50), or its salt, ester, solvate, optical isomer, geometric isomer, or isomer salt; wherein: L is N or CR 21M is N or CR 22 Q is N or CR 23 ; for R 20a Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens; R 27a Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, spirocycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, spirocycloalkyl, -O-(C3-C6 cycloalkyl) and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens.

[0017] R 21 R 22 and R 23 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 24a R 24b R 25a R 25b R 26a and R 26b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; R 28a and R 28b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the 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 (v) is applicable: (i) R 24b R 25a R 25b R 26a and R 26b Each of them is H, and R 24a For F; (ii)R21 R 22 and R 23 If it exists, it is H; (iii) L is CR 21 , where R 21 Selected from F, Cl and -OCH3, M is CR 22 , where R 22 H is H, and Q is N; (iv) R 20a Selected from -OCH3, unsubstituted O-(C3 cycloalkyl) and and (v)R 27a Selected from unsubstituted C3-C6 cycloalkyl groups, In one embodiment, when R 20a It is -OCH3 and R 27a When R is an unsubstituted C3 cycloalkyl group, 21 R 22 and R 23 At least one of the following is present and is selected from C1-C6 alkoxy groups and halogens. In one embodiment, the compound of formula (IIa-5010-WO50) is selected from:

[0018] In one embodiment, the compound of formula (II) is a compound of formula (IIb-5010-WO50): (IIb-5010-WO50), or its salt, ester, solvate, optical isomer, geometric isomer, or isomer salt; wherein: L is N or CR 21 M is N or CR 22 Q is N or CR 23 ; for R 20b Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens; R 27b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, spirocycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 28a R 28bThe C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and the C3-C6 cycloalkyl, spirocycloalkyl, -O-(C3-C6 cycloalkyl), and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl, and halogens; R 21 R 22 and R 23 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; R 28a and R 28b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the 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) is applicable: (i) R 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b Each of them is H; (ii)R 29a R 29b R 210b R 211a R 211b R 212a and R 212b Each of them is H and R 210a For F; (iii)R 21 R 22 and R 23 If it exists, it is H; (iv) L is CR 21 , where R 21 Selected from F, Cl and -OCH3, M is CR 22 , where R 22 H is H and Q is N; (v)R 20b Selected from -OCH3, -OCD3, unsubstituted -O-(C3 cycloalkyl) and and (vi)R 27bSelected from unsubstituted C3-C6 cycloalkyl groups, In one embodiment, when R 20b It is -OCH3 and R 27b When R is an unsubstituted C3 cycloalkyl group, 21 R 22 and R 23 At least one of the following is present and is selected from C1-C6 alkoxy groups and halogens. In one embodiment, the compound of formula (IIb-5010-WO50) is selected from:

[0019]

[0020]

[0021]

[0022]

[0023]

[0024] In one embodiment, the compound of formula (III) is a compound of formula (IIIa-5010-WO50): (IIIa-5010-WO50), or its salt, ester, solvate, optical isomer, geometric isomer, or isomer salt; wherein: R is N or CR 31 T is N or CR 32 U is N or CR 33 ; for R 37a Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazole groups, triazolyl groups, 2-pyrrolidone groups, and -C(=O)NR groups. 38a R 38b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and the C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl, and halogens; R 31 R 32 and R 33 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0025] R 34a R 34b R 35a R 35b R 36a and R 36b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; R 38a and R 38b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and one of R, T, or U is N. In one embodiment, at least one of (i) to (iv) is applicable: (i) R 34b R 35a R 35b R 36a and R 36b Each of them is H, and R 34a For F; (ii)R 31 R 32 and R 33 If it exists, it is H; (iii) R is CR 31 , where R 31 Let F be F and T be CR. 32 , where R 32 H is a variable, and U is a variable; and (iv) R is a variable. 37a Selected from In one embodiment, R 37a Not for In one embodiment, the compound of formula (IIIa-5010-WO50) is: In some embodiments, the compound of formula (III) is a compound of formula (IIIb-5010-WO50): (IIIb-5010-WO50), or its salt, ester, solvate, optical isomer, geometric isomer, or isomer salt; wherein: R is N or CR 31 T is N or CR 32 U is N or CR 33 ; for R 37b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazole groups, triazolyl groups, 2-pyrrolidone groups, and -C(=O)NR groups. 38a R 38bThe C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and the C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl, and halogens; R 31 R 32 and R 33 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0026] R 39a R 39b R 310a R 310b R 311a R 311b R 312a and R 312b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; R 38a and R 38b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and one of R, T, or U is N. In one embodiment, at least one of (i) to (v) is applicable: (i) R 39a R 39b R 310a R 310b R 311a R 311b R 312a and R 312b Each of them is H; (ii)R 39a R 39b R 310b R 311a R 311b R 312a and R 312b Each of them is H and R 310a For F; (iii)R 31 R 32 and R 33 If it exists, it is H; (iv) R is CR 31 , where R 31 Let F be F and T be CR. 32 , where R 32 H is a constant and U is a constant; and (v)R is a constant. 37b Selected from In one embodiment, when R 37b for At that time, R31 R 32 and R 33 At least one of the following is present and is selected from C1-C6 alkoxy groups and halogens. In one embodiment, the compound of formula (IIIb-5010-WO50) is selected from: In one embodiment, (i) 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 isomer salt thereof is an inhibitor of at least one of IRAK1, IRAK4, and FLT3; (ii) 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 isomer salt thereof is an inhibitor of at least one of IRAK1, IRAK4, and FLT3; and (ii) 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), formula (IIIb-5010-WO50), formula (II ...IIb-5010-WO50), formula (IIIb-5010-WO50), formula ( (i) A compound of formula (Ib-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt thereof of any of these formulas is an inhibitor of IRAK1 and IRAK4 and not an inhibitor of FLT3; or (ii) A 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 isomer salt thereof of any of these formulas is an inhibitor of each of IRAK1, IRAK4, and FLT3.

[0027] In another aspect, this disclosure provides a composition comprising a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt 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 of the above, wherein the composition further comprises a formulation ingredient, an adjuvant, or a carrier.

[0028] In another aspect, this disclosure provides a method for treating a disease or condition in a subject in need, the method comprising administering to the 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 a salt or ester of any of these. The disease or condition may be a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt of a compound comprising (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO50), or (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt thereof. In one embodiment, the disease or condition is relieved by inhibition of at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition. In one embodiment, the disease or condition comprises hematopoietic system cancer. In one embodiment, the hematopoietic system 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 mutation, follicular lymphoma, and marginal zone lymphoma. In one embodiment, the disease or condition is selected from: 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 one embodiment, the disease or condition includes at least one cancer selected from: myeloma, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer.In one embodiment, the disease or condition comprises at least one inflammatory disease or autoimmune disease selected from the following: chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, and Sjögren's syndrome. Syndrome), ankylosing spondylitis, systemic sclerosis, type 1 diabetes, Crohn's disease, colitis, and atopic dermatitis. In one embodiment, the method further comprises administering one or more adjunctive therapies to the subject, the adjunctive therapies being selected from: chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or isocitrate dehydrogenase 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, smooth receptor antagonists. This includes ERK inhibitors (including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors), PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog protein (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR inhibitors, PKC and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, AuraA inhibitors, and aurora kinases. The adjunctive therapy includes inhibitors of kinase, EGFR inhibitors, AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT1, AKT2 and / or AKT3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, and multi-kinase inhibitors. In one embodiment, the adjunctive 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 thereof, the CDK inhibitor is selected from CDK4 / 6 inhibitor palbociclib, CDK7 inhibitor THZ1 and / or CDK9 inhibitor BAY1251152 and avecilib, or a pharmaceutically acceptable salt thereof, 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 isomer salt thereof, or a composition comprising 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 isomer salt thereof, is administered with one or more adjunctive therapies in a single administration or in a 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 a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt thereof, or a compound containing formula (Ib-5010-WO50), or any of these, is used. Compositions of compounds of formulas (Id-5010-WO50), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO50), (IIIb-5010-WO50), or salts, esters, solvates, optical isomers, geometric isomers, or isomer salts thereof, administered separately with one or more adjunctive therapies in more than one administration or in more than one composition.In one embodiment, the compound is a compound of any one of the formulas (Ib-5010-WO50), (Id-5010-WO50), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO50), and (IIIb-5010-WO50), or a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt of any one of them.

[0029] On the other hand, this disclosure provides a method for increasing the survival of a subject diagnosed with or suspected of having acute myeloid leukemia (AML), the method comprising administering to the subject a therapeutically effective amount of a compound of formula (Ib-5010-WO50), formula (Id-5010-WO50), formula (IIa-5010-WO50), formula (IIb-5010-WO50), formula (IIIa-5010-WO50), and formula (IIIb-5010-WO50). A salt, ester, solvate, optical isomer, geometric isomer, or isomer salt of any of the following, or a composition comprising 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 isomer salt of any of the following. In one embodiment, the subject's survival is increased compared to a subject treated with a therapeutically effective amount of standard care for AML. In one embodiment, standard care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is a human. In one embodiment, the survival of the subject was increased by approximately 1 year, approximately 2 years, approximately 3 years, approximately 4 years, approximately 5 years, approximately 6 years, approximately 7 years, approximately 8 years, approximately 9 years, approximately 10 years, approximately 11 years, approximately 12 years, approximately 13 years, approximately 14 years, approximately 15 years, approximately 16 years, approximately 17 years, approximately 18 years, approximately 19 years, or approximately 20 years compared to a subject treated with a therapeutically effective amount of standard care for AML. In one embodiment, the method comprises administering to the subject a therapeutically effective amount of the following formulas approximately every 6 hours, every 12 hours, every 18 hours, daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or weekly: 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). A compound or a salt, ester, solvate, optical isomer, geometric isomer or isomer salt of any of the above, or a composition comprising 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 isomer salt of any of the above.In one embodiment, the method further comprises administering one or more adjunctive therapies to the subject, the adjunctive therapies being selected from: chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or isocitrate dehydrogenase 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. Smooth receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog protein (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 Inhibitors include A-type inhibitors, aurora kinase inhibitors, EGFR inhibitors, AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT1, AKT2 and / or AKT3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, and multi-kinase inhibitors. In one embodiment, the adjunctive therapy is at least one of BCL2 inhibitors, BTK inhibitors, glucocorticoids, CDK inhibitors, and DNA methyltransferase inhibitors. 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 thereof, the CDK inhibitor is selected from CDK4 / 6 inhibitor palbociclib, CDK7 inhibitor THZ1 and / or CDK9 inhibitor BAY1251152 and avecilib, or a pharmaceutically acceptable salt thereof, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.In one embodiment, AML is selected from: 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 a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt thereof, or a composition comprising 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 isomer salt thereof, is administered with one or more adjunctive therapies in a single administration or in a 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 a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt thereof, or a compound containing formula (Ib-5010-WO50), or any of these, is used. Compositions of compounds of formulas (Id-5010-WO50), (IIa-5010-WO50), (IIb-5010-WO50), (IIIa-5010-WO50), (IIIb-5010-WO50), or salts, esters, solvates, optical isomers, geometric isomers, or isomer salts thereof, administered separately with one or more adjunctive therapies in more than one administration or in more than one composition. Attached Figure Description

[0030] Figure 1 The relative concentrations (nM) of the representative compounds of this disclosure and gitertinib (“Gil”) required for a fully enhanced (<20%) CellTiterGlo response with 312.5 nM venetoclax in THP1 cells at 48 hours are depicted. Lower concentrations indicate higher potency in synergistic effect with venetoclax.

[0031] Figure 2The relative concentrations (nM) of the representative compounds of this disclosure and gitertinib (“Gil”) required for a 62.5 nM venetoclax CellTiter Glo response in 48-hour fully enhanced (<10%) MOLM14(D835Y) cells are depicted. Lower concentrations indicate higher potency in synergistic effect with venetoclax.

[0032] Figure 3 Provided in Figure 4 and Figures 5A to 5B The structure of the compound studied in the study.

[0033] Figure 4 This is a survival graph of mice with intravascularly implanted AML cells, comparing the survival rates of compound C (30 mg / kg) with the control, gitertinib SOC (30 mg / kg), and CA-4948 (emavusertib, 30 mg / kg).

[0034] Figures 5A to 5B This is a chart depicting the leukemia grade at the time of autopsy. When adjusted for survival, all treated animals showed significant improvement compared to the control group, and the F06 score was lower compared to standard care (F02). Figure 5A Leukemia grade at autopsy (statistical analysis used is the mean, confidence interval is 95%). Figure 5B Leukemia grade adjusted for survival at autopsy (the statistical analysis used is the geometric mean with geometrical SD). All compounds used in this study were administered at 30 mg / kg. Detailed Implementation

[0035] The following related applications are incorporated herein by reference in their entirety and for all purposes: International Publication No. WO 2018081738, filed October 30, 2017, Treatment of Disses Assaulted with Actualized Irk; U.S. Publication No. 2021 / 0292843, filed April 4, 2019, Treatment of Disses Assaulted with Actualized Irk; International Publication No. 2014190163, filed May 22, 2014, Combination Therapy for MDS; U.S. Patent No. 9,168,257, issued October 27, 2015, Combination Therapy for MDS; and U.S. Patent No. 9,504,706, issued November 29, 2016, Combination Therapy for MDS; U.S. Patent No. 9,855,273, issued January 2, 2018, Combination Therapy for MDS; International Publication No. WO 2018038988, filed August 16, 2017, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds; U.S. Patent No. 11,254,667, issued February 2, 2022, Substitutedimidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors; U.S. Publication No. 2022 / 0213094, filed January 4, 2022, Substituted imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors; U.S. Publication No. 2020 / 0199123, filed February 28, 2020, Substituted imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors; U.S. Publication No. 2022 / 0235042, filed January 28, 2022, Substitutedimidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors;International Publication No. WO 2020252487, filed June 15, 2020, entitled "Rational therapeutic targeting of oncogenic immune signaling states in myeloid malignancies via the ubiquitin conjugating enzyme UBE2N"; International Publication No. WO 2022026935, filed July 31, 2021, entitled "Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof"; International Publication No. WO 2022140647, filed December 23, 2021, entitled "Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof"; International Publication No. WO 2023009833, filed July 29, 2022, entitled "Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof". Thereof; International Patent Application No. PCT / US2023 / 068520, filed June 15, 2023, entitled Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof; International Patent Application No. PCT / US2023 / 068897, filed June 22, 2023, entitled Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof; International Patent Application No. PCT / US2023 / 071435, filed August 1, 2023, entitled Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof; and International Patent Application No. PCT / US2023 / 034438, filed October 4, 2023, entitled Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof.

[0036] Although embodiments covering the overall inventive concept may take various forms, as described herein, it should be understood that this disclosure is to be considered exemplary only, and the overall inventive concept is not intended to be limited to the disclosed embodiments.

[0037] Some embodiments of the invention include compounds of the invention (e.g., compounds of formula (I)). Other embodiments include compositions comprising compounds of the invention (e.g., pharmaceutical compositions). Still other embodiments of the invention include compositions for treating, for example, certain diseases using compounds of the invention. Some embodiments include methods of administering and treating using compounds of the invention (e.g., in a composition or in a pharmaceutical composition). Additional embodiments include methods for preparing compounds of the invention. Still additional embodiments include methods for determining whether a particular patient is likely to respond to such treatment with compounds and compositions of the invention.

[0038] Unless otherwise stated, the terminology should be understood in accordance with the common usage of those skilled in the art in the relevant field.

[0039] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described in this article are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0040] When a substituent is specified by its conventional chemical formula (written from left to right), it equally covers the chemically identical substituents produced when the structure is written from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0041] As used herein, with respect to compounds of formulas (I), (II), (III), etc., the term “connected” indicates a stable covalent bond, and certain preferred connection points will be obvious to those skilled in the art.

[0042] As used herein (unless otherwise specified), the term "alkyl" means a monovalent, straight-chain or branched hydrocarbon chain that can be fully saturated, monounsaturated or polyunsaturated, and can include divalent and polyvalent groups having a specified number of carbon atoms (i.e., C1-C1). 10 (This refers to one to ten carbon atoms). For example, the terms "C1-C7 alkyl" or "C1-C4 alkyl" refer to straight-chain or branched saturated hydrocarbon groups having one to seven (e.g., one, two, three, four, five, six, or seven) or one to four (e.g., one, two, three, or four) carbon atoms, respectively. Examples of C1-C7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, n-hexyl, and n-heptyl. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

[0043] As used herein (unless otherwise stated), the term "alkenyl" means a monovalent straight-chain or branched hydrocarbon chain comprising one or more (e.g., 1, 2, 3, or 4) double bonds. The double bonds can occur at any stable point along the chain, and the carbon-carbon double bonds can have cis or trans configurations. For example, this definition should include, but is not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nontrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, 1-pentyl-3-cyclohexenyl, etc. Similarly, "heteroalkenyl" refers to a heteroalkyl group having one or more double bonds. Other 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.

[0044] As used herein (unless otherwise stated), the term "alkynyl" means a monovalent straight-chain or branched hydrocarbon chain comprising one or more (e.g., 1, 2, 3, or 4) triple bonds and optionally one or more (e.g., 1, 2, 3, or 4) double bonds. 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.

[0045] As used herein (unless otherwise stated), the term "alkoxy" means any of the aforementioned alkyl, alkenyl, or alkynyl groups connected to the remainder of the molecule by an oxygen atom (alkyl-O-). Examples of alkoxy groups include, but are not limited to, methoxy (sometimes shown as MeO-), ethoxy, isopropoxy, propoxy, and butoxy.

[0046] Unless otherwise stated, the term "alkylene", either on its own or as part of another substituent, refers to a divalent group derived from an alkyl, alkenyl, or alkynyl group, such as, but not limited to, those exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) will have 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. "Lower alkyl" or "lower alkylene" refers to a short-chain alkyl or alkylene group, typically having eight or fewer carbon atoms.

[0047] As used herein (unless otherwise stated), the term "cycloalkyl" refers to a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered hydrocarbon group, whether monocyclic or bicyclic. The ring may be saturated or partially unsaturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicyclic alkyl groups (e.g., bicyclic octane (such as [2.2.2]bicyclic octane or [3.3.0]bicyclic octane, bicyclic nonane (such as [4.3.0]bicyclic nonane) and bicyclic decane (such as [4.4.0]bicyclic decane (decahydronaphthalene)) or spirocyclic compounds) or spirocyclic compounds). For monocyclic cycloalkyl groups, the ring is not aromatic. For bicyclic cycloalkyl groups, if one ring is aromatic, the other is not aromatic. For bicyclic cycloalkyl groups, one or both rings may be substituted.

[0048] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term means a stable straight or branched chain or combination thereof consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein nitrogen and sulfur atoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. Heteroatoms O, N, P, S, and Si may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. At most two heteroatoms can be consecutive, for example, -CH2-NH-OCH3.

[0049] Similarly, unless otherwise stated, the term "heteroalkylene" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, those exemplified by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom may also occupy any one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further still, for alkylene and heteroalkyl linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups as used herein include those groups attached to the remainder of the molecule via heteroatoms, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO2R'. Where the term "heteroalkyl" is followed by a specific heteroalkyl group, such as -NR'R", it should be understood that the terms heteroalkyl and -NR'R are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is described for clarity. Therefore, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups such as -NR'R".

[0050] As used herein (unless otherwise stated), the terms "halogen" or "halogenated" mean monovalent Cl, F, Br, or I. Additionally, terms such as "halogenated alkyl" refer to both monohalogenated and polyhalogenated alkyl groups. For example, the term "halogenated (C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0051] As used herein (unless otherwise stated), the term "aryl" means a monovalent, monocyclic or bicyclic, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered aromatic hydrocarbon group, and also means a polyunsaturated, aromatic hydrocarbon substituent that can be fused together (i.e., fused-ring aryl) or covalently linked one or more rings (preferably one to three rings). A fused-ring aryl refers to a plurality of rings fused together, wherein at least one ring in the fused ring is an aryl ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. For bicyclic aryl groups, one or both rings may be substituted.

[0052] As used herein (unless otherwise stated), the term "heteroaryl" means a 5, 6, 7, 8, 9, 10, 11, or 12-membered hydrocarbon group of a monocyclic or bicyclic form, wherein one, two, three, four, five, or six carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the monocyclic or bicyclic system is aromatic. A heteroaryl (or ring) may contain one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Therefore, the term "heteroaryl" includes fused-ring heteroaryl (i.e., a plurality of rings fused together, wherein at least one ring in the fused ring is a heteroaryl ring). A 5,6-fused-ring heteroaryleline refers to two rings fused together, wherein one ring has five members and the other ring has six members, and wherein at least one ring is a heteroaryl ring. Similarly, a 6,6-fused-ring heteroarylene refers to two fused rings, one having six members and the other having six members, and at least one of the rings being a heteroarylene ring. And a 6,5-fused-ring heteroarylene refers to two fused rings, one having six members and the other having five members, and at least one of the rings being a heteroarylene ring. Heteroarylene groups can be attached to the rest of the molecule via carbon or heteroatoms. Examples of heteroarylene groups include, but are not limited to, thiophene (or phenylthio), furanyl, indolyl, pyrrole, pyridyl, pyrazinyl, oxazolyl, thiazolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisooxazolyl, 1H-pyrrole-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl. For bicyclic heteroaryl groups, if one ring is aryl, the other is heteroaryl. For bicyclic heteroaryl groups, one or both rings may have one or more heteroatoms. For bicyclic heteroaryl groups, one or both rings may be substituted.

[0053] "Arylene" and "heteroarylene" refer, alone or as part of another substituent, to divalent groups derived from aryl and heteroaryl groups, respectively. Therefore, the term "aryl" can refer to an unsubstituted, monosubstituted, disubstituted, or trisubstituted monocyclic, polycyclic, diaryl, or heterocyclic aromatic group covalently attached to any ring position capable of forming a stable covalent bond, with certain preferred attachment sites being apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl). Aryl substituents are independently selected from the group consisting of: halogenated, nitro, cyano, trihalomethyl, C... 1-16 Alkyl, aryl C 1-16 Alkyl, C 0-16 Alkoxy C 0-16 Alkyl, aryl C 0-16 Alkoxy C 0-16 Alkyl, C 0-16 Alkyl thio group C0-16 Alkyl, aryl C 0-16 Alkyl thio group C 0-16 Alkyl, C 0-16 Alkylamino C 0-16 Alkyl, aryl C 0-16 Alkylamino C 0-16 Alkyl, di(aryl C) 1-16 alkyl)aminoC 0-16 Alkyl, C 1-16 Alkyl carbonyl C 0-16 Alkyl, aryl C 1-16 Alkyl carbonyl C 0-16 Alkyl, C 1-16 alkyl carboxyl C 0-16 Alkyl, aryl C 1-16 alkyl carboxyl C 0-16 Alkyl, C 1-16 alkyl carbonyl amino C 0-16 Alkyl, aryl C 1-16 alkyl carbonyl amino C 0-16 Alkyl, -C 0-16 Alkyl COOR4,-C 0-16 Alkyl group CONR5R6, wherein R4, R5, and R6 are independently selected from hydrogen, C1-C6. 11 Alkyl, aryl C0-C 11 Alkyl groups, or R5 and R6, together with the nitrogen atoms they are attached to, form a ring system containing 3 to 8 carbon atoms, said ring system having or not having one carbon atom. 1-16 Alkyl, aryl C0-C 16 Alkyl or CO-Cl 16 Alkyl aryl substituents. Aryl groups include, but are not limited to, pyrazolyl and triazolyl groups.

[0054] For the sake of brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthoxy, arylalkyl) includes both aryl rings and heteroaryl rings as defined above. Therefore, the terms "arylalkyl," "arylalkyl," etc., refer to those groups in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), said alkyl group comprising those alkyl groups in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthoxy)propyl, etc.) or a sulfur atom. Thus, the terms "arylalkyl," etc. (e.g., (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represent an aryl group as defined above attached by an alkyl group having the indicated number of carbon atoms as defined above.

[0055] Unless otherwise stated, the terms “cycloalkyl” and “heterocycloalkyl” (also known as “heterocyclic group”), whether used alone or in combination with other terms, refer to the cyclic form of “alkyl” and “heteroalkyl”, respectively. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. As used herein (unless otherwise stated), the terms “heterocycloalkyl” or “heterocyclic group” mean a 5, 6, 7, 8, 9, 10, 11, or 12-membered hydrocarbon group of a monocyclic or bicyclic ring, wherein one, two, three, four, five, or six carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic system is not aromatic. Additionally, for heterocycloalkyl groups, the heteroatom may occupy the position of the heterocycle attached to the remainder of the molecule. Examples of heterocyclic alkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, and pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidinyl...). Pyrrolidine-2-yl, pyrrolidine-3-yl, or pyrrolidine-4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, or piperazin-4-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl), and morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl). For bicyclic heterocyclic groups, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), the other ring is not aromatic. For bicyclic heterocyclic groups, one or both rings may have one or more heteroatoms. For bicyclic heterocyclic groups, one or both rings may be substituted, etc. "Cycloalkylene" and "heterocyclic alkylene" themselves, or as part of another substituent, refer to divalent groups derived from cycloalkyl and heterocyclic alkyl groups, respectively.

[0056] As used herein (unless otherwise stated), the term "heteroatom" means an atom selected from nitrogen, oxygen, or sulfur atoms.

[0057] As used herein (unless otherwise stated), the term "hydroxyl" or "hydroxyl" refers to a monovalent -OH group.

[0058] Unless otherwise stated, the term "acyl" means -C(O)R, where R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0059] As used in this article, the term "oxo" refers to oxygen bonded to a carbon atom in a double bond.

[0060] As used herein, the term "alkylsulfonyl" means having the formula -S(O2)-R', where R' is an alkyl group as defined above. R' may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0061] The term "carbonyloxy group" refers to a carbonyl group connected by an oxygen bridge.

[0062] In the above definitions, the terms "alkyl" and "alkenyl" are used interchangeably, as will be obvious to those skilled in the art as long as they form a stable chemical entity.

[0063] The term "connector" refers to a linking group between substituents. In some embodiments, the connector includes an amide group (-CONH-R). n or -NHCO-R n ), thioamide group (-CSNH-R) n or -NHCS-R n ), carboxyl group (-CO2-R) n or -OCOR n ), carbonyl (-CO-R) n ), urea (-NHCONH-R) n ), thiourea (-NHCSNH-R) n ), sulfonamide group (-NHSO2-R) n or -SO2NH-R n ), ether (-OR) n ), sulfonyl (-SO2-R) n ), sulfonyloxy (-SO-R) n ), carbamoyloxy (-NHCO2-R) n or -OCONH-R n ) or amino (-NHR) n (Connecting part)

[0064] Each of the above terms (e.g., "alkyl", "heteroalkyl", "aryl", and "heteroaryl") includes both substituted and unsubstituted forms of the indicated group. Preferred substituents are provided herein for each type of group.

[0065] As used herein (unless otherwise stated), the term "substituted" (e.g., as in substituted alkyl groups) means that one or more hydrogen atoms in a chemical group (having one or more hydrogen atoms) may be substituted by one or more non-hydrogen substituents selected from a particular option. Substitution may occur at one or more positions. The term "optionally substituted" means that one or more hydrogen atoms in a chemical group (having one or more hydrogen atoms) may, but must, be substituted.

[0066] As used herein, "substituent" refers to a non-hydrogen substituent, which may be, and preferably is, a group selected from the following:

[0067] (A) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxyl, oxo, -CN, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfonyl (-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

[0068] (B) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups substituted with at least one of the following:

[0069] (i) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxyl, oxo, -CN, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfonyl (-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

[0070] (ii) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups substituted with at least one of the following:

[0071] (a) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxyl, oxo, -CN, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfonyl (-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

[0072] (b) A C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group substituted with at least one of the following: -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxyl, oxo, -CN, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfonyl (-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.

[0073] As used herein, “size-limited substituent” or “size-limited substituent group” means a group, such as a “substituent” selected from all the substituents described above, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C. 20 Alkyl group, each substituted or unsubstituted heteroalkyl group being a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group being a substituted or unsubstituted C4-C8 cycloalkyl group, and each substituted or unsubstituted heterocycloalkyl group being a substituted or unsubstituted 4- to 8-membered heterocycloalkyl group.

[0074] As used herein, “lower substituent” or “lower substituent group” means a group, such as a “substituent” selected from all the substituents described above, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C5- to 7-membered heteroalkyl group, and each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 5- to 7-membered heterocycloalkyl group.

[0075] Unless otherwise explicitly stated, the term “about” as used in a numerical context refers to a range of + / -10% of the numerical value.

[0076] For any one of one or more chiral centers, some compounds of the present invention may have one or more chiral centers and may exist and be separated in optically active and racemic forms. Some compounds may exhibit polymorphism. The compounds of the present invention (e.g., Formula I) encompass any optically active form, racemic form, stereoisomer form, polymorphism, or mixture thereof. If the chiral center does not provide an indication of its configuration (i.e., R or S) in the chemical structure, it should be assumed to represent R, S, or a racemic mixture.

[0077] As used herein, the term "sample" encompasses a sample obtained from a subject or patient. A sample can be 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 or fine-needle biopsy samples, cell-containing body fluids, free floating nucleic acids, urine, feces, peritoneal and pleural fluids, tears, or cells therein. Samples may also include tissue sections, such as frozen or fixed sections for histological purposes, or microdissected cells or their extracellular portions. The sample to be analyzed can be tissue material or excised cellular material from a tissue biopsy obtained by aspiration or perforation, excision, or by any other surgical method leading to a biopsy. Such samples may contain cells obtained from a subject or patient. In some embodiments, the sample is a body fluid, including, but not limited to, blood, serum, mucus, plasma, lymph, ascites, gynecological fluid, or urine. In some embodiments, the sample can be a non-invasive sample, such as saline mouthwash, buccal scraper, buccal swab, etc.

[0078] As used in this article, "blood" may include, for example, plasma, serum, whole blood, blood lysates, etc.

[0079] As used herein, the term “evaluation” includes any form of measurement and includes determining the presence of an element. The terms “determine,” “measurement,” “evaluating,” “assessing,” “analysis,” and “determination” are used interchangeably and include quantitative and / or qualitative determination.

[0080] As used herein, the term "monitoring" in relation to cancer type refers to a method or process for determining the severity or extent of a cancer type or stratifying cancer types based on risk and / or mortality. In some embodiments, monitoring involves a method or process for determining the therapeutic efficacy of a treatment administered to a patient.

[0081] As used herein, “outcome” can refer to the results of a study. In some embodiments, “outcome” can refer to survival / mortality rates over a given time frame. For example, “outcome” can refer to survival / mortality rates over a period of more than 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer. In some embodiments, an increased risk of adverse outcomes indicates poor efficacy of the therapy, and a decreased risk of adverse outcomes indicates good efficacy of the therapy.

[0082] As used herein, the term "high-risk clinical trial" refers to a test in which the test kit has "more than the minimum risk" (as defined by the terminology used by an institutional review board or IRB). In some embodiments, a high-risk clinical trial is a drug trial.

[0083] As used herein, the term "low-risk clinical trial" refers to a test kit for which the subject has "minimal risk" (as defined by the terminology used by the IRB). In some embodiments, a low-risk clinical trial is a trial that is not a drug trial. In some embodiments, a low-risk clinical trial is a trial involving the use of a monitor or clinical practice procedure. In some embodiments, a low-risk clinical trial is an observational clinical trial.

[0084] As used herein, the terms “modulated” or “modulation,” “regulated” or “regulation,” and “differential regulation” can refer to upregulation (i.e., activation or stimulation, such as through pain or enhancement) and downregulation (i.e., inhibition or suppression, such as through antagonism, reduction, or suppression) unless otherwise specified or clearly indicated from the context of the particular use.

[0085] As used herein, the term "subject" refers to any suitable (e.g., treatable) member of the animal kingdom. In the method, the subject is preferably a mammal. In the method, the subject is preferably a human patient. In the method, the subject can be a mammalian pediatric patient. In the method, the pediatric patient is a mammalian (e.g., preferably human) patient under the age of 18, and an adult patient is 18 or older.

[0086] As used herein, unless otherwise stated, the term “treating” (and its variations, such as “treatment”, “treating”, “treat”, etc.) shall be considered in its broadest context and refers to achieving the desired pharmacological and / or physiological effects. In particular, for example, the term “treating” may not necessarily mean or require treating an animal until full recovery. Therefore, “treating” includes the reduction of symptoms, the alleviation of symptoms or effects associated with the condition, the reduction or prevention of the severity of the condition, the preventive relief of symptoms, or otherwise the reduction of the risk of developing a particular condition. In some respects, “treating” may not require or include prevention. As used herein, references to “treating” animals include, but are not limited to, preventive and therapeutic treatment. The effect may be preventive in relation to the complete or partial prevention of the disease or its symptoms, and / or therapeutic in relation to the partial or complete cure of the disease and / or side effects attributable to the disease. As used herein, “treatment” encompasses any treatment of a subject’s disease, preferably of a mammal (e.g., a human), and may include one or more of the following: (a) preventing the disease from occurring in a subject who may be predisposed to having the disease but has not yet been diagnosed with it; (b) inhibiting the disease, i.e., preventing its development; and (c) alleviating the disease, i.e., causing the disease to regress or be eliminated and / or alleviating one or more symptoms of the disease. In specific aspects of the methods, such as symptoms or conditions characterized by dysregulation of IRAK expression or dysregulation (e.g., hyperactivity) of IRAK-mediated signaling pathways, treatment may be or may include reducing such expression or signaling. “Treatment” may also encompass the delivery of a pharmaceutical agent or administration of a therapy to provide a pharmacological effect, even in the absence of a disease or symptom. Any of the compositions described herein (e.g., pharmaceutical compositions) may be used to treat a suitable subject.

[0087] "Therapeutic effective amount" means the amount that effectively achieves the desired and / or beneficial effect. An effective amount can be administered in one or more applications. In the methods described, the therapeutic effective amount is the amount appropriate for the therapeutic indication. Therapeutic indication means achieving any desired effect, such as alleviating, improving, stabilizing, reversing, slowing or delaying disease progression, increasing quality of life, or prolonging lifespan, or one or more of these effects. Such achievement can be measured by any suitable method, such as a measurement of tumor size or blood cell count, or any other suitable measurement.

[0088] As used herein, the term "marker" or "biomarker" refers to a biomolecule, such as a nucleic acid, peptide, protein, hormone, etc., whose presence or concentration can be detected and is associated 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 used as part of a predictive, prognostic, or diagnostic process for a health condition or disease state, or alternatively, in methods for identifying useful therapeutic or preventative therapies.

[0089] As used herein, an mRNA “isotype” is an alternative transcript of a specific mRNA or gene. This term includes premRNA, immature mRNA, mature mRNA, cleaved or otherwise shortened, shortened or aberrant mRNA, modified mRNA (e.g., containing any residue modifications, capped variants, polyadenylated variants, etc.), etc.

[0090] An "antibody" or "antibody peptide" refers to a complete antibody or its binding fragment that competes with the complete antibody for specific binding; this definition also covers monoclonal and polyclonal antibodies. The binding fragment is generated by recombinant DNA technology or by enzymatic or chemical cleavage of the complete antibody. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies. Antibodies other than "bispecific" or "bifunctional" antibodies are understood to have identical binding sites at each of their binding sites. For example, when an excess of antibody reduces the amount of receptor binding to the antireceptor by at least about 20%, 40%, 60%, or 80%, and more typically greater than about 85% (as measured in an in vitro competitive binding assay), the antibody essentially inhibits receptor-antireceptor adhesion.

[0091] The embodiments of the invention described herein include compounds of the invention (e.g., compounds of formula (I), such as compounds of formula (II) and (III)). Other embodiments include compositions comprising compounds of the invention (e.g., pharmaceutical compositions). Still other embodiments of the invention include compositions for treating, for example, certain diseases using compounds of the invention (e.g., pharmaceutical compositions). Some embodiments include methods of using compounds of the invention (e.g., in a composition or in a pharmaceutical composition) for administration and treatment (e.g., diseases such as cancer or blood disorders). Some embodiments include methods for determining whether a patient is suitable for or likely to respond favorably to a particular treatment. Additional embodiments include methods for preparing compounds of the invention. Further embodiments of the invention are also discussed herein.

[0092] Compounds and compositions, including pharmaceutical compositions

[0093] In one aspect, this disclosure relates to compounds of formula (I), (II) or (III):

[0094]

[0095] Or a salt, ester, solvate, optical isomer, geometric isomer, isomer salt, prodrug, or derivative thereof. In one embodiment, the compound is a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, isomer salt, prodrug, or derivative of a compound of formula (I), (II), or (III). In some embodiments, the compound is not an ester, solvate, or prodrug of a compound of formula (I), (II), or (III).

[0096] In one embodiment, A in formula (I), (II), or (III) is selected from N and CR. 5 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 CR. 5 D is CR 4 And E is CR 3 .

[0097] In an exemplary embodiment, R of formula (I), (II), or (III) 1 R 2 R 3 R 4 and R 5Each group is independently selected from H, halogen, hydroxyl, oxo group, -CN, amide group, formyl group (-COH), carboxyl group (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, -C(=O)NR 31 R 32 Cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl or -O-fused-ring heteroaryl, wherein the amide group, formyl group (-COH), carboxyl group (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl or -O-fused-ring heteroaryl are optionally one or more of the following. Substitutions include: deuterium, halogen, hydroxyl, oxo, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, 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.

[0098] In some embodiments of formula (I), (II) or (III), R 1It can be H, deuterium, halogen, hydroxyl, oxo group, -CN, amide group, formyl group (-COH), carboxyl group (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic group, -O-heterocyclic group, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl, wherein amide group, formyl group (-COH), carboxyl group (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic group, -O-heterocyclic group, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl may optionally be substituted with one or more of the following: deuterium, halogen, hydroxyl, oxo, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl; R 2It can be H, deuterium, halogen, hydroxyl, oxo group, -CN, amino, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirofused cycloalkyl, -O-spirofused cycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl or -O-fused-ring heteroaryl, wherein amino, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirofused-ring alkyl, -O-spirofused-ring alkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl or - The O-fused-ring heteroaryl group is optionally substituted with one or more of the following: deuterium, halogen, hydroxyl, oxo, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclic, spirofused-ring alkyl, aryl, fused-ring aryl, heteroaryl, fused-ring heteroaryl, or C1-C7 alkyl substituted with cycloalkyl; R 3 R 4 and R 5It can be H, deuterium, halogen, hydroxyl, oxo group, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl, wherein formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heterocyclic, The aryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl group may optionally be substituted with one or more of the following: deuterium, halogen, hydroxyl, oxo, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0099] R in equation (I), (II) or (III) 6 It can be

[0100]

[0101] R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14It can be H, deuterium, halogen, hydroxyl, oxo group, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirofused cycloalkyl, -O-spirofused cycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl, wherein formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirofused cycloalkyl, -O-spirofused cycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl The heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl may optionally be substituted with one or more of the following: deuterium, halogen, hydroxyl, oxo group, -C(=O)H, -C(=O)OH, nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, -SO3H, cycloalkyl, heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)NH2, -C(=O)N(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl; 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 30It can be H, deuterium, halogen, hydroxyl, oxo group, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused Cycloheteroaryl, wherein a formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, -O-cycloalkyl, spirocycloalkyl, -O-spirocycloalkyl, heterocyclic, -O-heterocyclic, aryl, -O-aryl, heteroaryl, -O-heteroaryl, fused-ring heteroaryl, or -O-fused-ring heteroaryl is optionally composed of one of the following: Substitution by one or more: deuterium, halogen, hydroxyl, oxo group, -C(=O)H, -C(=O)OH, nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, -SO3H, cycloalkyl, heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)N H2, -C(=O)N(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy or C1-C7 alkyl substituted with cycloalkyl; and m, n, o, p, q, r, s, t, u, v, w and x may be 0, 1, 2, 3, 4 or 5, wherein q+r+s+t is at least 1, and wherein u+v+w+x is at least 1.

[0102] In some embodiments, R in formula (I), (II), or (III) 1 The derivative is H, deuterium, halogen, -CONH2, -CONHCH3, -CON(CH3)2, benzyl, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or -O-cycloalkyl, wherein the C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or -O-cycloalkyl is optionally substituted with one or more deuterium, halogen, hydroxyl, C1-C7 alkyl, or C1-C7 haloalkyl groups. In some embodiments, R 1 The derivative is H, Cl, -CONH2, -CONHCH3, methoxy, -OCD3, ethoxy, cyclopropyl, C1-C4 alkyl, or -O-C3 cycloalkyl, wherein the methoxy, ethoxy, cyclopropyl, C1-C4 alkyl, or -O-C3 cycloalkyl may optionally be substituted with one or more F, -OH, methyl, or CF3. In some embodiments, R 1 For H. In some embodiments, R 1 Not H.

[0103] In some embodiments, R of formula (I), (II), or (III) 2The following are possible meanings: H, deuterium, halogen, hydroxyl, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclic, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, wherein O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclic, aryl, Fused-ring aryl, heteroaryl, or fused-ring heteroaryl may optionally be substituted with one or more of the following: deuterium, halogen, hydroxyl, -CN, amino, cycloalkyl, heterocyclic, aryl, heteroaryl, fused-ring aryl, fused-ring heteroarylpyrrole, piperidinyl, piperazine, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 2 H, halogen, hydroxyl, O-aryl, amino, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, wherein the O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted by one or more of the following: halogen, hydroxyl, amino, cycloalkyl, heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 2 H, Cl, hydroxyl, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -OCHF2, -OPh, -CF3, -CHF2, unsubstituted C1-C7 alkyl, substituted amino, substituted C1-C7 alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic group, substituted pyrazolyl, substituted fused-ring heteroaryl, or unsubstituted fused-ring heteroaryl. In some embodiments, R 2 Not H.

[0104] In some embodiments, R of formula (I), (II), or (III) 3It is H, deuterium, halogen, hydroxyl, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl or C1-C7 alkoxy, wherein the C1-C7 alkyl or C1-C7 alkoxy is optionally substituted by one or more of the following: deuterium, halogen, hydroxyl, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, 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 It can be H, halogen, hydroxyl, -CN, methyl, -CF3, -OCD3, or methoxy. In some embodiments, R 3 For H. In some embodiments, R 3 Not H.

[0105] In some embodiments, R of formula (I), (II), or (III) 4 It is H, deuterium, halogen, hydroxyl, -CN, formyl (-COH), carboxyl (CO2H), C1-C7 alkyl or C1-C7 alkoxy, wherein the C1-C7 alkyl or C1-C7 alkoxy is optionally substituted by one or more of the following: deuterium, halogen, hydroxyl, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, 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 It can be H, halogen, hydroxyl, -CN, methyl, -CF3, -OCD3, or methoxy. In some embodiments, R 4 For H. In some embodiments, R 4 Not H.

[0106] In some embodiments, R of formula (I), (II), or (III) 5The radical is H, deuterium, halogen, hydroxyl, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, wherein the C1-C7 alkyl or C1-C7 alkoxy is optionally substituted by one or more of the following: halogen, hydroxyl, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 5 It can be H, halogen, hydroxyl, -CN, methyl, -CF3 or methoxy.

[0107] In some embodiments, R of formula (I), (II), or (III) 4 It is methyl or -CF3, and R 3 and R 5 At least one of them is H or a halogen.

[0108] In some embodiments of formula (I), (II) or (III), R 6 A chiral center is present at the carbon junction. In some embodiments, the chiral center is an R-chiral center, an S-chiral center, or a racemic mixture. In some embodiments, the chiral center may be represented by the following bonds: or As those skilled in the art will understand, the straight bond shown may also be present at other positions in compounds according to formulas (I), (II), or (III), where chiral centers may exist. or

[0109] In some embodiments, R of formula (I), (II), or (III) 6 for

[0110]

[0111] In some embodiments, R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14If present, independently selected from H, deuterium, halogen, hydroxyl, oxo group, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, -C(=O)NR 31 R 32 Cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl, wherein the formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl are optionally substituted by one or more of the following groups: deuterium, halogen, hydroxyl, oxo, formyl (-COH), carboxyl (-CO2H), nitro (-NO2). -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrroleyl, piperidinyl, 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 one embodiment, R 7 R 8 R 9 R 10 R 11 R 12 R 13 and R 14 At least one of them is not H. In one embodiment, R 7 R 8 R 9 R 10 R 11 R 12 R 13 and R 14 Each of them (if it exists) is H.

[0112] In an exemplary 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 30If present, independently selected from H, deuterium, halogen, hydroxyl, oxo, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl, wherein the formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl are optionally substituted by one or more of the following groups. : Deuterium, halogen, hydroxyl, oxo group, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, 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 one embodiment, R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 29 R 29 and R 30 At least one of them 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 them (if it exists) is H.

[0113] 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, wherein q+r+s+t is at least 1, and u+v+w+x is at least 1.

[0114] In some embodiments, R of formula (I), (II), or (III) 6 for

[0115]

[0116] In some embodiments, R of formula (I), (II), or (III) 6 for

[0117]

[0118] In some embodiments, R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 (If present) independently selected from H, deuterium, halogen, hydroxyl, oxo, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl, wherein the formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl is optionally surrounded by one or more of the following groups. Substitution: deuterium, halogen, hydroxyl, oxo, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl, provided that R 7 R 8 R 9 R 10 R 11 R 12 R 13 and R 14 At least one of them is not H. In another embodiment, R 7 R8 R 9 R 10 R 11 R 12 R 13 and R 14 Each of them (if it exists) is H. In some embodiments, R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 29 R 29 and R 30 (If present) independently selected from H, deuterium, halogen, hydroxyl, oxo, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl, wherein the formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl is optionally composed of one or more of the following Group substitutions: deuterium, halogen, hydroxyl, oxo, formyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfonyl (-SO3H), heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -CO-morpholin-4-yl, -CONH2, -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, m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5, wherein q+r+s+t is at least 1, and wherein u+v+w+x is at least 1.

[0119] In one embodiment, R 31 and R 32 Each of them is independently selected from H, deuterium, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted by one or more halogens.

[0120] In one embodiment, the compound of formula (I) is a compound of formula (I-5010), (II-5010), or (III-5010).

[0121]

[0122] Or its salts, esters, solvates, optical isomers, geometric isomers, isomer salts, prodrugs, or derivatives, wherein A, D, E, R 1 R 2 and R 6 As defined in equations (I), (II) and (III).

[0123] In one embodiment, formula (I), (II), or (III) is a compound of formula (V), (VI), or (VII):

[0124]

[0125] Or its salts, esters, solvates, optical isomers, geometric isomers, isomer salts, prodrugs or derivatives;

[0126] in:

[0127] I is N or CR 51 ;

[0128] J is N or CR 52 ;

[0129] K is N or CR 53 ;

[0130] Selected from

[0131] Each R 50 Independently selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, spirocycloalkyl, -O-(C3-C6 cycloalkyl), C3-C9 heteroaryl, C2-C9 heterocyclic and -C(=O)NR 552a R 552b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, spirocycloalkyl, -O-(C3-C6 cycloalkyl) and C2-C9 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens.

[0132] R 51 R 52 and R 53 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0133] 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 Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms;

[0134] R 552a and R 552b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and

[0135] N is one of I, J, or K.

[0136] 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 One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In another 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 550bR 551a and R 551b Each of them is H.

[0137] Formula (Ia-5010-WO)

[0138] In one embodiment, the compound of formula (I) is a compound of formula (Ia-5010-WO):

[0139]

[0140] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0141] in:

[0142] V is N or CR 11 ;

[0143] W is N or CR 12 ;

[0144] X is N or CR 13 ;

[0145] for

[0146] R 10a Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0147] R 11 R 12 and R 13 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0148] R 14a R 14b R 15a R 15b R 16a and R 16b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms;

[0149] R 18a and R18b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and

[0150] N is one of V, W, or X.

[0151] In one embodiment, R in equation (Ia-5010-WO) 14a R 14b R 15a R 15b R 16a and R 16b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 15a R 15b R 16a and R 16b Each of them is H, and R 14a and / or R 14b It is a halogen. In one embodiment, R... 15a R 15b R 16a and R 16b Each of them is H, and R 14a and / or R 14b For F. In one embodiment, R 14b R 15a R 15b R 16a and R 16b Each of them is H, and R 14a It is F.

[0152] In one embodiment, R in equation (Ia-5010-WO) 10a It is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 10a Selected from -OCH3 and In one embodiment, R 10a It is an unsubstituted -O-(C3-C6 cycloalkyl). In one embodiment, R 10a It is an unsubstituted -O-(C3 cycloalkyl). In another embodiment, R 10a It is a C1-C6 alkoxy group substituted with one or more halogens. In one embodiment, R 10a Selected from

[0153] In one embodiment, R of formula (Ia-5010-WO) 11 R 12 and R 13(If it exists) is H.

[0154] In one embodiment, the compound of formula (Ia-5010-WO) is the compound covered by the above formula and shown in Table 1 of this application.

[0155] Formula (Ib-5010-WO)

[0156] In another embodiment, the compound of formula (I) is a compound of formula (Ib-5010-WO):

[0157]

[0158] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0159] in:

[0160] V is N or CR 11 ;

[0161] W is N or CR 12 ;

[0162] X is N or CR 13 ;

[0163] for

[0164] R 10b Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0165] R 17b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0166] R 11 R12 and R 13 Each is independently selected from H and halogens;

[0167] R 14a R 14b R 15a R 15b R 16a R 16b R 18a and R 18b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and

[0168] N is one of V, W, or X.

[0169] In one embodiment, R in equation (Ib-5010-WO) 14a R 14b R 15a R 15b R 16a and R 16b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 15a R 15b R 16a and R 16b Each of them is H, and R 14a and / or R 14b It is a halogen. In one embodiment, R... 15a R 15b R 16a and R 16b Each of them is H, and R 14a and / or R 14b For F. In one embodiment, R 14b R 15a R 15b R 16a and R 16b Each of them is H, and R 14a It is F.

[0170] In one embodiment, R in formula (Ib-5010-WO) 10b For H. In another embodiment, R 10b It is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 10b It is -OCH3.

[0171] In one embodiment, R of formula (Ib-5010-WO) 17bIt is a C1-C6 alkyl group substituted with a -OH group and / or a halogen. In one embodiment, R 17b Selected from

[0172] In one embodiment, the compound of formula (Ib-5010-WO) is the compound covered by the above formula and shown in Table 1 of this application.

[0173] Formula (Ib-5010-WO50)

[0174] In one embodiment, the compound of formula (I) is a compound of formula (Ib-5010-WO50):

[0175]

[0176] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0177] in:

[0178] V is N or CR 11 ;

[0179] W is N or CR 12 ;

[0180] X is N or CR 13 ;

[0181] for

[0182] R 10b Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0183] R 17b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C3-C9 heterocyclic groups, imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18bThe C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens.

[0184] R 11 R 12 and R 13 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0185] R 14a R 14b R 15a R 15b R 16a R 16b R 18a and R 18b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and

[0186] N is one of V, W, or X.

[0187] In one embodiment, R in formula (Ib-5010-WO50) 14a R 14b R 15a R 15b R 16a and R 16b Each of them is H. In one embodiment, R 14a R 14b R 15a , 15b R 16a and R 16b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 15a R 15b R 16a and R 16b Each of them is H, and R 14a and / or R 14b It is a halogen. In one embodiment, R... 15a R 15b R 16a and R 16b Each of them is H, and R 14a and / or R 14b For F. In one embodiment, R 14b R 15aR 15b R 16a and R 16b Each of them is H, and R 14a It is F.

[0188] In one embodiment, R in equation (Ib-5010-WO50) 10b For H. In another embodiment, R 10b It is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 10b It is -OCH3.

[0189] In one embodiment, R in equation (Ib-5010-WO50) 11 R 12 and R 13 (If present) is H. In another embodiment, V is CR. 11 , where R 11 F is F, W is CR 12 , where R 12 Let H be a variable and X be a variable N.

[0190] In one embodiment, R of formula (Ib-5010-WO50) 17b It is a C1-C6 alkyl group substituted with a -OH group and / or a halogen. In one embodiment, R 17b Selected from

[0191] In one embodiment, the compound of formula (I) is a compound of formula (Ib-5010-WO50) when R 17b for At that time, R 10b For H. In one embodiment, the compound of formula (I) is a compound of formula (Ib-5010-WO50) when R 17b for At that time, R 11 R 12 and R 13 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

[0192] In one embodiment, the compound of formula (Ib-5010-WO50) is not:

[0193]

[0194]

[0195] In one embodiment, the compound of formula (Ib-5010-WO50) is selected from:

[0196]

[0197] In one embodiment, the compound of formula (Ib-5010-WO50) is selected from:

[0198]

[0199]

[0200] Formula (Ic-5010-WO)

[0201] In another embodiment, the compound of formula (I) is a compound of formula (Ic-5010-WO):

[0202]

[0203] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0204] in:

[0205] V is N or CR 11 ;

[0206] W is N or CR 12 ;

[0207] X is N or CR 13 ;

[0208] for

[0209] R 10c Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0210] R 11 R 12 and R 13 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0211] R 19a R 19b R 110a R 110b R 111a R 111b R 112a and R112b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms;

[0212] R 18a and R 18b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and

[0213] N is one of V, W, or X.

[0214] In one embodiment, R in formula (Ic-5010-WO) 19a R 19b R 110a R 110b R 111a R 111b R 112a and R 112b Each of them 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 Selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 19a R 19b R 111a R 111b R 112a and R 112b Each of them is H, and R 110a and / or R 110b It is a halogen. In one embodiment, R... 19a R 19b R 111a R 111b R 112a and R 112b Each of them is H, and R 110a and / or R 110b For F. In one embodiment, R 19a R 19b R 110b R 111a R 111b R 112a and R 112b For H, and R 110a It is F.

[0215] In one embodiment, R in formula (Ic-5010-WO) 10c It is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 10c Selected from -OCH3 and In one embodiment, R 10c It is an unsubstituted -O-(C3-C6 cycloalkyl). In one embodiment, R 10c It is an unsubstituted -O-(C3 cycloalkyl). In another embodiment, R 10c It is a C1-C6 alkoxy group substituted with one or more halogens. In one embodiment, R 10c Selected from

[0216] In one embodiment, R in formula (Ic-5010-WO) 11 , R12和R13 (If it exists) is H.

[0217] In one embodiment, the compound of formula (Ic-5010-WO) is the compound covered by the above formula and shown in Table 1 of this application.

[0218] Formula (Id-5010-WO)

[0219] In another embodiment, the compound of formula (I) is a compound of formula (Id-5010-WO):

[0220]

[0221] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0222] in:

[0223] V is N or CR 11 ;

[0224] W is N or CR 12 ;

[0225] X is N or CR 13 ;

[0226] for

[0227] R 10d Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18bThe C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0228] R 113d Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0229] R 11 R 12 and R 13 Each is independently selected from H and halogens;

[0230] R 18a R 18b R 19a R 19b R 110a R 110b R 111a R 111b R 112a and R 112b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and

[0231] N is one of V, W, or X.

[0232] In one embodiment, R in formula (Id-5010-WO) 19a R 19b R 110a R 110b R 111a R 111b R 112a and R 112b Each of them is H. In another embodiment, one or more R 19a R 19b R 110a R 110b R 111a R 111b R 112a and R 112bSelected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 19a R 19b R 111a R 111b R 112a and R 112b Each of them is H, and R 110a and / or R 110b It is a halogen. In one embodiment, R... 19a R 19b R 111a R 111b R 112a and R 112b Each of them is H, and R 110a and / or R 110b For F. In one embodiment, R 19a R 19b R 110b R 111a R 111b R 112a and R 112b For H, and R 110a It is F.

[0233] In one embodiment, R in formula (Id-5010-WO) 10d For H. In another embodiment, R 10d It is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 10d It is -OCH3.

[0234] In one embodiment, R of formula (Id-5010-WO) 113d It is a C1-C6 alkyl group substituted with a -OH group and / or a halogen. In one embodiment, R 113d Selected from

[0235] In one embodiment, the compound of formula (Id-5010-WO) is the compound covered by the above formula and shown in Table 1 of this application.

[0236] Formula (Id-5010-WO50)

[0237] In another embodiment, the compound of formula (I) is a compound of formula (Id-5010-WO50):

[0238]

[0239] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0240] in:

[0241] V is N or CR 11 ;

[0242] W is N or CR 12 ;

[0243] X is N or CR 13 ;

[0244] for

[0245] R 10d Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0246] R 113d Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens.

[0247] R 11 R 12 and R 13 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0248] R 18a and R 18b Each is independently selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens;

[0249] R 19a R 19b R 110a R 110b R 111a R 111b R112a and R 112b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and

[0250] N is one of V, W, or X.

[0251] In one embodiment, R in formula (Id-5010-WO50) 19a R 19b R 110a R 110b R 111a R 111b R 112a and R 112b Each of them 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 Selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 19a R 19b R 111a R 111b R 112a and R 112b Each of them is H, and R 110a and / or R 110b It is a halogen. In one embodiment, R... 19a R 19b R 111a R 111b R 112a and R 112b Each of them is H, and R 110a and / or R 110b For F. In one embodiment, R 19a R 19b R 110b R 111a R 111b R 112a and R 112b For H, and R 110a It is F.

[0252] In one embodiment, R of formula (Id-5010-WO50) 10d For H. In another embodiment, R 10dIt is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 10d It is -OCH3.

[0253] In one embodiment, R of formula (Id-5010-WO50) 11 R 12 and R 13 (If present) is H. In another embodiment, V is CR. 11 , where R 11 F is F, W is CR 12 , where R 12 Let H be a variable and X be a variable N.

[0254] In one embodiment, R of formula (Id-5010-WO50) 113d It is a C1-C6 alkyl group substituted with a -OH group and / or a halogen. In one embodiment, R 113d Selected from

[0255] In one embodiment, the compound of formula (I) is a compound of formula (Id-5010-WO50) when R 113d for At that time, R 10d For H. In one embodiment, the compound of formula (I) is a compound of formula (Id-5010-WO50) under the condition that R 113d for At that time, R 11 R 12 and R 13 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

[0256] In one embodiment, the compound of formula (Id-5010-WO50) is not:

[0257]

[0258]

[0259] In one embodiment, the compound of formula (Id-5010-WO50) is selected from:

[0260]

[0261]

[0262] In one embodiment, the compound of formula (Id-5010-WO50) is selected from:

[0263]

[0264] In one embodiment, the compound of formula (II) is a compound of formula (IIa-5010-WO):

[0265]

[0266] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0267] in:

[0268] L is N or CR 21 ;

[0269] M is N or CR 22 ;

[0270] Q is N or CR 23 ;

[0271] for

[0272] R 20a Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0273] R 27a Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0274] R 21 R 22 and R 23 Each is independently selected from H and halogens;

[0275] R 24a R 24b R 25a R 25b R 26a R 26bR 28a and R 28b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and

[0276] N is one of L, M, or Q.

[0277] In one embodiment, R in formula (IIa-5010-WO) 24a R 24b R 25a R 25b R 26a and R 26b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 25a R 25b R 26a and R 26b Each of them is H, and R 24a and / or R 24b It is a halogen. In one embodiment, R... 25a R 25b R 26a and R 26b Each of them is H, and R 24a and / or R 24b For F. In one embodiment, R 24b R 25a R 25b R 26a and R 26b Each of them is H, and R 24a It is F.

[0278] In one embodiment, R in formula (IIa-5010-WO) 20a Not H. In one embodiment, R 20a It is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 20a It is -OCH3.

[0279] In one embodiment, R in formula (IIa-5010-WO) 27a It is an unsubstituted C3-C6 cycloalkyl group. In one embodiment, R 27a It is an unsubstituted C3 cycloalkyl group. In one embodiment, R 27a It is a C1-C6 alkyl group substituted with a -OH group and / or a halogen. In one embodiment, R 27a for

[0280] In one embodiment, the compound of formula (IIa-5010-WO) is the compound covered by the above formula and shown in Table 1 of this application.

[0281] Formula (IIa-5010-WO50)

[0282] In one embodiment, the compound of formula (II) is a compound of formula (IIa-5010-WO50):

[0283]

[0284] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0285] in:

[0286] L is N or CR 21 ;

[0287] M is N or CR 22 ;

[0288] Q is N or CR 23 ;

[0289] for

[0290] R 20a Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0291] R 27a Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, spirocycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, spirocycloalkyl, -O-(C3-C6 cycloalkyl) and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens.

[0292] R 21 R 22 and R 23 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0293] R 24a R 24b R 25a R 25b R 26a and R 26b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms;

[0294] R 28a and R 28b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and

[0295] N is one of L, M, or Q.

[0296] In one embodiment, R in formula (IIa-5010-WO50) 24a R 24b R 25a R 25b R 26a and R 26b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 25a R 25b R 26a and R 26b Each of them is H, and R 24a and / or R 24b It is a halogen. In one embodiment, R... 25a R 25b R 26a and R 26b Each of them is H, and R 24a and / or R 24b For F. In one embodiment, R 24b R 25a R 25b R 26a and R 26b Each of them is H, and R 24a It is F.

[0297] In one embodiment, R in formula (IIa-5010-WO50) 20a Not H. In one embodiment, R20a It is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 20a For -OCH3. In another embodiment, R 20a It is a C1-C6 alkoxy group substituted with one or more halogens. In one embodiment, R 20a for In another embodiment, R 20a It is an unsubstituted -O-(C3-C6 cycloalkyl). In one embodiment, R 20a It is an unsubstituted -O-(C3 cycloalkyl).

[0298] In equation (IIa-5010-WO50), one R 21 R 22 and R 23 H is denoted by CR (if present). In another embodiment, L is CR. 21 , where R 21 Selected from F, Cl and -OCH3, M is CR 22 , where R 22 Let H be a variable and Q be a variable N.

[0299] In one embodiment, R in formula (IIa-5010-WO50) 27a It is an unsubstituted C3-C6 cycloalkyl group. In one embodiment, R 27a Unsubstituted C3 cycloalkyl or In another embodiment, R 27a It is a C3-C6 cycloalkyl group substituted with one or more -CH3 and / or F. In one embodiment, R 27a Selected from In one embodiment, R 27a It is a C1-C6 alkyl group substituted with one or more -OH groups and / or one or more halogens. In one embodiment, R 27a Selected from In one embodiment, R 27a It is a spirocycloalkyl group. In one embodiment, R 27a for In another embodiment, R 27a It is an unsubstituted C2-C6 heterocyclic group. In one embodiment, R 27a It is an unsubstituted C2-C6 heterocyclic group comprising one oxygen atom, one nitrogen atom, or one oxygen atom and one nitrogen atom. In one embodiment, R 27a Selected from In one embodiment, R 27a for In one embodiment, R27a for In another embodiment, R 27a It is a C2-C6 heterocyclic group substituted with one or more F.

[0300] In one embodiment, R 27a for

[0301] In one embodiment, the compound of formula (II) is a compound of formula (IIa-5010-WO50), provided that R 20a For -OCH3 and R 27a When R is an unsubstituted C3 cycloalkyl group, 21 R 22 and R 23 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

[0302] In one embodiment, the compound of formula (IIa-5010-WO50) is not...

[0303]

[0304] In one embodiment, the compound of formula (IIa-5010-WO50) is selected from:

[0305]

[0306]

[0307]

[0308] In one embodiment, the compound of formula (IIa-5010-WO50) is selected from:

[0309]

[0310]

[0311]

[0312] Formula (IIb-5010-WO)

[0313] In another embodiment, the compound of formula (II) is a compound of formula (IIb-5010-WO):

[0314]

[0315] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0316] in:

[0317] L is N or CR 21 ;

[0318] M is N or CR 22 ;

[0319] Q is N or CR 23 ;

[0320] for

[0321] R 20b Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0322] R 27b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0323] R 21 R 22 and R 23 Each is independently selected from H and halogens;

[0324] R 28a R 28b R 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and

[0325] N is one of L, M, or Q.

[0326] In one embodiment, R in formula (IIb-5010-WO) 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b Each of them is H. In another embodiment, R 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 29a R 29b R 211a R 211b R 212a and R 212b Each of them is H, and R 210a and / or R 210b It is a halogen. In one embodiment, R... 29a R 29b R 211a R 211b R 212a and R 212b Each of them is H, and R 210a and / or R 210b For F. In one embodiment, R 29a R 29b R 210b R 211a R 211b R 212a and R 212b Each of them is H, and R 210a It is F.

[0327] In one embodiment, R in formula (IIb-5010-WO) 20b Not H. In one embodiment, R 20b It is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 20b It is -OCH3.

[0328] In one embodiment, R in formula (IIb-5010-WO) 27b It is an unsubstituted C3-C6 cycloalkyl group. In one embodiment, R 27bIt is an unsubstituted C3 cycloalkyl group. In one embodiment, R 27b It is a C1-C6 alkyl group substituted with a -OH group and / or a halogen. In one embodiment, R 27b for

[0329] In one embodiment, the compound of formula (IIb-5010-WO) is the compound covered by the above formula and shown in Table 1 of this application.

[0330] Formula (IIb-5010-WO50)

[0331] In another embodiment, the compound of formula (II) is a compound of formula (IIb-5010-WO50):

[0332]

[0333] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0334] in:

[0335] L is N or CR 21 ;

[0336] M is N or CR 22 ;

[0337] Q is N or CR 23 ;

[0338] for

[0339] R 20b Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0340] R 27b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, spirocycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 28a R 28bThe C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, spirocycloalkyl, -O-(C3-C6 cycloalkyl) and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens.

[0341] R 21 R 22 and R 23 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0342] R 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms;

[0343] R 28a and R 28b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and

[0344] N is one of L, M, or Q.

[0345] In one embodiment, R in formula (IIb-5010-WO50) 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b Each of them is H. In another embodiment, R 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 29a R 29b R 211a R 211bR 212a and R 212b Each of them is H, and R 210a and / or R 210b It is a halogen. In one embodiment, R... 29a R 29b R 211a R 211b R 212a and R 212b Each of them is H, and R 210a and / or R 210b For F. In one embodiment, R 29a R 29b R 210b R 211a R 211b R 212a and R 212b Each of them is H, and R 210a It is F.

[0346] In one embodiment, R in formula (IIb-5010-WO50) 20b Not H. In one embodiment, R 20b It is an unsubstituted C1-C6 alkoxy group. In one embodiment, R 20b For -OCH3. In one embodiment, R 20b For -OCD3. In another embodiment, R 20b It is a C1-C6 alkoxy group substituted with one or more F. In one embodiment, R 20b for In another embodiment, R 20b It is an unsubstituted -O-(C3-C6 cycloalkyl). In one embodiment, R 20b It is an unsubstituted -O-(C3 cycloalkyl).

[0347] In one embodiment, R in formula (IIb-5010-WO50) 21 R 22 and R 23 (If present) is H. In another embodiment, L is CR. 21 , where R 21 Selected from F, Cl and -OCH3, M is CR 22 , where R 22 Let H be a variable and Q be a variable N;

[0348] In one embodiment, R in formula (IIb-5010-WO50) 27b It is an unsubstituted C3-C6 cycloalkyl group. In one embodiment, R 27b Unsubstituted C3 cycloalkyl or In one embodiment, R 27b It is a C1-C6 alkyl group substituted with one or more -OH groups and / or one or more halogens. In one embodiment, R 27b for In one embodiment, R 27b It is a C3-C6 cycloalkyl group substituted with one or more -CH3, -OH and / or F. In one embodiment, R 27b Selected from In one embodiment, R 27b It is a spirocycloalkyl group. In one embodiment, R 27b for In another embodiment, R 27b It is an unsubstituted C2-C6 heterocyclic group. In one embodiment, R 27b It is an unsubstituted C2-C6 heterocyclic group comprising one oxygen atom, one nitrogen atom, or one oxygen atom and one nitrogen atom. In one embodiment, R 27b Selected from In one embodiment, R 27b for In one embodiment, R 27b for In another embodiment, R 27b It is a C2-C6 heterocyclic group substituted with one or more F and / or -CH3. In one embodiment, R 27b for In one embodiment, R 27b for

[0349] In one embodiment, the compound of formula (II) is a compound of formula (IIb-5010-WO50), provided that R 20b For -OCH3 and R 27b When R is an unsubstituted C3 cycloalkyl group, 21 R 22 and R 23 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

[0350] In one embodiment, the compound of formula (IIb-5010-WO50) is not:

[0351]

[0352] In one embodiment, the compound of formula (IIb-5010-WO50) is selected from:

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362] In one embodiment, the compound of formula (IIb-5010-WO50) is selected from:

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370] Formula (IIIa-5010-WO)

[0371] In another embodiment, the compound of formula (III) is a compound of formula (IIIa-5010-WO):

[0372]

[0373] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0374] in:

[0375] R is N or CR 31 ;

[0376] T is N or CR 32 ;

[0377] U is N or CR 33 ;

[0378] for

[0379] R 37a Selected from halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, 2-pyrrolidone, and -C(=O)NR 38a R 38b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0380] R 31 R 32 and R 33 Each is independently selected from H and halogens;

[0381] R 34a R 34b R 35a R 35b R 36a R 36b R 38a and R 38b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and

[0382] N is one of R, T, or U.

[0383] In one embodiment, R in formula (IIIa-5010-WO) 34a R 34b R 35a R 35b R 36a and R 36b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 35a R 35b R 36a and R 36b Each of them is H, and R 34a and / or R 34b It is a halogen. In one embodiment, R... 35a R 35b R 36a and R 36b Each of them is H, and R34a and / or R 34b For F. In one embodiment, R 34b R 35a R 35b R 36a and R 36b Each of them is H, and R 34a It is F.

[0384] In one embodiment, R of formula (IIIa-5010-WO) 37a It is a C1-C6 alkyl group substituted with a -OH group and / or a halogen. In one embodiment, R 37a for In one embodiment, R 37a It is a 2-pyrrolidone group. In one embodiment, R 37a for

[0385] In one embodiment, the compound of formula (IIIa-5010-WO) is the compound covered by the above formula and shown in Table 1 of this application.

[0386] Formula (IIIa-5010-WO50)

[0387] In another embodiment, the compound of formula (III) is a compound of formula (IIIa-5010-WO50):

[0388]

[0389] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0390] in:

[0391] R is N or CR 31 ;

[0392] T is N or CR 32 ;

[0393] U is N or CR 33 ;

[0394] for

[0395] R 37a Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazole groups, triazolyl groups, 2-pyrrolidone groups, and -C(=O)NR groups. 38a R 38bThe C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl) and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens.

[0396] R 31 R 32 and R 33 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0397] R 34a R 34b R 35a R 35b R 36a and R 36b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms;

[0398] R 38a and R 38b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and

[0399] N is one of R, T, or U.

[0400] In one embodiment, R of formula (IIIa-5010-WO50) 31 R 32 and R 33 (If present) is H. In another embodiment, R is CR. 31 , where R 31 Let F be F and T be CR. 32 , where R 32 Let H be a variable and U be an integer.

[0401] In one embodiment, R in formula (IIIa-5010-WO50) 34a R 34b R 35a R 35b R 36a and R 36b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 35a R 35b R 36a and R 36bEach of them is H, and R 34a and / or R 34b It is a halogen. In one embodiment, R... 35a R 35b R 36a and R 36b Each of them is H, and R 34a and / or R 34b For F. In one embodiment, R 34b R 35a R 35b R 36a and R 36b Each of them is H, and R 34a It is F.

[0402] In one embodiment, R of formula (IIIa-5010-WO50) 37a It is a C1-C6 alkyl group substituted with one or more -OH groups and / or one or more halogens. In one embodiment, R 37a for

[0403] In one embodiment, the compound of formula (III) is a compound of formula (IIIa-5010-WO50) under the condition that R 37a Not for

[0404] In one embodiment, the compound of formula (IIIa-5010-WO50) is:

[0405]

[0406] In one embodiment, the compound of formula (IIIa-5010-WO50) is:

[0407]

[0408] Formula (IIIb-5010-WO)

[0409] In another embodiment, the compound of formula (III) is a compound of formula (IIIb-5010-WO):

[0410]

[0411] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0412] in:

[0413] R is N or CR 31 ;

[0414] T is N or CR 32;

[0415] U is N or CR 33 ;

[0416] for

[0417] R 37b Selected from halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, 2-pyrrolidone, and -C(=O)NR 38a R 38b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens.

[0418] R 31 R 32 and R 33 Each is independently selected from H and halogens;

[0419] R 38a R 38b R 39a R 39b R 310a R 310b R 311a R 311b R 312a and R 312b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and

[0420] N is one of R, T, or U.

[0421] In one embodiment, R of formula (IIIb-5010-WO) 31 R 32 and R 33 (If present) is H. In another embodiment, R is CR. 31 , where R 31 Let F be F and T be CR. 32 , where R 32 Let H be a variable and U be an integer.

[0422] In one embodiment, R in formula (IIIb-5010-WO) 39a R 39b R 310a R 310bR 311a R 311b R 312a and R 312b Each of them is H. In another embodiment, R 39a R 39b R 310a R 310b R 311a R 311b R 312a and R 312b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 39a R 39b R 311a R 311b R 312a and R 312b Each of them is H, and R 310a and / or R 310b It is a halogen. In one embodiment, R... 39a R 39b R 311a R 311b R 312a and R 312b Each of them is H, and R 310a and / or R 310b For F. In one embodiment, R 39a R 39b R 310b R 311a R 311b R 312a and R 312b Each of them is H, and R 310a It is F.

[0423] In one embodiment, R of formula (IIIb-5010-WO) 37b It is a C1-C6 alkyl group substituted with a -OH group and / or a halogen. In one embodiment, R 37b for In one embodiment, R 37b It is a 2-pyrrolidone group. In one embodiment, R 37b for

[0424] In one embodiment, the compound of formula (IIIb-5010-WO) is the compound covered by the above formula and shown in Table 1 of this application.

[0425] Formula (IIIb-5010-WO50)

[0426] In another embodiment, the compound of formula (III) is a compound of formula (IIIb-5010-WO50):

[0427]

[0428] Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts;

[0429] in:

[0430] R is N or CR 31 ;

[0431] T is N or CR 32 ;

[0432] U is N or CR 33 ;

[0433] for

[0434] R 37b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazole groups, triazolyl groups, 2-pyrrolidone groups, and -C(=O)NR groups. 38a R 38b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl) and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens.

[0435] R 31 R 32 and R 33 Each is independently selected from H, C1-C6 alkoxy groups, and halogens;

[0436] R 39a R 39b R 310a R 310b R 311a R 311b R 312a and R 312b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms;

[0437] R 38a and R 38bEach is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and

[0438] N is one of R, T, or U.

[0439] In one embodiment, R of formula (IIIb-5010-WO50) 31 R 32 and R 33 (If present) is H. In another embodiment, R is CR. 31 , where R 31 Let F be F and T be CR. 32 , where R 32 Let H be a variable and U be an integer.

[0440] In one embodiment, R in formula (IIIb-5010-WO50) 39a R 39b R 310a R 310b R 311a R 311b R 312a and R 312b Each of them is H. In another embodiment, R 39a R 39b R 310a R 310b R 311a R 311b R 312a and R 312b One or more of them are selected from halogens, -OH, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 39a R 39b R 311a R 311b R 312a and R 312b Each of them is H, and R 310a and / or R 310b It is a halogen. In one embodiment, R... 39a R 39b R 311a R 311b R 312a and R 312b Each of them is H, and R 310a and / or R 310b For F. In one embodiment, R 39a R 39b R 310b R 311a R311b R 312a and R 312b Each of them is H, and R 310a It is F.

[0441] In one embodiment, R of formula (IIIb-5010-WO50) 37b It is a C1-C6 alkyl group substituted with a -OH group and / or a halogen. In one embodiment, R 37b for In one embodiment, R 37b It is an unsubstituted C2-C6 heterocyclic group. In one embodiment, R 37b It is an unsubstituted C3 heterocyclic group. In one embodiment, R 37b for

[0442] In one embodiment, the compound of formula (III) is a compound of formula (IIIb-5010-WO50), provided that R 37b for At that time, R 31 R 32 and R 33 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

[0443] In one embodiment, the compound of formula (IIIb-5010-WO50) is not:

[0444]

[0445] In one embodiment, the compound of formula (IIIb-5010-WO50) is selected from:

[0446]

[0447]

[0448] In one embodiment, the compound of formula (IIIb-5010-WO50) is selected from:

[0449]

[0450] In some embodiments, the compounds described herein may be in the form of salts, optical isomers, geometric isomers, and isomeric salts. In other embodiments, the compounds may be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating, pharmaceutically acceptable salts, including but not limited to hydrochlorides, hydrobromicates, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates. In some cases, for acidic compounds, the salt may include a metal, amine, or organic cation (e.g., a quaternary ammonium salt). In yet another embodiment, simple derivatives (e.g., ethers, esters, or amides) of compounds having desired retention and release properties but readily hydrolyzed by human pH, enzymes, or other suitable mechanisms may be used.

[0451] In some embodiments, the compounds of the present invention have a chiral center and can exist and be separated in both optically active and racemic forms. In other embodiments, the compounds may exhibit polymorphism. Some embodiments of the present invention cover any racemic, optically active, polycrystalline, or stereoisomeric forms or mixtures thereof of the compounds described herein, including isotopically labeled and radiolabeled compounds. See, for example, Goding, 1986, *Monoclonal Antibodies Principles and Practice*; Academic Press, p. 104. Such isomers can be separated by standard separation techniques, including, for example, fractional crystallization, chiral chromatography, etc. See, for example, Eliel, EL and Wilen SH, 1993, *Stereochemistry in Organic Compounds*; John Wiley & Sons, New York. The preparation of the optically active form can be accomplished by any suitable method, including but not limited to the separation of the racemic form by recrystallization, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.

[0452] In some embodiments, the compounds disclosed herein have an asymmetric center and may occur as racemates, racemic mixtures, and individual enantiomers or diastereomers, wherein 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 that are too unstable to be synthesized and / or isolated.

[0453] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions on one or more atoms constituting such compounds. For example, the compounds may contain, for instance, tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling with radioactive isotopes. All isotopic variations of the compounds disclosed herein, whether or not radioactive, are included within the scope contemplated.

[0454] In some embodiments, metabolites of the compounds disclosed herein may be used in the methods disclosed herein.

[0455] In some embodiments, the compounds contemplated herein may be provided in the form of prodrugs. The term "prodrug" refers to a compound that can be converted in vivo into a compound (e.g., a bioactive compound) described herein. Prodrugs are useful for various reasons known in the art, including ease of administration due to increased bioavailability during oral administration. Prodrugs may also have increased solubility in pharmaceutical compositions compared to bioactive compounds. A non-limiting example of a prodrug is a compound administered in the form of an ester (i.e., a "prodrug") to facilitate transmembrane transport, wherein water solubility is detrimental to mobility but is metabolically hydrolyzed into the active substance, a carboxylic acid, once inside a water-soluble, beneficial cell. Conversion procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs" (edited by H. Bundgaard, Elsevier, 1985), which is hereby incorporated by reference for the limited purpose of describing methods and preparation of suitable prodrug derivatives.

[0456] Some of the compounds disclosed herein may exist in both solvated and solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are covered within the scope of the contemplated compounds. Some of the compounds of the present invention may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent to the compounds and methods contemplated herein and are intended to be within the scope of the disclosure herein.

[0457] In some embodiments, one or more compounds of the present invention (e.g., formulas (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 part of the composition and It may be present in the following amounts (by weight of the total composition): 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%, not exceeding about 75%, not exceeding about 90%, not exceeding about 95%, not exceeding about 99%, or not exceeding about 99.99%, about 0.0001% to about 99%, about 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%.

[0458] In some embodiments, one or more compounds of the present disclosure (e.g., formulas (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 purified or fractionated. The amount (by weight of the total composition) of the product 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%, not exceeding about 75%, not exceeding about 90%, not exceeding about 95%, not exceeding about 99%, not exceeding about 99.99%, about 0.0001% to about 99%, about 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%.

[0459] Preparation methods of compounds of formula (I), (II) or (III)

[0460] In some embodiments, compounds of formulas (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, comprising one or more steps set forth in the examples herein. The synthetic routes shown and described in the examples can be used, for example, to prepare the compounds listed herein as in the table and structurally related compounds.

[0461] Pharmaceutical compositions and formulations

[0462] Some embodiments of the present invention include compositions comprising one or more 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)). In some embodiments, the composition is a pharmaceutical composition, such as a composition suitable for administration to animals (e.g., mammals, primates, monkeys, humans, dogs, cats, pigs, mice, rabbits, rats, etc.). In some embodiments, a pharmaceutical composition comprising the compounds disclosed herein and pharmaceutically acceptable excipients is provided. The compound may be a compound of any of the formulas (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 listed in the respective tables, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, isomer salt, prodrug, or derivative thereof. In some embodiments, the compounds are listed in any of the tables herein.

[0463] The term "pharmaceutically acceptable salt" is intended to include salts of active compounds prepared with a relatively non-toxic acid or base according to specific substituents found on the compounds described herein. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds disclosed herein contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired acid, pure 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, hydrocarbonic acid, phosphoric acid, phosphoric acid monohydrogen phosphate, phosphoric acid dihydrogen phosphate, sulfuric acid, hydrosulfuric acid, hydroiodic acid, or phosphorous acid; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Some of the specific compounds disclosed herein contain both basic and acidic functional groups that allow these compounds to be converted into base addition salts or acid addition salts.

[0464] The compounds disclosed herein can exist as salts, such as in conjunction with pharmaceutically acceptable acids. Therefore, the compounds contemplated herein include such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts containing amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0465] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents).

[0466] Pharmaceutically acceptable salts of the aforementioned compounds (where a basic or acidic group is present in the structure) are also included within the scope of compounds contemplated herein. When acidic substituents are present, such as -NHSO3H, -COOH, and -P(O)(OH)2, ammonium, sodium, potassium, and calcium salts can be formed and used as dosage forms. Basic groups, such as amino or basic heteroaryl groups, or pyridyl groups, and acidic salts, such as hydrochlorides, hydrobromic acids, acetates, maleates, palmitates, methanesulfonates, and p-toluenesulfonates, can be used as dosage forms.

[0467] In addition, in embodiments where R-COOH is present, pharmaceutically acceptable esters, such as methyl, ethyl, tert-butyl, neopentyloxymethyl, etc., as well as those known in the art for altering solubility or hydrolytic properties, can be used as sustained-release or prodrug formulations.

[0468] In some cases, the pharmaceutical composition is non-toxic, does not cause side effects, or both. In some embodiments, inherent side effects may exist (e.g., they may harm the patient or may have some degree of toxicity or harmfulness in some patients).

[0469] In some embodiments, one or more compounds of the present invention (e.g., those of formulas (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 pharmaceuticals. A portion of the composition and may be in the following amounts: 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%, not exceeding about 75%, not exceeding about 90%, not exceeding about 95%, not exceeding about 99%, not exceeding about 99.99%, about 0.001% to about 99%, about 0.001% to about 50%, about 0.1% to about 99%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%. In some embodiments, the pharmaceutical composition may be present in a dosage form suitable for topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, skin, nasal, vaginal, or ocular administration. In other embodiments, the pharmaceutical composition may be present in a dosage form suitable for parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. The pharmaceutical composition may be in, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, oral medications, delivery devices, suppositories, enemas, injections, implants, sprays, aerosols, or other suitable forms.

[0470] In some embodiments, the compounds disclosed herein may be administered orally as tablets, aqueous or oily suspensions, lozenges, tablets, powders, granules, emulsions, capsules, syrups, or elixirs. Compositions for oral administration may contain one or more pharmaceutical agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to produce pharmaceutically palatable formulations. Therefore, pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein are also provided.

[0471] In some embodiments, the tablets contain an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for the preparation of the tablets. These excipients may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate, carboxymethyl cellulose, or sodium phosphate; (2) granulating and disintegrants such as corn starch or alginate; (3) binders such as starch, gelatin, or gum arabic; and (4) lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used.

[0472] For pharmaceutical compositions prepared from the compounds disclosed herein, pharmaceutically acceptable carriers may be solid or liquid. Solid dosage forms include powders, tablets, pills, capsules, pouches, suppositories, and dispersible granules. Solid carriers may be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulation materials.

[0473] The compounds disclosed herein (in the form of free compounds or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts) can be used for in vivo application by injection or by gradual perfusion over time via parenteral administration. Administration can be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavitary, or transdermal. For in vitro studies, the compounds can be added to or dissolved in appropriate bioacceptable buffers and added to cells or tissues.

[0474] In powder form, the carrier is a finely dispersed solid in a mixture with a finely dispersed active component. In tablet form, the active component is mixed with a carrier having the desired binding properties in a suitable proportion and compacted into the desired shape and size.

[0475] 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, astragalus gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. The term "formulation" is intended to include a mixture of an active compound and an encapsulating material that serves as a carrier to provide a capsule, wherein the active component, with or without other carriers, is surrounded by a carrier, which thereby associates with the active component. Similarly, capsules and tablets are included. Tablets, powders, capsules, pills, capsules, and tablets can be used as solid dosage forms suitable for oral administration.

[0476] To prepare suppositories, first melt a mixture of low-melting-point waxes, such as fatty acid glycerides or cocoa butter, and then uniformly disperse the active ingredients therein by stirring. The molten, homogeneous mixture is then poured into a mold of a convenient size, allowing it to cool and solidify.

[0477] Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral administration, liquid formulations can be prepared in a solution of polyethylene glycol in an aqueous solution.

[0478] When parenteral application is required or desired, particularly suitable mixtures for the compounds disclosed herein are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions, or implants containing suppositories. This suspension can be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known methods. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable mediators, carriers, and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild fixed oil containing synthetic monoglycerides or diglycerides can be used. Furthermore, fatty acids such as oleic acid have been found to be suitable for the preparation of injectable formulations. Specifically, carriers for parenteral administration include aqueous solutions of dextran, physiological saline, purified water, ethanol, glycerin, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, etc. Ampoules provide a convenient unit dose. The compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches. Suitable pharmaceutical mixtures for use in the pharmaceutical compositions and methods disclosed herein include, for example, those described in *Pharmaceutical Sciences* (17th edition, Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of which are hereby incorporated by reference.

[0479] In some embodiments, formulations 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 containing saline and buffer media. Commonly 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, alcohols, glycerol, and polyols. Intravenous mediators include fluids and nutritional supplements. Parenteral mediators include sodium chloride solution, Ringer's dextran, dextran, and sodium chloride. Intravenous lactate Ringer's dextran mediators include fluids and nutritional supplements, electrolyte supplements (such as those based on Ringer's dextran), etc. Preservatives and other additives may also be present, such as antibacterial agents, antioxidants, chelating agents, growth factors, and inert gases.

[0480] Preservatives include antimicrobial agents, antioxidants, chelating agents, and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients including salts, preservatives, buffers, and the like, as exemplified in, for example, *Remington's Pharmaceutical Sciences*, 15th ed., Easton: Mack Publishing Co., 1405-1412, 1461-1487 (1975) and *National Formulary XIV*, 14th ed., Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated herein by reference. The pH and precise concentration of the various components of the pharmaceutical composition are adjusted according to conventional techniques in the art. See, for example, Goodman and Gilman (eds.), 1990, *The Pharmacological Basis for Therapeutics* (7th ed.).

[0481] Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral administration can be prepared by dispersing finely dispersed 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 typically contain active materials mixed with excipients suitable for preparing aqueous suspensions. = Microwave excipients can be (1) suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; (2) dispersants or wetting agents, which can be (a) naturally occurring phospholipids, such as lecithin; (b) condensation products of olefin oxides and fatty acids, such as polyoxyethylene stearate; (c) condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadecanoethanol; (d) condensation products of ethylene oxide and partial esters derived from fatty acids and hexanol, such as polyoxyethylene sorbitan monooleate; or (e) condensation products of ethylene oxide and partial esters derived from fatty acids and hexanoic anhydrides, such as polyoxyethylene dehydrated sorbitan monooleate.

[0482] This also includes solid formulations that are intended to be converted into liquid formulations for oral administration shortly before use. Such liquid compositions include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0483] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as tablets, capsules, and powders packaged in vials or ampoules. Similarly, the unit dosage form can be capsules, tablets, sachets, or lozenges themselves, or it can be any of these packaging forms in appropriate quantities.

[0484] In some embodiments, the pharmaceutical composition may include one or more formulation ingredients. A "formulation ingredient" can be any suitable ingredient (e.g., suitable for one or more drugs, suitable for a dosage of one or more drugs, suitable for a release time of one or more drugs, suitable for a disease, suitable for a disease state, or suitable for a route of delivery), including but not limited to water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or chloroform-containing water), sugars (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups derived therefrom), ethanol, glycerol, ethylene glycol (e.g., propylene glycol), acetone, ether, DMSO, and surfactants (e.g., anionic surfactants). Agents, cationic surfactants, amphoteric surfactants or nonionic surfactants (e.g., polysorbate), 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 glycerol), 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.

[0485] In some embodiments, the pharmaceutical composition may be formulated to release the active ingredient (e.g., one or more compounds of the present invention, such as formula (I)) substantially immediately after administration or at any substantially predetermined time after administration. Such formulations may include, for example, controlled-release formulations, such as various controlled-release compositions and coatings.

[0486] In some embodiments, other formulations (e.g., formulations of pharmaceutical compositions) may include formulations that incorporate a drug (or controlled-release formulation) into food, food ingredients, feed, or beverages.

[0487] Some compounds may have limited solubility in water and therefore may require surfactants or other suitable co-solvents in the compositions. Such co-solvents include: polysorbates 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrins; and polyoxyethylene 35 castor oil. These co-solvents are typically used at levels between about 0.01% and about 2% by weight.

[0488] Viscosities greater than those of a simple aqueous solution can reduce variability in dispersion formulations, reduce physical separation of components in suspensions or emulsions, and / or otherwise improve the desired properties of the formulation. Such viscosity modifiers include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations thereof. These agents are typically used at levels between about 0.01% and about 2% by weight.

[0489] The compositions disclosed herein may include components for providing sustained release and / or comfort. Such components include high molecular weight, anionic viscous polymers, gelling polysaccharides, and finely dispersed drug carrier substrates. These components are discussed in more detail in the following U.S. Patents: 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

[0490] Various pharmaceutical compositions are provided for use in improving certain diseases and conditions. A pharmaceutical composition according to one embodiment is prepared by compounding, alone or in combination with other pharmaceutical agents, in the form of a free compound or pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt, said compound being suitable for administration to a subject using a carrier, excipient, and additive or adjuvant. Commonly used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water, alcohols, glycerol, and polyols. Intravenous mediators include fluids and nutritional supplements.

[0491] Various pharmaceutical compositions are provided for use in improving certain diseases and conditions. A pharmaceutical composition according to one embodiment is prepared by compounding, alone or in combination with other pharmaceutical agents, in the form of a free compound or pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt, said compound being suitable for administration to a subject using a carrier, excipient, and additive or adjuvant. Commonly used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water, alcohols, glycerol, and polyols. Intravenous mediators include fluids and nutritional supplements.

[0492] Methods of treating and preventing diseases

[0493] In addition to their ability to inhibit IRAK, IRAK inhibitors have been shown to be selective for a variety of 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). Inhibition of one or more kinases (e.g., IRAK and FLT3) may allow 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), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans), including but not limited to hematopoietic cancers (e.g., bone marrow hematopoietic stem cell disorders or bone marrow lineage-related disorders), MDS, AML, myeloproliferative disorders, and diseases associated with mutations in IRAK1, IRAK4, and / or FLT3 (e.g., mutations in the juxtamembranous region of FLT3, mutations in the kinase domain of FLT3, point mutations in FLT3, internal tandem repeat mutations in FLT3, FLT3-ITD mutations, D835YFLT3 mutations, D835VFLT3 mutations, F691LFLT3 mutations, or R834QFLT3 mutations) (e.g., hematopoietic cancers).

[0494] In some embodiments, the compounds of the present invention can inhibit the activity of one or more of the following: FLT3, mutations in FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, point mutations in FLT3, internal tandem repeat mutations in FLT3, FLT3-ITD mutations, D835YFLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), IRAK4 (interleukin-1 receptor-associated kinase 4), isotypes of IRAK4, mutations in IRAK4, IRAK1 (interleukin-1 receptor-associated kinase 1), isotypes of IRAK1, and / or mutations in IRAK1. In some embodiments, the compounds of the present invention can inhibit the activity of one or both of the following: FLT3 and mutations in FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, point mutations in FLT3, internal tandem repeat mutations in FLT3, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691LFLT3 mutations, or R834QFLT3 mutations), and optionally inhibit one or more of the following: IRAK4, isotypes of IRAK4, mutations in IRAK4, IRAK1, isotypes of IRAK1, or mutations in IRAK1. In some embodiments, the compounds of the present invention can inhibit the activity of one or both of the following: FLT3 and mutations in FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, point mutations in FLT3, internal tandem repeat mutations in FLT3, FLT3-ITD mutations, D835YFLT3 mutations, D835VFLT3 mutations, F691L FLT3 mutations, or R834QFLT3 mutations), and optionally inhibit one or both of the following: IRAK4 and IRAK1, or their isotypes or mutations. In some embodiments, the compounds of the present invention can inhibit FLT3 by combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In one embodiment, the compounds of the present invention are pan-FLT3 inhibitors. In one embodiment, the compounds of the present invention are IRAK1, IRAK4, and pan-FLT3 inhibitors.

[0495] In some embodiments, the compound exhibits inhibitory activity against IRAK and / or FLT-3, wherein the activity is ≥1 μM, for example 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, wherein the activity is between 0.1 nM and 1 nM, for example, about 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM, 0.9 nM, or 1.0 nM. In some embodiments, the compounds described herein exhibit inhibitory activity against IRAK and / or FLT-3, wherein the activity is ≤0.1 μM, for example, about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. It is also envisioned that a range of values ​​for the upper and / or lower limits be used, such as, but not limited to, 1 nM to 10 nM, 10 nM to 100 nM, 1 nM to 100 nM, 0.1 nM to 1 nM, 0.1 nM to 100 nM, 0.1 nM to 200 nM, 1 nM to 200 nM, 10 nM to 200 nM, 100 nM to 200 nM, 200 nM to 500 nM, 0.1 nM to 500 nM, 1 nM to 500 nM, 10 nM to 500 nM, 500 nM to 1000 nM, 0.1 nM to 1000 nM, 1 nM to 1000 nM, 10 nM to 1000 nM, or 100 nM to 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 nM to 10 nM, 10 nM to 100 nM, 0.1 μM to 1 μM, 1 μM to 10 μM, 10 μM to 100 μM, 100 μM to 200 μM, 200 μM to 500 μM, or even 500 μM to 1000 μM. It should be understood that, for quantitative purposes, the terms “activity,” “inhibitory activity,” “biological activity,” “IRAK activity,” “IRAK1 activity,” “IRAK4 activity,” “FLT-3 activity,” etc., in the context of the inhibitory compounds disclosed herein, can be quantified in a variety of ways known in the art. Unless otherwise stated, as used herein, such terms refer to IC in the conventional sense. 50(That is, the concentration at which half of the maximum inhibition is achieved). It should be understood that, for quantitative purposes, the terms “activity,” “inhibitory activity,” “biological activity,” “IRAK activity,” “IRAK1 activity,” “IRAK4 activity,” “FLT-3 activity,” etc., in the context of the inhibitory compounds disclosed herein can be quantified in a variety of ways known in the art. Unless otherwise stated, as used herein, such terms refer to IC50 in the conventional sense. 50 (That is, reaching half the concentration of maximum inhibition).

[0496] In some embodiments, hematopoietic system cancers in animals (e.g., mammals, pigs, dogs, poultry (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) that can be treated with the compounds of the present invention (e.g., formula (I)) may include, but are not limited to, hematopoietic system cancers and blood cell myeloid cancers, cancers with increased risk due to other blood disorders, cancers with increased risk due to chemical exposure (e.g., anticancer therapy or occupational chemical exposure), cancers with increased risk due to ionizing radiation (e.g., anticancer therapy), cancers that evolve from myelodysplastic syndromes, cancers that evolve from myeloproliferative disorders, and B-cell cancers.

[0497] In some embodiments, the hematopoietic system cancers that can be treated include, but are not limited to, MDS, AML, lymphoma, leukemia, myeloma, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., ABCDLBCL with a MYD88 mutation (e.g., L265P), follicular lymphoma, or marginal zone lymphoma or combinations thereof.

[0498] In some embodiments, cancers characterized by IRAK (IRAK1 and / or IRAK4) expression and / or IRAK-mediated intracellular signaling dysregulation can be treated, and include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, as well as combinations thereof.

[0499] In some embodiments, the compounds of the present invention can be used to inhibit targets in an additional symptom background characterized by excessive activity of IRAK1 and / or IRAK4. According to a specific aspect of the invention, the compounds of the present invention can be used to inhibit excessive activity of IRAK1 and / or IRAK4 in conditions such as inflammatory diseases and autoimmune diseases characterized by excessive activity of IRAK1 and / or IRAK4. In some embodiments, inflammatory and autoimmune diseases characterized by IRAK (IRAK1 and / or IRAK4) expression and / or IRAK-mediated intracellular signaling dysregulation (e.g., excessive activity) can be treated, and 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 combinations thereof.

[0500] In some embodiments, the MDS of subjects (e.g., mammals, pigs, dogs, poultry (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) treated with the compounds of the present invention (e.g., formula (I)) may include, but are not limited to, MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations, and refractory cytopenia with monolineage dysplasia (e.g., refractory anemia, refractory neutrophils). Refractory thrombocytopenia and refractory anemia with ringed sideroblasts, refractory thrombocytopenia with multilineage dysplasia (e.g., refractory thrombocytopenia with multilineage dysplasia and ringed sideroblasts and animals with pathological changes (not limited to erythrocytes) such as marked leukocyte precursor and platelet precursor (megakaryocyte) proliferation abnormalities), refractory anemia with increased blast I and II, 5q syndrome, megakaryocyte proliferation abnormalities with fibrosis, and refractory thrombocytopenia in children. In some embodiments, treatable MDS include, but are not limited to, hereditary MDS, MDS with an increased risk of occurrence due to genetic predisposition, MDS with an increased risk due to other blood disorders, MDS with an increased risk due to chemical exposure, MDS with an increased risk due to ionizing radiation, MDS with an increased risk due to cancer treatment (e.g., the combined use of radiation and similar alkylating agents such as busulfan, nitrosourea, or procarbazine (latency of 5 to 7 years) or DNA topoisomerase inhibitors), acquired aplastic anemia and Fanconi's anemia following immunosuppressive therapy, MDS with an increased risk due to splicing factor mutations, MDS with an increased risk due to mutations in isocitrate dehydrogenase 1, and MDS with an increased risk due to mutations in isocitrate dehydrogenase 2. Animals that can be treated include, but are not limited to, mammals, rodents, primates, monkeys (e.g., macaques, rhesus monkeys, or pig-tailed macaques), humans, dogs, cats, pigs, poultry (e.g., chickens), cattle, mice, rabbits, and rats. In these methods, the term "subject" can refer to both human and non-human subjects. In some cases, the subject requires treatment (e.g., by exhibiting signs of disease or MDS, or by having a low blood cell count).

[0501] In some embodiments, the MDS in subjects (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) who can be treated with the compounds of the present invention (e.g., formula (I)) may include, but are not limited to, MDS that can be treated by inhibiting one or more of the following: FLT3 (e.g., using an FLT3 inhibitor), a mutation of FLT3 (e.g., using an inhibitor of an FLT3 mutant), IRAK4 (e.g., using an IRAK4 inhibitor), a mutation of IRAK4 (e.g., using an inhibitor of an IRAK4 mutant), IRAK1 (e.g., using an IRAK1 inhibitor), and / or a mutation of IRAK1 (e.g., using an inhibitor of an IRAK1 mutant). In some embodiments, treatable MDS may 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 and IRAK1 (or a mutation thereof), or MDS that can be treated by inhibiting both IRAK4 (or a mutation thereof) and IRAK1 (or a mutation thereof). In some embodiments, treatable MDS includes, but is not limited to, MDS that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or a combination of both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or a combination of both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that may be or become resistant to FLT3 inhibitors due to adaptive resistance mechanisms, such as those driven by IRAK. In some embodiments, the treatable MDS is characterized by MDS having enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, the MDS is not driven by FLT3 mutations but expresses IRAK4-Long (e.g., as described in U.S. Patent Application 16 / 339,692; and Smith, MA et al., (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0502] In some embodiments, AML in subjects (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) treated with compounds of the present invention (e.g., formula (I)) includes, but is not limited to, hereditary AML, AML with an increased risk of occurrence due to genetic predisposition, AML with one or more recurrent genetic abnormalities (e.g., with inversions or translocations, such as MLLT3 / MLL with a translocation between chromosomes 9 and 11 (“MLL”), AML with a translocation between chromosomes 8 and 21, AML with a translocation or inversion in chromosome 16, AML with a translocation or inversion in chromosomes 9 and 11). AML involving translocations between chromosomes, APL (M3) involving translocations between chromosomes 15 and 17, AML involving translocations between chromosomes 6 and 9, AML involving translocations or inversions in chromosome 3, etc., AML involving translocations between chromosomes 1 and 22 (promegakaryocytes), AML with myelodysplastic changes, AML associated with prior chemotherapy or radiation therapy (e.g., AML associated with alkylating agents, AML associated with topoisomerase II inhibitors, etc.), and AML not otherwise classified (not belonging to the above categories - similar to the FAB classification; e.g., very poorly differentiated AML (M0), very poorly mature AML (M1), mature AML, etc.). AML (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroid leukemia (M6), acute promegakaryocytic leukemia (M7), acute basophilic leukemia, acute panmyelodysplastic leukemia, etc.), myeloid sarcoma (also known as granulocytic sarcoma, chloroma, or extramedullary myeloid sarcoma), undifferentiated and biphenotyped acute leukemia (also known as mixed phenotyped acute leukemia), AML with increased risk due to other hematologic disorders, AML with increased risk due to chemical exposure, AML with increased risk due to ionizing radiation, AML evolving from myelodysplastic syndromes, AML arising from myeloproliferative disorders, etc. AML can be categorized into several types, including: AML arising from genetic diseases; AML with increased risk due to FLT3 mutations; AML with increased risk due to FLT3 mutations in the juxtamembrane region of FLT3; AML with increased risk due to FLT3 mutations in the juxtamembrane region of FLT3 with internal tandem repeats; AML with increased risk due to FLT3 mutations in the kinase domain of FLT3; AML with increased risk due to FLT3 mutation D835Y; AML with increased risk due to FLT3 mutation D835V; AML with increased risk due to FLT3 mutation F691L; and AML with increased risk due to FLT3 mutation R834Q, among others.In some embodiments, treatable AML includes, but is not limited to, mutations that can be treated by inhibiting one or more FLT3 (e.g., using an FLT3 inhibitor), FLT3 (e.g., using an inhibitor of FLT3 mutants), IRAK4 (e.g., using an IRAK4 inhibitor), IRAK4 (e.g., using an inhibitor of IRAK4 mutants), IRAK1 (e.g., using an IRAK1 inhibitor), and / or IRAK1 (e.g., using an inhibitor of IRAK1 mutants). In some embodiments, treatable AML includes, but is not limited to, AML that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting IRAK1 (or its mutations), or AML that can be treated by inhibiting IRAK4 (or its mutations) and IRAK1 (or its mutations). In some embodiments, treatable AML includes, but is not limited to, AML that can be treated by inhibiting FLT3 with IRAK4, IRAK1, or a combination of 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 become resistant to FLT3 inhibitors due to adaptive resistance mechanisms, such as those driven by IRAK. In some embodiments, the treatable AML is characterized by enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, the AML is not driven by FLT3 mutations but expresses IRAK4-Long (e.g., as described in U.S. Patent Application 16 / 339,692; and Smith, MA et al., (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activateinnate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0503] In some embodiments, the hematopoietic system cancers of subjects (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) who can be treated with the compounds of the present invention (e.g., formula (I)) include, but are not limited to, hematopoietic system cancers (e.g., MDS, AML, DLBCL, etc., as described above) that can be treated by inhibiting (e.g., reducing activity or expression) one or more of the following: FLT3 (e.g., using an FLT3 inhibitor), a mutation of FLT3 (e.g., using an inhibitor of an FLT3 mutant), IRAK4 (e.g., using an IRAK4 inhibitor), an isotype of IRAK4, a mutation of IRAK4 (e.g., using an inhibitor of an IRAK4 mutant), IRAK1 (e.g., using an IRAK1 inhibitor), an isotype of IRAK1, or a mutation of IRAK1 (e.g., using an inhibitor of an IRAK1 mutant). In some embodiments, treatable hematopoietic cancers include, but are not limited to, cancers that can be treated by inhibiting (e.g., reducing their activity or expression) FLT3 (or a mutation thereof) and IRAK4 (or a mutation thereof), hematopoietic cancers that can be treated by inhibiting (e.g., reducing their activity or expression) FLT3 (or a mutation thereof) and IRAK1 (or a mutation thereof), or hematopoietic cancers that can be treated by inhibiting (e.g., reducing their activity or expression) FLT3 (or a mutation thereof), IRAK4 (or its isotype or mutation thereof), and IRAK1 (or its isotype or mutation thereof). In some embodiments, treatable hematopoietic cancers include, but are not limited to, hematopoietic cancers that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or a combination of both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or a combination of both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that may be or become resistant to FLT3 inhibitors due to adaptive resistance mechanisms, such as those driven by IRAK.In some embodiments, the hematopoietic cancer that can be treated is characterized by hematopoietic cancer with enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein the hematopoietic cancer is not driven by FLT3 mutations but expresses IRAK4-Long based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application 16 / 339,692; and Smith, MA et al., (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0504] In some embodiments, treatable cancers include, but are not limited to: glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, as well as combinations thereof, which can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides treatment for tumors with FLT3 mutations that may be or become resistant to FLT3 inhibitors due to adaptive resistance mechanisms, such as those driven by IRAK. In some embodiments, the treatable cancer is characterized by enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, the cancer is not driven by FLT3 mutations but expresses IRAK4-Long (e.g., as described in U.S. Patent Application 16 / 339,692; and Smith, MA et al., (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0505] In some embodiments, treatable inflammatory and autoimmune diseases characterized by IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling dysregulation 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 combinations thereof, which can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In one embodiment, the treatable inflammatory disease is Crohn's disease or colitis. In one embodiment, the treatable inflammatory disease 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 or become resistant to FLT3 inhibitors due to adaptive resistance mechanisms, such as those driven by IRAK. In some embodiments, the treatable inflammatory and autoimmune diseases are characterized by enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, the inflammatory and autoimmune diseases are not driven by FLT3 mutations but express IRAK4-Long (e.g., as described in U.S. Patent Application 16 / 339,692; and Smith, MA et al., (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5):640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0506] Regarding the treatment of MDS (e.g., MDS with splice factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2), treatment may include, but is not limited to, prophylactic and therapeutic treatment. Therefore, treatment may include, but is not limited to: preventing MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) in animals or humans with intrinsic or acquired resistance to other MDS treatments; reducing the risk of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); and improving or alleviating the symptoms of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations). Mutated MDS; triggering a bodily response to MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); inhibiting the development or progression of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); inhibiting or preventing the occurrence of MDS-related symptoms (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); reducing the severity of MDS. The degree of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); the resolution of one or more of the symptoms associated with MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) or MDS-related symptoms (e.g., increased blood cell count); the remission of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); by prevention or maximal... Reducing FLT3 mutations (e.g., internal tandem repeat mutations or D835Y mutations) to induce remission of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); preventing relapse of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); or preventing relapse of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations). In some embodiments, the treatment does not include preventative treatment of MDS (e.g., preventing or improving future MDS).

[0507] Regarding the treatment of hematopoietic system cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma or Waldenström 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, etc.), treatment may include, but is not limited to, preventive and therapeutic treatments. Therefore, treatment may include, but is not limited to: prevention of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, myeloma, non-Hodgkin's lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.) in animals with intrinsic or acquired resistance to other cancer treatments (e.g., to some FLT3 inhibitors or to MLL). Cancer, leukemia, myeloma, non-Hodgkin's lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof; improving or alleviating symptoms of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, myeloma, non-Hodgkin's lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, etc.). Cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, myeloma, non-Hodgkin's lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); inhibiting the development or progression of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, myeloma, non-Hodgkin's lymphoma, or Waldenström macroglobulinemia). Proteinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.; suppressing or preventing the occurrence of cancer-related symptoms (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.);Reduces the severity of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.); causes cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma). (and combinations thereof, etc.) or the resolution of one or more cancer-related symptoms (e.g., reduction in tumor size); remission of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.); remission of cancer by preventing or maximizing the reduction of FLT3 mutations (e.g., internal tandem repeat mutations or D835Y mutations) (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); Lymphoma, leukemia, myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.; to induce remission of acute myeloid leukemia by preventing or maximizing the reduction of FLT3 mutations (e.g., internal tandem repeat mutations or D835Y mutations); to prevent relapse of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma, etc.). The treatment may include: prevention of cancer relapse (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); or prevention of acute myeloid leukemia relapse in animals with intrinsic or acquired resistance to other cancer treatments (e.g., to some FLT3 inhibitors or to MLL). In some embodiments, the treatment does not include prophylactic treatment for cancer (e.g., prevention or improvement of future cancer).

[0508] Treatment of the subject may be performed using any suitable method of administration (such as those disclosed herein) and using any suitable amount of the compounds of the present invention (e.g., formula (I)). In some embodiments, the treatment method comprises treating MDS in animals or humans (e.g., MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2). In some embodiments, the treatment method comprises treating hematopoietic system cancers in animals or humans (e.g., acute myeloid leukemia, lymphoma, leukemia, myeloma, non-Hodgkin lymphoma, Waldenström 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 treatment following one or more of a hematologic disorder, myelodysplastic syndrome, myeloproliferative disorder, chemical exposure, exposure to ionizing radiation, or treatment of hematopoietic system cancers (e.g., chemotherapy, ionizing radiation, or both). Some embodiments of the present invention include a method of treating a subject (e.g., an animal, such as a human or primate) with a composition (e.g., a pharmaceutical composition) containing a compound of the present invention (e.g., formula (I)), said method comprising one or more administrations of one or more such compositions; if more than one administration is present, the compositions may be the same or different.

[0509] In some embodiments, the treatment method includes administering to a subject an effective amount of a composition comprising the compounds of the present invention (e.g., formulas (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 a subject's treatment (e.g., treatment of MDS, such as but not limited to MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); or treatment of hematopoietic system cancers, such as but not limited to acute myeloid leukemia, lymphoma, leukemia, myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCLMYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.). In some embodiments, the effective amount may encompass the therapeutically effective amount, as disclosed herein. In some embodiments, the effective amount may vary depending on the subject and the specific treatment affected. For example, the exact amount required may vary, for example, between subjects, depending on the subject's age and general condition, the specific adjuvant used (if applicable), the administration regimen, etc. Thus, the effective amount can vary, for example, based on specific circumstances, and an appropriate effective amount can be determined for specific circumstances. The effective amount can, for example, include any dosage or composition amount disclosed herein. In some embodiments, the effective amount of at least one compound of the invention (which can be administered to a subject, such as a mammal, primate, monkey, or human) can be an amount of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 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.In some embodiments, the dosage may be approximately 0.5 mg / kg body weight or approximately 6.5 mg / kg body weight. In some cases, the effective amount of at least one compound of the present invention (e.g., of formula (I), such as 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) 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 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, the effective amount of at least one compound of the present invention (which can be applied to animals, such as mammals, primates, monkeys, or humans) can be from about 1 to about 1000 mg / kg body weight, from about 5 to about 500 mg / kg body weight, from about 10 to about 200 mg / kg body weight, from about 25 to about 100 mg / kg body weight, from about 1 mg / kg, from about 2 mg / kg, from about 5 mg / kg, from about 10 mg / kg, from about 25 mg / kg, from about 50 mg / kg, from about 100 mg / kg, from about 150 mg / kg, from about 200 mg / kg, from about 300 mg / kg, from about 400 mg / kg, from about 500 mg / kg, from about 600 mg / kg, from about 700 mg / kg, from about 800 mg / kg, from about 900 mg / kg, or from about 1000 mg / kg. Under certain conditions, the dosage can be from about 20 mg / kg human body weight or from about 100 mg / kg human body weight. In some cases, the effective amount of at least one compound of the present invention (which can be applied to animals, such as mammals, rodents, mice, rabbits, cats, pigs or dogs) can be from about 1 to about 1000 mg / kg body weight, from about 5 to about 500 mg / kg body weight, from about 10 to about 200 mg / kg body weight, from about 25 to about 100 mg / kg body weight, from about 1 mg / kg, from about 2 mg / kg, from about 5 mg / kg, from about 10 mg / kg, from about 25 mg / kg, from about 50 mg / kg, from about 100 mg / kg, from about 150 mg / kg, from about 200 mg / kg, from about 300 mg / kg, from about 400 mg / kg, from about 500 mg / kg, from about 600 mg / kg, from about 700 mg / kg, from about 800 mg / kg, from about 900 mg / kg or from about 1000 mg / kg.

[0510] 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, anti-angiogenic therapy (e.g., bevacizumab), and hormone therapy such as administration of LHRH agonists; anti-estrogens such as tamoxifen; high-dose progestins; aromatase inhibitors; and / or adrenalectomy. Chemotherapy may be used as a single agent or in combination with known or novel therapies.

[0511] 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 therapies include treatment of cancers as disclosed herein through mechanisms as described herein and for cancers as disclosed herein, including but not limited to tumors. Corresponding primary therapies may include, but are 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 chemotherapeutic agent or immunotherapy, which increases the specificity of cancer treatment and may limit additional systemic side effects. In other embodiments, the compounds of the present invention (e.g., formula (I)) may be used as adjuvants in conjunction with other chemotherapeutic agents. In some cases, the use of the compounds of the present invention (e.g., formula (I)) may reduce the duration of doses of drugs and drug combinations, thereby reducing side effects.

[0512] In some embodiments, administration to a subject may reduce the incidence of one or more symptoms associated with MDS / AML / a hematopoietic system cancer. In some embodiments, administration may reduce bone marrow failure, immune dysfunction, transformation to overt leukemia, or a combination thereof in the subject compared to subjects who have not received the composition.

[0513] In some embodiments, the method can reduce markers of viability of MDS cells or cancer cells in a subject. Specifically, the method can reduce markers of viability of MDS, AML, and / or cancer cells. These markers may be selected from time-varying indicators of survival, proliferation, growth, migration, colony formation, color assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or combinations thereof.

[0514] Combination therapy

[0515] In one embodiment, the compound of formula (I) is administered in combination 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, selenobromide modulators, purine nucleoside antimetabolites, type II topoisomerase inhibitors, DNA intercalators, hedgehog protein antagonists, IDH2 inhibitors, IDH1 inhibitors, ribonucleotide reductase inhibitors, adenosine deaminase inhibitors, Mek 1 / 2 inhibitors, ERK 1 / 2 inhibitors, AKT inhibitors, PTPN11 inhibitors, SHP2 inhibitors, glucocorticoid steroids, menin inhibitors, MDM2 inhibitors, BTK inhibitors, and mutated / inactivated p53 reactivators.

[0516] 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 (a celebron modulator). In one embodiment, the immunomodulatory imide (celebron modulator) is lenalidomide. In one embodiment, the therapeutic agent comprises a purine nucleoside antimetabolite. In one embodiment, the purine nucleoside antimetabolite is clofarabine. In one embodiment, the therapeutic agent comprises a type II topoisomerase inhibitor / DNA intercalator. In one embodiment, the type II topoisomerase inhibitor / DNA intercalator is vosaroxin. In one embodiment, the therapeutic agent comprises a hedgehog protein antagonist. In one embodiment, the hedgehog protein antagonist is glasdegib. In one embodiment, the therapeutic agent comprises an IDH1 inhibitor. In one embodiment, the IDH1 inhibitor is iverosinib. In one embodiment, the therapeutic agent comprises an IDH2 inhibitor. In one embodiment, the IDH2 inhibitor is etanerceptinib. In one embodiment, the therapeutic agent comprises a ribonucleotide reductase inhibitor. In one embodiment, the ribonucleotide reductase inhibitor is gemcitabine. In one embodiment, the therapeutic agent comprises an adenosine deaminase inhibitor. In one embodiment, the adenosine deaminase inhibitor is cladribine. In one embodiment, the therapeutic agent comprises a Mek 1 / 2 inhibitor. In one embodiment, the Mek 1 / 2 inhibitor is trametinib. In one embodiment, the therapeutic agent comprises an ERK 1 / 2 inhibitor. In one embodiment, the ERK 1 / 2 inhibitor is unitinib. In one embodiment, the therapeutic agent comprises an AKT inhibitor. In one embodiment, the AKT inhibitor is capiva cetibub (AZD5363). In one embodiment, the therapeutic agent comprises a PTPN11 / SHP2 inhibitor. In one embodiment, the PTPN11 / SHP2 inhibitor is TNO-155. In one embodiment, the therapeutic agent comprises a glucocorticoid steroid. In one embodiment, the glucocorticoid steroid is prednisolone. In one embodiment, the therapeutic agent comprises a menin inhibitor. In one embodiment, the menin inhibitor is SNDX-5613. In one embodiment, the therapeutic agent comprises an MDM2 inhibitor.In one embodiment, the MDM2 inhibitor is navtemadlin (AMG 232, KRT-232). In one embodiment, the therapeutic agent comprises a BTK inhibitor. In one embodiment, the BTK inhibitor is selected from ibrutinib, acalabrutinib, and zanubrutinib. In one embodiment, the therapeutic agent comprises a mutated / inactivated p53 reactivator. In one embodiment, the mutated / inactivated p53 reactivator is epretap (APR-246).

[0517] 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.

[0518] In one embodiment, the CDK inhibitor comprises the inhibitor described in one of the following patents or patent applications: US20210332071, US20210330653, WO 2021214253, WO 2021178595, WO2021207632, US8685660, US20200361906, US10695346, US11142507, WO2021198439, WO2021201170, US8153632, US11013743, US11135198, US20210299111, WO 2021190637, WO 2021188855, WO2021188849, US20210292299, US11124836, US10961527, US20210284629, US20210283265, WO2021183994, WO 2021181233, US11116755, WO 2021176045, WO 2021177816, WO2021176049, WO 2021176349, US 20210275522, US20210275491, US20210277037, US11111250, WO 2021142448, WO 2021172359, WO 2021174195, US20210260209, US20210261609, US20210261636, US20210261546, WO 2021168341, US 11014911, US 9932344, US 8415355, US11091485, US11091490, US 20210246422, US20210246138, US20210244715, US11083722, US11083728, US 20210238226, US 20190142835, WO 2021155006、WO2021152107、WO 2021155192, US 10294234, US 11077156, WO 2021148793, WO 2021149817, US 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20090170847、WO 2009010298、US 20090142337、US20090130118、US 7388010、WO 2007033208、US 20080188524、US 20090105687、US20090099160、US 7511063、US 7511136、US 20090081645、US 20050209292、US20090076268、US7501257、WO 2009022104、WO 2009020580、US 7485638、US 20090029992、US 20090030005、US 6610677、WO 2008132138、US 7189716、US 20070238745、US20080312223、US 7465728、US 6710227、US 20080293785、US 7456191、US 6916798、WO2008137139、US 20080280906、US 7449544、US 20080275063、US 7446195、US 7446105、WO2008130569、US 7442697、WO 2008120098、WO 2008115499、US 7388015、US 7427626、WO2008073304、US 7329799、US 7407745、US 7393953、US 20080153822、US 20080146555、WO2007044401、US 6821990、US 7041824、US 7354946、US 7348335、US 7335674、WO2008021210、US 20080026992、US 20080027052、US 7312225、US 20070287718、WO2007139732、WO 2007110649、US 20070275382、US 7300943、WO 2007123686、US 7288547、US 7279473、WO 2007022241、US 7268231、WO 2007098090、WO 2007098089、WO2007097109、WO 2007095389、US 7258981、WO 2007054725、US 20070179161、US 7250515、WO 2007081060、US 20070167466、US 20070155816、US 7232826、US 7081454、US 7208598、US 6645990、US 6822097、US 20070021419、US 7166602、US 20070004684、US 7153964、US6914062、US 20060269482、US 20060252748、US 20040147561、US20060241297、US20060239973、WO 2006106046、WO 2006105386、US 7109220、US 20060194883、US20060148828、US 20060147922、WO 2006070202、WO 2004066935、US 7008953、US20060142312、US 6838464、US 20060135589、US 20050125054、US 20060078535、US6635640、US 20060111378、WO 2006051951、WO 2006024945、US 7026313、US 6982260、US20040077601、US 20050288307、US 20050277656、US 20050276866、US 20050272755、US20040029151、US 20050267066、US 6627633、US 20050261260、US 20050136177、US20040219214、US 20050222163、US 6953783、US 20050222054、US 6949558、US 6667311、WO2005002576、WO 2005083096、WO 2004078925、US 6939872、US 20050175592、US 6927031、US 6899731、US 20050164976、US 20050153991、US 6838558、WO 2005044274、US20050090529、US 20040082613、US 20050070591、US 20040180844、US 20030157704、US6863647、US 6858709、US 6849631、US 20050004120、WO 2004113353、US 20040254094、US20040248905、WO 2004107240、US 20040242869、US 20040225077、US 6812232、US6720427、US 20040185506、US 20040186288、US 6747046、US 20040180043、US20040180848、US 20040176431、US 20040156826、US20040152651、US 20040138245、US6756385、US 20040110775、US 20040110770、US 6747128、US 6743785、WO 2004004730、WO2004031158、US 6720332、WO 2004028571、US 6716831、US 6713267、US 6710052、US6706718、US 20040048849、US 20030187007、US 6696546、US 6683095、US 20040010027、US6677345、US 6630464、US 20030229105、US 6569878、US 20030215861、US 6649608、US20030064426、WO 2003091700、US 6642231、US 6632820、US 6620818、US 20030166016、US6596694、US 6586203、US 20030119816、US 20030113897、US 20030114504、US 6579903、US6576647、US 6573044、US 6043030、US 20030049602、US 20030100477、US 20030032177、WO2003030909、US 6319918、WO 2003027299、US 20030060397、US 6504034、WO 2002074742、WO 2002053096、US 20030018005、US 6500846、WO 2002100401、US 6486166、WO2002072085、US 6462069、US 6451618、US 6420345、WO 2002051849、US 6413974、US6414013、US 6407103、WO 2001083716、US 5672508、US 6291504、WO 2001038532、WO2001027080、US 6303618、US 6290951、WO 2001055148、WO 2001053293、US 6001868、US6197804、WO 1999066055、US 6013646、WO 1999043676、US 5767258、US5733920, and any INPADOC family member of each of the above references, each of which is incorporated herein by reference in its entirety. In another embodiment, the CDK inhibitor comprises the inhibitor described in the following literature: Alsfouk, A., Journal of Enzyme Inhibition and Medicinal Chemistry, 2021, 36(1):693-706; Goel, B. et al., Curr. Top. Med. Chem., 2020, 20(17):1535-1563; Heptinstall, AB et al., Future Med. Chem., 2018, 10(11):1369-1388; Sánchez-Martínez, C. et al., Bioorganic & Medicinal Chemistry Letters, 2019, 29:126637; Di Sante, G. et al., Expert Review of Anticancer Therapy, 2019, 19(7): 569-587; Whittaker, SR et al., Pharmacology & Therapeutics, 2017, 173: 83-105; Chou, J. et al., Cancer Discovery, 2020, 10: 351-370; Galbraith, MD et al., Transcription, 2019, 10(2): 118-136; Goel, B. et al., Current Topics in Medicinal Chemistry, 2020, 20: 1535-1563; Heptinstall, AB et al., Future Medicinal Chemistry, 2018, 10(11): 1369-1388; Each of these references is incorporated into this paper in its entirety by way of citation.

[0519] In one embodiment, the CDK inhibitor is a CDK9 inhibitor. In one embodiment, the CDK9 inhibitor is aviniclizol (BAY-1143572) or BAY-1251152 (VIP152). In one embodiment, BAY-1251152 (VIP152) is a selective CDK9 inhibitor, while aviniclizol (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.

[0520] Exemplary CDK inhibitors include, but are not limited to: compound 21 (PMID27326333) CYC065; YKL-1-116; i-CDK9; JH-VII-49; JH-XI-10-02; SEL120-34A; MM-D37K; PF-06873600; BEY-1007; BEY-1107; birocinib (XZP-3297); FCN-4 37; 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-Hydroxyastrocytosine; BS-194; PHA-690509; Cdk4 / 6 inhibitor IV; FCN437c;

[0521] Dinaciclib (SCH 727965) CDKI-73(LS-007); Flavopiridol (alvocidib); SNS-032(BMS-387032); (RGB286638); (zortiraciclib, TG02, SB1317); (Avecili (atuveciclib), BAY-1143572); (AZD4573); Abemaciclib (LY283219, Verzenio); Palbociclib (PD-0332991, Ibrance); Ribociclib (LEE-011, Kisqali) PF-06873600; Trilaciclib (G1T28); Lerocin (G1T38); SHR-6390; Milciclib (PHA-848125); FN-1501; Inditinib (AGM-130); (+)-BPI-16350; AT-7519; AZD-4573; voruciclib (P-1446A-05);

[0522] BCD-115; CT7001 (ICEC 0942); CYC-065; Seliciclib (R-roscovitine, CY-202); SY-1365; Sroniciclib (BAY-1000394);

[0523] THZ1; THZ2; THZ531; E9; FMF-04-159-2; YKL-5-124; NU6300; SY-314; SY-351; dabrafenib; Rebastinib; K03861; MC180295; BRD6989; SR-3029; Nordihydroguaiacol (NDGA); Prostaglandin E1; adapalene; Fluspirilene; Candesartan cilexil; Indocyanine green; Rafoxanide; HSD922; 20-223 (CP668863); roxyl-zhc-84; abemaciclib; vorinostat; Cabozantinib; Cortistatin A; MSC2530818; CCT251545; CCT251921; ZK-304709; Rivicini (P276-00); R547; AZD5438; AG-024322; LDC3140; LDC4297; wogonin; CMPD14; LDC000067; CMPD 93; Sorafenib; Senexin A; Senexin B; CMPD 20; CMPD 32; SEL120; PHA-793887; IIIM-290; olomoucine; Rohitukine; Fascaplysin; Hymenialdisine; Varian B (variolin B); Konbu'acidin A; staurosporine; LY2857785; BS-181;

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539] Where Ar is

[0540]

[0541] Where X is N, Y is -C(=O)H, and Ar is

[0542] X is N, Y is -CH2OH, and Ar is

[0543] Or X is CH, Y is -CH2OH, and Ar is

[0544] Where X is NH or O;

[0545] Where X is NH or O;

[0546] Where R1 is

[0547] Where R is H or -CH3;

[0548] Where R is -CH3 and X is F, R

[0549] If R is H and X is F, or R is -CH3 and X is Cl;

[0550] Where R is tetrahydro-pyran-4-yl and R' is H, R is -CH2CH3 and R' is -OCH3, R is isopropyl and R' is H, or R is -CH2CH3 and R' is F; Where R is tert-butylcarboxyl and n is 1, or R is H and n is 2;

[0551] Where X is NH or O;

[0552] Where R is H and R' is F, R is F and R' is F, or R is H and R' is H;

[0553] Where R is -OCH3 and R' is F, R is F and R' is SF5, or R is -OCH3 and R' is -SF5;

[0554] Where R is F and R' is -CH3 or R is -SF5 and R' is H;

[0555] Where R is -CF3 and R' is -CH3 or R is H and R' is cyclopropyl;

[0556] Where R is 3-fluoroaniline-1-yl and R' is F or R is phenyl and R' is -CH3;

[0557] Where R is H or F and the alkyl group is -CH3 or -CH2CH3;

[0558] Where R is 3-fluorophenyl or morpholino-4-yl; Where R is cyclopropane-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 cyclopropane-1-1-yl, X is F, and n is 1; or butylcyclo-3-yl, X is -CH3, and n is 1.

[0559] Where R is 1,2-oxazol-3-yl or 3,4-difluorophenyl-1-yl;

[0560] Where R is H, C(=O)NHCH3, -SO2NH2, SO2CH3 or 2,3-dihydroxypropane-1-yl;

[0561] Where R is H, CH3, 2-aminoethane-1-yl, 3-aminopropane-1-yl, or 2,3-dihydroxypropane-1-yl;

[0562] Where R is H or -CH3;

[0563] Where R is H, C(=O)NHCH3 or -SO2CH3;

[0564] Where R is 3-fluorobenzyl or 3-fluoropyridin-3-yl;

[0565] Wherein the aryl group is 4-fluorophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 4-methylphenyl, 2-ethylphenyl or 3-pyridyl and R is H, cyclopropyl, cyclopentyl or cycloheptyl;

[0566] Where R is 2-phenylethane-1-yl or (furan-2-yl)methyl;

[0567] Where R is H or -C(=O)CH2OH;

[0568] Where R is -NHC(=O)CH3 or -NHSO2CH3;

[0569] Where R is H or isobutyl;

[0570] Where R is H and R' is -CH3 or R is -CN and R' is H;

[0571] Where R is 3,4-dimethyl-1H-pyrazol-4-yl and R' is -CH3 or R is piperazine-1-yl and R' is H;

[0572] Wherein R is 2,6-dichlorophenyl, 2,3,4,5,6-tetrafluorophenyl, or 3-fluorophenyl;

[0573] Where R is -CH2NCH3 or H;

[0574] Where R is -CH2N(CH3)2 or H;

[0575] Where R is H, -SO2CH3, -CH2C(=O)N(CH3)2, 4-carboxylic acid-cyclobutane-1-yl or (2(hydroxymethyl)pyrrolidine-1-yl)-2-one-ethane-1-yl, R' is H or F, and R" is H or -CH2CH3;

[0576] Where 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

[0577] Where R is piperidine-3-yl, pyrrolidine-3-yl, or morpholino-2-yl.

[0578] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor and a DNMT inhibitor. In another embodiment, the therapeutic agent comprises venetoclax or a salt thereof, and 5-azacitidine or a salt thereof.

[0579] In some embodiments, the treatments disclosed herein may include the use of other drugs (e.g., antibiotics) or therapies used to treat diseases such as MDS / AML / a type of hematopoietic system cancer. For example, antibiotics may be used to treat infections and may be combined with the compounds of the present invention to treat diseases (e.g., infections). In other embodiments, intravenous immunoglobulin (IVIG) therapy may be used as part of a treatment regimen (i.e., in addition to the administration of 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, replacement therapy, immunotherapy, etc.

[0580] Therefore, in some embodiments, the compounds and / or compositions described herein may be used to administer once or multiple times to a subject in combination with one or more of the following: one or more BCL2 inhibitors, BTK inhibitors, chemotherapy, targeted therapy, replacement therapy, immunotherapy, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smooth receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, etc., or one or more combinations thereof, wherein if more than one administration is performed, the compositions may be the same or different. In some embodiments, if more than one administration is performed, at least one composition used for at least one administration is different from at least one other administered composition. In one embodiment, a composition comprising a compound of formula (I), (II), or (III) is administered to a subject, respectively, as well as a composition comprising a therapeutic agent described elsewhere herein.

[0581] In particular, IRAK inhibitors have been shown to have synergistic effects when administered in combination with apoptosis regulators / inhibitors, such as BCL2 inhibitors. As described in U.S. Patent Publication 2020 / 0199123 (incorporated herein by reference in its entirety), exemplary apoptosis / BCL2 inhibitors have been shown to have synergistic effects when combined with exemplary IRAK inhibitors for use in a variety of AML cell lines. Venetoclax has been used as a representative apoptosis / BCL2 inhibitor.

[0582] When the concentration of the exemplary IRAK inhibitor is combined with venetoclax, the efficacy of venetoclax is unexpectedly increased by up to approximately 50-fold. According to a specific aspect of the invention, this synergistic combination can increase the efficacy of venetoclax at lower doses, thereby avoiding at least some of the clinically observed toxicities. According to that specific aspect, the degree of interaction depends on the dose ratio used, wherein lower concentrations of the exemplary IRAK inhibitor provide a larger variation in the venetoclax IC50. This unexpectedly significant variation in the venetoclax IC50 is far more than an additive response and demonstrates an unexpected synergistic effect between the two drugs even in cell lines not expressing the activated FLT3 mutant.

[0583] Therefore, the present invention covers methods for treating diseases or conditions that respond to inhibition of IRAK, the methods comprising administering to a subject a composition comprising an IRAK inhibitory compound, and some embodiments of the methods may also involve administering an apoptosis regulator. The apoptosis regulator may comprise a BTK and / or a BCL2 inhibitor. BTK and BCL2 inhibitors may be, for example, those known in the art. In some embodiments, the method may include the step of administering the apoptosis regulator to the subject. In some embodiments, the apoptosis regulator may comprise a BCL2 inhibitor selected from the following: 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 combinations thereof. Those skilled in the art will understand that many known BCL2 inhibitors can be used according to the present invention. In some embodiments, the BCL2 inhibitor comprises venetoclax.

[0584] In some embodiments, the administration step includes administering to a subject a composition comprising an IRAK inhibitor and a BCL2 inhibitor. In some embodiments, the administration step includes administering a combination of a composition comprising an IRAK inhibitor and a composition comprising a BCL2 inhibitor.

[0585] In some embodiments, the IRAK inhibitory compound is selected from compounds 1-77, 209-214, 1a-115a or their salts, isomers, derivatives or analogs, and the BCL2 inhibitor is venetoclax or its salts, isomers, derivatives or analogs.

[0586] In some embodiments, the method may further involve administering an immunomodulatory agent to the subject. The immunomodulatory agent may include, for example, lenalidomide (Revlamid; Celgene Corporation). In some embodiments, the method may involve administering an epigenetic modulator. The epigenetic modulator may include, for example, a hypomethylating agent, such as azacitidine, decitabine, or a combination thereof.

[0587] In some embodiments, the compounds and / or compositions described herein may be administered to a subject once or multiple times together with or in combination with one or more BTK inhibitors (e.g., ibrutinib or its salts, isomers, derivatives or analogs).

[0588] For example, the compounds and / or compositions described herein may be used together or in combination with the following for single or multiple administrations: DNA methyltransferase inhibitors / hypomethylating agents, such as azacitidine, decitabine, cytarabine (ara-C; cytosine arabinoside), and / or guadecitabine; anthracyclines, such as daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (cytarabine and daunorubicin in a fixed molar ratio of 5:1), etc.; histone deacetylase (HDAC) inhibitors, such as vorinostat, panobinostat, valproic acid, and / or pracinostat, etc.; purine nuclei Glycoside analogues (antimetabolites), such as fludarabine, cladribine, and / or clofarabine, etc.; isocitrate dehydrogenase 1 or isocitrate dehydrogenase 2 (IDH1 and / or IDH2) inhibitors, such as ivosidenib (Tibsovo). For more information, see McCafferty, EH et al., Drugs & Therapy Perspectives, 2 019, 35:160-166, the references of which are incorporated herein by reference), AGI-6780, BAY1436032, FT-2102, IDH305, AGI-5198, ML309 (AGI-5027), GSK321 and DC_H31 and / or enasidenib (Idhifa, for more information see Dugan, J. et al., Expert Review of Clinical Pharmacology, 2018, 11:755-760, the references of which are incorporated herein by reference), etc.; antibody-drug conjugates, such as anti-CD33 (e.g. Ac225-lintuzumab, vadastuximab or gemtuzumab-ozogamicin) and / or anti-CD45 (e.g. I 131- apamitumab, etc.; mAbs / immunotherapy, such as anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., fluteuzumab (CD123×CD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab). b) atezolizumab, avelumab, PDR001, MBG453) and / or anti-CD47 (e.g., 5F9 (magrolimab, see Sallman, DA et al., Blood, 2019, 134:569, which is incorporated herein by reference), etc.; Plk inhibitors, such as volasertib and / or rigosertib. 1.5 β-blockers, etc.; MEK inhibitors, such as trametinib, cobimetinib, selumetinib, pimasertib, and / or refametinib, etc.; CDK inhibitors, such as alvociclib, atuveciclib, palbociclib, and ribociclib. And / or zotiraciclib; CDK9 inhibitors, such as avocidib, Bay1143572, diaciclib (SCH727965), SNS-032 (BMS-387032), TG02, CDKI-73 (LS-007), LY2857785 and / or voruciclib, etc. (For more information on CDK9 inhibitors, see Boffo, S.)(Ceder, S. et al., Journal of Experimental & Clinical Cancer Research, 2018, 37:36, cited herein by reference); CDK8 inhibitors, such as SEL120, etc.; retinoic acid receptor agonists, such as ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist), tamibarotene, adapalene, bexarotene, etc.; TP53 activators (including non-functionally mutated TP53 reactivators), such as APR-246 (Eprenetapopt); for more information, see Ceder, S. et al., EMBO Mol. Med., 2021, 13:e10852 (the cited reference is incorporated herein by reference in its entirety), APR-548, RETRA and / or PC14586, etc.; CELMoDs, such as lenalidomide, pomalidomide, CC-92480, CC-90009, avadomide and / or icerdomide; smooth receptor antagonists, such as glasdegib, etc.; ERK inhibitors, such as ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, such as ulixertinib (for more information, see Sullivan, RJ).(e.g., Cancer Discovery, 20188:185-195, the references cited are incorporated herein by reference), SCH772984, ravoxertinib, MK-8353, PD98059 and / or VTX-11e, etc.; PI3K inhibitors, such as copanlisib, gedatolisib, pictilisib, fimepinostat (CUDC-907), alpelisib ), leniolisib (CDZ-173), pilaralisib (XL147, SAR245408) and / or bimiralisib (PQR-309), etc.; mTOR inhibitors, such as onatasertib, sirolimus, temsirolimus, bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), everolimus, and / or visteusertib (AZD2014), etc.; steroid or glucocorticoid receptor modulators, such as agonists, including prednisolone, beclometasone, methylprednisolone, and prednisone. e) fluticasone, budesonide, dexamethasone, and / or cortisol, and / or antagonists comprising mifepristone, miricorilant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15), etc.; and / or EZH2 inhibitors, such as tazemetostat, etc. In some embodiments, when used in combination with an EZH2 inhibitor, the compound and pharmaceutical composition comprising it may be used for the prevention of secondary malignancies.

[0589] In one embodiment, the compounds and / or compositions described herein may be used together or in combination with: hedgehog protein (Hh) inhibitors, such as daurismo (glasdegibu maleate), for more information see Wolska-Washer, A. et al., Future Oncology, 2019, 15:3219-3232 (the cited literature is incorporated herein by reference); Vismodegib, Erismodegib, Erivedge, Sonidegib, Odomzo, Saridegib, Exelexis, and / or Taladegib; BCL-2 inhibitors, such as venetoclax (Venclexta), navitoclax, WEHI-539, and / or A-1331852; DNA methyltransferase inhibitors / hypomethylating agents, such as decitabine (For more information, see Stresemann, C. International Journal of...). Cancer, 2008, 123:8-13 (the cited literature is incorporated herein by reference) or cytarabine (for more information, see Cancer, 2008, 123:8-13, cited ... B. et al., N. Engl. J. Med., 2011, 364:1027-1036 (the cited literature is incorporated herein by reference); topoisomerase I inhibitors, such as topotecan and / or irinotecan; topoisomerase II inhibitors, such as mitoxantrone, doxorubicin and / or daunorubicin; aminopeptidase / leukotriene A4 hydrolase inhibitors, such as bestatin (Ubenimex, for more information see Hitzerd, SM et al., Amino Acids, 2014, 46:793-808 (the cited literature is incorporated herein by reference), ubenimex and / or tosedostat; FLT3 / Axl / ALK inhibitors, such as Xospata (Gilteritinib, see Dhillon, S., Drugs, 2019, 79:331-339, the cited literature is incorporated herein by reference) and / or ASP2215; FLT3 / KIT / PDGFR, PKC and / or KDR inhibitors, such as Rydapt (midostaurin, see Sheridan, C. for more information). ., Nature Biotechnology, 2017, 35:696-698 (the cited literature is incorporated herein by reference); Syk inhibitors, such as fostamatinib (R788), entoppletinib (GS-9973, for more information see Walker, AR et al., Blood, 2016, 128:2831, the cited literature is incorporated herein by reference), cerdulatinib (PRT062070) and / or TAK-659; E-selectin inhibitors, such as uproleselan (for more information see Barbier, V. et al., Nature Commun., 2020, 11:2042); NEDD8 activators, such as pevonedistat (for more information, see Swords, RT et al., British J. Haematology, 2015, 169:534-543, which is incorporated herein by reference); MDM2 inhibitors, such as idasanutlin (for more information, see Lehmann, C.).AMG-232 and / or CGM-097; PLK1 inhibitors, such as onvansertib, BI2536 and / or volasetib (for more information see Vanden Bossche, J. et al., Medicinal Research Reviews, 2016, 36:749-786, which are incorporated herein by reference); Aura A inhibitors, such as alisertib (MLN8237; for more information see Goldberg, SL et al., Leukemia Research Reports, 2014, 3:58-61, which is incorporated herein by reference), MLN8054, TAS-119, and / or erbumine (LY3295668); and aurora kinase inhibitors, such as alisertib, Danusertib, and Barasertib. AKT1, AKT2 and / or AKT3 inhibitors, such as erlotinib, dacomitinib and / or varlitinib; AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, such as erlotinib (ABT-348; for more information see Garcia-Manero, G. et al., Investigational New Drugs, 2015, 33:870-880, which are incorporated herein by reference); AKT1, AKT2 and / or AKT3 inhibitors, such as uprosertib (for more information see Darici, S. et al., J. Clin. Med.).,2020,9:2934, the references mentioned are incorporated herein by reference), Afuresertib (GSK2110183), CCT128930, Miransertib (ARQ 092), 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; farnesyltransferase inhibitors, such as tipifranib (for more information, see Epling-Burnette, PK et al., Expert Opinion on Investigational Drugs, 2010, 19:689-698 (the cited literature is incorporated herein by reference); lonafarnib, manumycin A, gingerol, gliotoxin and / or α-hydroxyfarethic acid; BRAF / MAP2K1 / MAP2K2 inhibitors, such as trametinib; Menin-KMT2A / MLL inhibitors, such as Ko-539 and / or SNDX-5613 (for more information on Ko-539 and SNDX-5613, see Gundry, MC et al., Cancer). Cell, 2020, 37:267-269 (the cited literature is incorporated herein by reference); antimetabolites, such as cytarabine, floxuridine, 5-fluorouracil, prexasertib, raltitrexed, and / or methotrexate; and / or multi-kinase inhibitors, such as dasatinib.

[0590] In one embodiment, the compounds and / or compositions described herein are used for one or more administrations, together with or in combination with lenalidomide, a highly effective drug for treating myelodysplastic syndromes (MDS) with chromosome 5q deletion (del(5q)). Lenalidomide induces ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (called CRL4CRBN), leading to CK1α degradation. CK1α is encoded by a gene within a common deletion region in del(5q) MDS, and haploidentical underexpression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. In one embodiment, the compounds and / or compositions described herein are used for one or more administrations, together with or in combination with cytarabine (ara-C, cytosine arabinoside), which has been used for the treatment of acute myeloid leukemia (AML) for over thirty years. It was initially used for induction therapy at a dose of 100 to 200 mg per square meter of body surface area. From around 1975 to 1985, researchers began evaluating the use of high-dose cytarabine therapy, administered at a dose of 3000 mg per square meter twice daily for 6 days. In single-arm studies, response rates were high in relapsed patients, and promising results were also reported in patients newly diagnosed with AML. However, recent studies have shown that lower doses of cytarabine induction therapy have produced the greatest antileukemic effect on all response endpoints, indicating a plateau in the dose-response relationship above the stated dose level, thus suggesting that high doses of cytarabine lead to excessive toxicity without therapeutic benefit. In one embodiment, the compounds and / or compositions described herein are used for single or multiple administrations, together with or in combination with hypomethylating agents (such as azacitidine, decitabine, and / or Venclexta). 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 across successive generations of cells without altering the underlying DNA sequence, hypomethylating agents are considered a class of epigenetic therapies. Currently available hypomethylating agents block the activity of DNA methyltransferases (DNA methyltransferase inhibitors / DNMT inhibitors). Two members of this class, azacitidine and decitabine, have been approved by the FDA in the United States for the treatment of myelodysplastic syndromes. 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 and supportive care, 16% of patients with myelodysplastic syndromes (MDS) who received azacitidine experienced complete or partial restoration of normal blood cell counts and bone marrow morphology, a phenomenon not observed in patients receiving supportive care. Approximately two-thirds of patients requiring transfusions no longer needed 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 treating myelodysplastic syndromes (MDS) by knocking out DNA methyltransferases and inducing DNA demethylation and exogenous genetic reprogramming. Venecella is a selective small-molecule inhibitor of BCL-2 (an anti-apoptotic protein). Overexpression of BCL-2 in cancer cells is associated with tumor cell survival and chemotherapy resistance. Therefore, BCL-2 inhibitors (such as veneclax) promote apoptosis by directly binding to the BCL-2 protein, replacing pro-apoptotic proteins, and triggering mitochondrial outer membrane permeation and caspase activation. In one embodiment, the compounds and / or compositions described herein are used together or in combination with an anti-CD47 monoclonal antibody (such as magnumab) for single or multiple administrations. Monoclonal antibodies targeting CD47 are designed to interfere with the recognition of CD47 by the SIRPα receptor on macrophages, thereby blocking the "don't eat me" signal used by cancer cells to avoid phagocytosis by macrophages. Magnumab is a first-class investigational monoclonal antibody targeting both CD47 and macrophage checkpoint inhibitors, being developed for the treatment of a variety of hematologic and solid tumor malignancies, including MDS. Magnumab 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 together or in combination with a SYK inhibitor (such as entoprinib) for single or multiple administrations. Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase primarily expressed in hematopoietic lineage cells. Constitutive activation of SYK in AML has been reported, targeting SYK-induced in vitro differentiation and exhibiting anti-leukemic activity in AML mouse models. SYK has also been shown to directly phosphorylate the FLT3 receptor, modulating its activation and potentially promoting its role in leukemia development. Entopinib, a selective inhibitor of orally bioavailable SYK, has shown clinical activity in B-cell malignancies. In one embodiment, the compounds and / or compositions described herein are administered, together with or in combination with an E-selectin inhibitor (such as upropselan), for single or multiple administrations. E-selectin directly triggers signaling pathways that promote the survival and regeneration of malignant cells. Using an acute AML mouse model, AML progenitor cells have been shown to release inflammatory mediators that upregulate E-selectin expression in the endothelial niche.Alterations in cell surface glycosylation associated with tumorigenesis enhance E-selectin binding in AML blasts and promote pro-survival signaling via the AKT / NF-κB pathway. In vivo AML blasts with the highest E-selectin binding potential are 12-fold more likely to survive chemotherapy and are a major factor in disease relapse. Therapeutic blockade of E-selectin using the small molecule mimic upproselan effectively inhibits this niche-mediated pro-survival signaling, suppresses AML blast regeneration, and exhibits a strong synergistic effect with chemotherapy, doubling the survival time in mice compared to chemotherapy alone. In one embodiment, the compounds and / or compositions described herein are used in combination with or in combination with a CDK9 inhibitor (such as avoricoxib) for single or multiple administrations. The cyclin-dependent kinase 9 (CDK9) pathway is dysregulated in AML, therefore targeting this pathway is an attractive approach for treating AML. Inhibition of CDK9 leads to downregulation of cell survival genes regulated by superenhancers such as MCL-1, MYC, and cyclin D1. Because CDK9 inhibitors are non-selective, predictive biomarkers that can help identify patients most likely to respond to CDK9 inhibitors are now being utilized to improve efficacy and safety. Avoricoxib is a polyserine-threonine cyclin-dependent kinase inhibitor that has significant in vitro and clinical activity in AML when combined with timed sequential chemotherapy regimens. In one embodiment, the compounds and / or compositions described herein are used together or in combination with Menin-KMT2A (MLL) inhibitors such as Ko-539 and / or SNDX-5613 for single or multiple administrations. Meningioma-1 (MN1) induces invasive AML when overexpressed in murine hematopoietic progenitor cells, characterized by an aberrant bone marrow precursor-like gene expression program that shares features of KMT2A rearrangement (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Menin (Men1) also plays a key role in the self-renewal of MN1-driven AML by maintaining a unique gene expression program. Genetic inactivation of Men1 leads to a reduction in the number of functional leukemia-initiating cells. Pharmacological inhibition of the KMT2A-Menin interaction has been shown to reduce colony-forming activity, induce differentiation programs in MN1-driven murine leukemia, and reduce leukemia burden in human AML xenografts. These results suggest that Menin inhibition is a promising therapeutic strategy for MN1-driven leukemia. The phase 2 clinical trial of SNDX-5613 will recruit patients based on disease and molecular genetics (MLLr AML, NPM1c AML, or MLLr acute lymphoblastic leukemia), while KO-539 is recruiting patients for a phase 1 study in relapsed / refractory AML.Both compounds have demonstrated excellent pharmacokinetic properties and low toxicity in preclinical studies. In one embodiment, the compounds and / or compositions described herein are used, together with or in combination with a nonfunctional mutant TP53 reactivator (such as epretap (APR-246)), for single or multiple administrations. TP53 gene mutations have been detected in approximately 10%–20% of patients with new-onset myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and 30%–40% of patients with treatment-related diseases. Existing therapies have poor outcomes for patients with TP53 mutations. Hypomethylating agents (HMAs) (such as azacitidine and decitabine) produce statistically similar complete remission (CR) rates in patients with TP53 mutant or wild-type MDS, at approximately 15%–20%. However, remission periods are short in patients with TP53 mutations, with a median overall survival (OS) of 5 to 12 months, reflecting an unmet medical need for targeted therapy in patients with TP53 mutant MDS and AML. Epretapone (APR-246) is converted into methylenequinine cycloketone (MQ), which targets the mutant p53 protein and interferes with cellular antioxidant homeostasis. APR-246 is currently being tested in a phase III clinical trial for myelodysplastic syndromes (MDS).

[0591] In some embodiments, one or more therapeutic agents may be in the form of salts, optical isomers, geometric isomers, and isomeric salts. In other embodiments, the therapeutic agent may be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating, pharmaceutically acceptable salts, including but not limited to hydrochlorides, hydrobroms, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates. In some cases, for acidic compounds, the salt may include metals, amines, or organic cations (e.g., quaternary ammonium salts). In yet another embodiment, simple derivatives (e.g., ethers, esters, or amides) of the therapeutic agent that have desired retention and release properties but are readily hydrolyzed by human pH, enzymes, or other suitable mechanisms may be used.

[0592] In some embodiments, the therapeutic agent has a chiral center and can be present and separated in both optically active and racemic forms. In other embodiments, the therapeutic agent may exhibit polymorphism. Some embodiments of this disclosure cover any racemic, optically active, polycrystalline, or stereoisomeric forms or mixtures thereof of the compounds described herein, including isotopically labeled and radiolabeled compounds. See, for example, Goding, 1986, *Monoclonal Antibodies: Principles and Practice*; Academic Press, p. 104. Such isomers can be separated by standard separation techniques, including, for example, fractional crystallization, chiral chromatography, etc. See, for example, Eliel, EL and Wilen SH, 1993, *Stereochemistry in Organic Compounds*; John Wiley & Sons, New York. The preparation of the optically active form can be accomplished by any suitable method, including but not limited to the separation of the racemic form by recrystallization, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.

[0593] In some embodiments, the therapeutic agent has an asymmetric center and may be in the form of a racemic mixture, a mixture of racemic compounds, and individual enantiomers or diastereomers, wherein 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 compounds known in the art that are too unstable to be synthesized and / or isolated.

[0594] The therapeutic agents disclosed herein may also contain atomic isotopes in non-natural proportions on one or more atoms constituting such compounds. For example, the compounds may contain, for instance, tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling with radioactive isotopes. All isotopic variations of the compounds disclosed herein, whether or not radioactive, are included within the scope contemplated.

[0595] In some embodiments, metabolites of the therapeutic agents disclosed herein may be used in the methods disclosed herein.

[0596] In some embodiments, the therapeutic agents contemplated herein may be provided in the form of a prodrug. The term "prodrug" refers to a compound that can be converted in vivo into a compound (e.g., a bioactive compound) described herein. Prodrugs are useful for various reasons known in the art, including ease of administration due to increased bioavailability during oral administration. Prodrugs may also have increased solubility in pharmaceutical compositions compared to bioactive compounds. A non-limiting example of a prodrug is a compound administered in the form of an ester (i.e., a "prodrug") to facilitate transmembrane transport, wherein water solubility is detrimental to mobility but is metabolically hydrolyzed into the active substance, a carboxylic acid, once inside a water-soluble, beneficial cell. Conversion procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs" (edited by H. Bundgaard, Elsevier, 1985), which is hereby incorporated by reference for the limited purpose of describing methods and preparation of suitable prodrug derivatives.

[0597] Some of the therapeutic agents disclosed herein may exist in both solvated and hydrated forms, including hydrated forms. Generally, the solvated form is equivalent to the non-solvated form and is covered within the scope of the contemplated compounds. Some of the therapeutic agents disclosed herein may exist in various crystalline or amorphous forms. In general, all physical forms are equivalent to the compounds and methods contemplated herein and are intended to be within the scope of the disclosure herein.

[0598] Other therapies are described below, and combination therapies are envisioned in the context of this invention.

[0599] Chemotherapy / Targeted Therapy / Alternative Therapy

[0600] Cancer is typically treated with chemotherapy and / or targeted and / or alternative therapies. Chemotherapy indiscriminately targets rapidly dividing cells, including both healthy and tumor cells, while targeted cancer therapies work by interfering with specific molecules or molecular targets involved in cancer growth and progression. Targeted therapies typically target only cancer cells, causing minimal damage to normal cells. Approved and / or clinically tested chemotherapy and targeted therapies are known to those skilled in the art. Any such compound may be used in the practice of this invention.

[0601] For example, approved chemotherapy drugs include abitrexate (methotrexate injection), abraxane (paclitaxel injection), adcetris (bentoximab / vitine injection), adriamycin (doxorubicin), adrucil injection (5-FU (fluorouracil)), afinitor (everolimus), afinitorDisperz (everolimus), alimta (pemetrexed), alkeran injection (melphalan injection), alkeran tablets (melphalan), aredia (pamidronate), arimidex (anastrozole), aromasin (exemestane), and aranon (nerabine). Arzerra (ofamumab injection), Avastin (bevacizumab), Beleodaq (belindustat injection), Bexxar (tosimomab), BiCNU (camustine), Blenoxane (bleomycin), Blincyto (belintoxicam injection), Bosulif (bosutinib), Busulfex (busulfan injection), Campath (alemumab), Camptosar (irinotecan), Caprelsa (vandetanib), Cascodex (bicalutamide), CeeNU (lomustine), CeeNU dosing pack (lomustine), Cerubidine (daunorubicin) Clolar (clofalabin injection), Cometriq (cazobantinib), Cosmegen (actinomycin D), Cotellic (cobimetinib), Cyramza (ramucirumab injection), CytosarU (cytarabine), Cytoxan (cyclophosphamide), Cytoxan injection (cyclophosphamide injection), Dacogen (decitabine), DaunoXome (daunorubicin lipid complex injection), Decadron (dexamethasone), DepoCyt (cytarabine lipid complex injection), Dexamethasone Intensol (dexamethasone), Deexpak Taperpa k (dexamethasone), docetaxel, doxil (doxorubicin lipid complex injection), droxia (hydroxyurea), DTIC (dacarbazine), eligard (leuprorelin), ellence (Ellence (epirarubicin)), eloxatin (Eloxatin (oxaliplatin)), elspar (asparaginase), emcyt (estrofustin), erbitux (cetuximab), erivedge (vemodilamide), erwinaze (Erwinia chrysanthemum asparaginase), ethyol (amifostine), etopophos (etoposide injection), eulexin (flutamide).Fareston (Toremifene), Farydak (Pabistat), Faslodex (Flavivestram), Femara (Letrozole), Firmagon (Degarelix Injection), Fludara (Fluordarabine), Folotyn (Methotrexate Injection), FUDR (Fluorouracil), Gazyva (Atrocilumab Injection), Gemzar (Gemcitabine), Gilotrif (Afatinib), Gleevec (Imatinib Mesylate), Gliadel Thin Tablets (Carmustine Thin Tablets), Halaven (Eribulin Injection) Herceptin (trastuzumab), Hexalen (hexamethylmelamine), Hycamtin (topotecan), Hydrea (hydroxyurea), Ibrance (pebocinib), Iclusig (ponatinib), Idamycin PFS (idarubicin), Ifex (ifosfamide), Imbruvica (ibrutinib), Inlyta (axitinib), Intron Aalfab (interferon alpha-2a), Iressa (gefitinib), Istodax (romidesin injection), Ixempra (ixapillon injection), Jakafi (Ruxolitinib), Jevtana (cabazitaxel injection), Kadcyla (adorostuzumab / etansin), Keytruda (pembrolizumab injection), Kyprolis (carfilzomib), Lanvima (lenvatinib), Leukeran (chlorambucil), Leukine (saxaglastine), Leustatin (cladribine), Lonsurf (trifluuridine and tipyrimidine), Lupron (leuprorelin), Lupron reservoir (leuprorelin), Lupron reservoir PED (leuprorelin), Lynparza (olaparib), Lysodren (mitotane) MarqiboKit (vincristine lipid complex injection), Matulane (procarbazine), Megace (medroxyprogesterone acetate), Mekinist (trametinib; for more information see Borthakur, G. et al., Blood, 2012, 120:677, which is incorporated herein by reference), Mesnex (Mesnex), Mesnex (Mesnex injection), Metastron (strontium chloride-89), Mexate (methoprene injection), Mustargen (dichloroethylmethylamine), Mustamycin (mitomycin), Myleran (Busulfan)Mylotarg (gestuzumab oxazolidin, see Norsworthy, KJ et al., Oncologist, 2018, 23:1103-1108 for more information, cited herein), Navelbine, Neosar injection (cyclophosphamide injection), Neulasta (filgrastim), Neulasta (pefilgrastim), Neupogen (filgrastim), Nexavar (sorafenib), Nilandron (nilumet), Nipent (pentoxatine), Nolvadex (tamoxifen), Novantrone (mitoxantrone, see Fox for more information). EJ, Neurology, 2004, 28(12Suppl6):S15-8, the references cited are incorporated herein by reference), Odomzo (solidazole), Oncaspar (pegaspargase), Oncovin (vincristine), Ontak (denylizumab toxin), onxol (paclitaxel injection), opdivo (nivolumab injection), panretin (alevitidine), paraplatin (carboplatin), perjeta (pertuzumab injection), platinol (cisplatin), platinol (cisplatin injection), platinolAQ (cisplatin), platinolAQ (cisplatin injection), pomalyst (pomalidomide), prednisone Intensol (prednisone), proleukin (alevizumab), purinethol (mercaptopurine), reclast (zoledronic acid), revlimid (lenalidomide); for more information, see, J. et al., Nature, 2015, 523:183-188, the references of which are incorporated herein by reference), actimid (pomadomino), rheumatrex (methoprene), rituxan (rituximab), roferon Aalfaa (interferon α-2a), rubex (doxorubicin), sandostatin (octreotide), sandostatin LAR reservoir (octreotide), soltamox (tamoxifen), sprycel (dasatinib); for more information, see Duong, VH et al., Leukemia Research, 2013, 37:300-304.The references mentioned above are incorporated herein by reference. (The references are listed below.) sterapred (prednisone), sterapredDS (prednisone), stivarga (regorafenib), supprelin LA (histamine relin implant), sutent (sunitinib), sylatron (pegylated interferon alpha-2b injection), sylvant (celetuximab injection), synribo (olmetacine injection), tabloid (thioguanine), taflinar (dabrafenib), tarceva (erlotinib), targretin capsules (bexarotin), tasigna (dacarbazine), paclitaxel (paclitaxel injection), taxotere (docetaxel), temodar (temozolomide), tepadina (thiotepa), thalomid (thalidomide), theraCysBCG (BCG), thioplex (thiotepa), TICE BCG (BCG), toposar (etoposide injection), torisel (tesiramolimus), treanda (bendamustine hydrochloride), trelstar (triptorelin injection), trexall (methotrexate), trisenox (arsenic trioxide), tykerb (lapatinib), unituxin (ditoxicumab injection), valstar (pentoxuridine intravesical formulation), vantas (histamine retinoid implant), vectibix (panitumumab), velban (vincrine), velcade (bortezomib), vepesid (etoposide), vepesid (etoposide injection), vesanoid (retinoic acid), vidaza (azacitidine), vincasarPFS (vincristine), vincristine (vincrex). otrient (pazopanib), vumon (teniposide), wellcovorin IV (tetrahydrofolate injection), xalkori (crizotinib), xeloda (capecitabine), xtandi (enzalutamide), yervoy (ipilimumab injection), yondelis (trabectedine injection), zaltrap (ziv-aflibercept injection), zanosar (streptozotocin), zelboraf (vemurafenib), zevalin (timolomaab / teucertan), zoladex (goserelin), zolinza (vorinostat), zometa (zoledronic acid), zortress (everolimus), zydelig (ederaris), zykadia (ceritinib), zytiga (abiraterone), etc., and their analogues and derivatives. For example,Approved targeted therapies include adorostuzumab (kadcyla), afatinib (Gilotrif), interleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campath), axitinib (Inlyta), bosutinib (Bosulif), bentoximab (Adcetris), cabozantinib (Cabometyx [tablets], Cometriq [capsules]), cannabinumab (Ilaris), carfilzomib (Kyprolis), and ceritinib ( Zykadia), cetuximab (Erbitux), cobimetinib (Cotellic), crizotinib (Xalkori), dabrafenib (Tafinlar), daratumumab (Darzalex), dasatinib (Sprycel), denosumab (Xgeva), unituxin, eleutuzumab (Empliciti), erlotinib (Tarceva). For more information, see Boehrer, S. et al., Blood, 2008, 111:2170-2180.The references mentioned are incorporated herein by reference. (Afinitor, gefitinib, Zevalin, imbruvica, Zydelig, Gleevec, Yervoy, Ninlaro, Tykerb, Lenvatinib, Portrazza, Nilotinib) Signa, Nivolumab (Opdivo), Atorizumab (Gazyva), Ofamumab (Arzerra, HuMax-CD20), Olaparib (Lynparza), Osimertinib (Tagrisso), Palbociclib (Ibrance), Panitumumab (Vectibix), Pembrolizumab (Farydak), Pazopanib (Votrient), Pembrolizumab (Keytruda), Pertuzumab (Perjeta), Ponatinib (Iclusig), Ramucirumab (Cyramza), Rapamycin, Regorafenib (Stivarga), Rituximab (Rituxan, Mabthera), Romidixin (Istodax), Ruxolitinib (Jakafi), Cetuximab (Sylvant), Ciprolux-T (Provenge), Sirolimus, Solidogen (Odomzo), Sorafenib (Nexavar), Sunitinib, Tamoxifen, Tessilolimus (Torise) l), tocilizumab (Actemra), tofacitinib (Xeljanz), tosimomab (Bexxar), trametinib (Mekinist), trastuzumab (Herceptin), vandetanib (Caprelsa), vemurafenib (Zelboraf), venetoclax (Venclexta), vemodedge (Erivedge), vorinostat (Zolinza), zifab-flibercept (Zaltrap), etc., and their analogues and derivatives. In one embodiment, the approved chemotherapy is anthracyclines, such as doxorubicin, daunarubicin, epirubicin, and / or idarubicin. In one embodiment, the approved chemotherapy is selected from azacitidine (for more information, see Keating, GM, Drugs, 2012, 72:1111-1136, which is incorporated herein by reference) and veneclade (for more information, see Raedler, LA, Journal of Hematology Oncology Pharmacy, 2017, 7:53-55, which is incorporated herein by reference).

[0602] Those skilled in the art can determine appropriate chemotherapy and / or targeted and / or alternative therapies, including approved treatments and those undergoing clinical trials or otherwise developed. Some targeted therapies are also immunotherapies. In the practice of this invention, any associated chemotherapy, targeted, and alternative treatment strategies can be used alone or in combination with one or more other cancer therapies.

[0603] Immunotherapy

[0604] In some embodiments, immunotherapy includes 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 (e.g., monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemically labeled antibodies, etc.), immune checkpoint inhibitors, vaccines (e.g., cancer vaccines (e.g., tumor cell vaccines, antigen vaccines, dendritic cell vaccines, vector-based vaccines, etc.), such as bacteriophages, ciproxetine, etc.), and immunomodulators (e.g. Immunotherapy can be categorized into several types, including: immunotherapy with interleukins, cytokines, chemokines, local immunotherapy (e.g., imiquimod), injectable immunotherapy, adoptive cell transfer, oncolytic virus therapy (e.g., tatamogen elaherparepvec (T-VEC)), immunosuppressive drugs, worm therapy, and other non-specific immunotherapies. Immune checkpoint inhibitor immunotherapy targets one or more specific proteins or receptors, such as PD-1, PD-L1, and CTLA-4. Immune checkpoint inhibitor immunotherapy includes ipilimumab (ipramab). Examples of nonspecific immunotherapies include nivolumab (Opdivo) and pembrolizumab (Keytruda). Nonspecific immunotherapies include cytokines, interleukins, and interferons. In some embodiments, the immunotherapy administered to a subject may include interleukins and / or interferons (IFN), and / or one or more suitable antibody-based agents, such as denosumab, and / or administration of antibody-based agents selected from the group consisting of: adorotrizumab, estansin, trastuzumab, alenumab, atezolizumab, bevacizumab, bonatumab, brentuximab, virdocin, cetuximab, caputuximab, and gemtruzzi. Monoclonal antibodies, including tiimumab, ilipimumab, natalizumab, nimotuzumab, nivolumab, oflamimumab, panitumumab, pembrolizumab, rituximab, tosimomumab, trastuzumab, and vivataxin. In some embodiments, the immunotherapy administered to or given to the subject may comprise an indoleamine 2,3-dioxygenase (IDO) inhibitor, adoptive T-cell therapy, viral therapy (T-VEC), and / or any other immunotherapy whose efficacy is broadly dependent on antitumor immunity.

[0605] Those skilled in the art can determine appropriate immunotherapy options, including approved treatments and those under clinical trials or otherwise developed. Any relevant immunotherapy strategy, alone or in combination with one or more other cancer therapies, can be used in the practice of this invention.

[0606] Other cancer treatments

[0607] In addition to chemotherapy, targeted therapy, replacement therapy, and immunotherapy, cancer can be treated with other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplantation, precision medicine, etc.; such treatments, and the compounds and compositions used therein, are known to those skilled in the art. Any such treatment strategy can be used in the practice of this invention.

[0608] Alternative treatment strategies are also used for various types of cancer. Such treatments can 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, nutrition, and dietary supplements; such treatments are known to those skilled in the art. In the practice of this invention, any such treatment strategy can be used alone or in combination with one or more other cancer therapies.

[0609] Dosage and route of administration

[0610] Other embodiments of the invention may include methods of administering or treating animals, the methods of which may involve treating with an amount of at least one compound of the invention (e.g., formula (I)) that is effective in treating a disease, symptom, or condition, so that the organism has, or is suspected of having, or is susceptible to, or brings about the desired physiological effect. In some embodiments, the composition or pharmaceutical composition comprises 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), (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-WO-WO50). WO50)) The compound may be administered to animals (e.g., mammals, primates, monkeys, or humans) in amounts of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, or about 15 mg / kg. For some conditions, the dose may be about 0.5 mg / kg human body weight or about 6.5 mg / kg human body weight. In some cases, the following doses may be administered to subjects (e.g., mammals, mice, rabbits, cats, pigs, or dogs): about 0.005 mg / kg to about 50 mg / kg body weight, about 0.01 mg / kg to about 15 mg / kg body weight, about 0.1 mg / kg to about 10 mg / kg body weight, about 0.5 mg / kg to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 80 mg / kg, about 100 mg / kg, or about 150 mg / kg.Of course, those skilled in the art will understand that multiple concentrations can be used in the methods of the present invention, and that any number of concentrations can be adjusted and tested in part using the guidance provided herein in order to find the concentration that achieves the desired result in a given situation. In some embodiments, the dose or therapeutically effective dose of the compound disclosed herein will be sufficient to achieve plasma concentrations of the compound or its active metabolite within the ranges listed herein, such as 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, such compounds are believed to be suitable for the treatment or administration of cancers of the hematopoietic system, such as MDS and / or AML and / or DLBCL, as described herein.

[0611] In other embodiments, the compounds and / or pharmaceutical compounds of the present invention (e.g., compounds of formula (I), (II) or (III) and pharmaceutical compositions comprising them) may be administered in combination with one or more other therapeutic agents targeting a particular disease, symptom or condition.

[0612] 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 may be used depending on the activity of the compound, the route of administration, the nature and severity of the disease or symptom, and the subject's age and weight.

[0613] However, in some cases, a higher or lower daily dose may be appropriate. Daily doses can be administered as a single dose unit or several smaller dose units, or as a series of smaller doses administered at specific intervals.

[0614] The compounds and pharmaceutical compositions envisioned in this article can be administered topically or systemically at therapeutically effective doses. Of course, the effective dose will depend on the severity of the disease or condition, as well as the subject's weight and general condition. Typically, in vitro dosages can provide useful guidance regarding in situ administration of the pharmaceutical composition, and animal models can be used to determine effective doses for treating specific conditions.

[0615] Various considerations are described, such as those in: Langer, 1990, Science, 249:1527; Goodman and Gilman's (eds.), 1990, ibid., each of which is incorporated herein by reference for all purposes. The parenteral dose of an active pharmaceutical ingredient can be converted to the corresponding oral dose by multiplying the parenteral dose by an appropriate conversion factor. For general applications, the parenteral dose in mg / mL multiplied by 1.8 equals the corresponding oral dose in milligrams (“mg”). For oncological applications, the parenteral dose in mg / mL multiplied by 1.6 equals the corresponding oral dose in mg. The average adult weight is approximately 70 kg. See, for example, Miller-Keane, 1992, Encyclopedia & Dictionary of Medicine, Nursing & Allied Health, 5th ed., WBSaunders Co., pp. 1708 and 1651.

[0616] However, it should be understood that the specific dosage level for any particular patient will depend on a wide variety of factors, including the activity of the specific compound used, age, weight, health status, sex, diet, time of administration, route of administration, excretion rate, drug combination, and the severity of the specific disease experienced during the therapy.

[0617] In some embodiments, the compound and / or pharmaceutical composition 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 them), combined with a pharmaceutically acceptable carrier, and may also include other pharmaceuticals, agents, carriers, adjuvants, diluents, and excipients. In some embodiments, the carrier, medium, or excipient may facilitate the administration, delivery, and / or improve the preservation of the composition. In other embodiments, one or more carriers include, but are not limited to, saline solutions such as physiological saline, Ringer's solution, PBS (phosphate-buffered saline), and mixtures of various salts generally, including potassium and phosphate salts with or without sugar additives (such as glucose). The carrier may include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, bactericidal antibiotics, and solutes that make the formulation isotonic with the body fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. In other embodiments, one or more excipients may include, but are not limited to, water, saline, dextran, glycerol, ethanol, and combinations thereof. Non-toxic adjuvants, such as wetting agents, buffers, or emulsifiers, may also be added to the composition. Oral formulations may include commonly used excipients, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.

[0618] Depending on the specific application and potency of the active ingredient, the amount of the active ingredient in a unit dose formulation can vary or be 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. If desired, the composition may also contain other compatible therapeutic agents.

[0619] The compounds of the present invention (e.g., compounds according to formula (I), (II), or (III)) can be administered to subjects via a variety of suitable routes of administration or formulations. The compounds of the present invention (e.g., formulas (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 a variety of diseases in subjects. Subjects include, but are not limited to, mammals, primates, monkeys (e.g., macaques, rhesus monkeys, or pig-tailed macaques), humans, dogs, cats, cattle, pigs, poultry (e.g., chickens), mice, rabbits, and rats. As used herein, unless otherwise stated, the term "subject" encompasses both human and non-human subjects.

[0620] The compounds of the present invention (e.g., formula (I)) can be administered via any suitable route. Routes of administration can be, but are not limited to, oral, parenteral, skin, nasal, rectal, vaginal, and ocular routes. In other embodiments, routes of administration can be parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular. The choice of route of administration can depend on the identity of the compound (e.g., the physical and chemical properties of the compound), the age and weight of the animal, the specific disease (e.g., cancer or MDS), and the severity of the disease (e.g., stage or severity of cancer or MDS). Of course, combinations of routes of administration can be used as needed.

[0621] Some embodiments of the present invention include a method of providing a subject with a composition (e.g., a pharmaceutical composition) comprising one or more of the compounds of the present invention described herein (e.g., formula (I)), the method comprising one or more administrations of one or more such compositions; if multiple administrations are present, the compositions may be the same or different.

[0622] Methods to increase the survival rate of test subjects

[0623] In another aspect, this disclosure provides a method for increasing the survival of a subject diagnosed with or suspected of having acute myeloid leukemia (AML), the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (II), (III), (V), (VI), or (VII) (including (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)). Compounds of (I), (II), (III), (V), (VI), (VII) or their salts, esters, solvates, optical isomers, geometric isomers or isomer salts, or compounds comprising formulas (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (Id-5010-WO50), (Ib ... Compositions of compounds of (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 their salts, esters, solvates, optical isomers, geometric isomers, or isomer salts. In one embodiment, the subject's survival is increased compared to a subject treated with a therapeutically effective amount of standard care for AML. In one embodiment, standard care for AML comprises gititinib or a pharmaceutically acceptable salt thereof.

[0624] In one embodiment, the method comprises administering to a subject a therapeutically effective amount of a compound of formula (I), (II), (III), (V), (VI), or (VII) (including formula (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-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) about every 6 hours, every 12 hours, every 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week) Compounds of (I), (II), (III), (V), (VI), (VII) or their salts, esters, solvates, optical isomers, geometric isomers or isomer salts, or compounds comprising formulas (Ia-5010-WO), (Ib-5010-WO), (Ic-5010-WO), (Id-5010-WO), (Ib-5010-WO50), (Id-5010-WO50), (Id-5010-WO50), (Ib ... Compositions of compounds of (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 their salts, esters, solvates, optical isomers, geometric isomers, or isomer salts. In one embodiment, the administration comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In one embodiment, the compound is administered to the subject at an amount from about 0.005 mg / kg of subject body weight to about 1,000 mg / kg of subject body weight.In one embodiment, a lower dose of a compound of formula (I), (II), (III), (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), (IIb-5010-WO50), (IIIa-5010-WO), (IIIb-5010-WO), (IIIa-5010-WO50) or (IIIb-5010-WO50)) or its salt, ester, solvate, optical isomer, geometric isomer, or isomer compared to a standard care dose. Body salts, or compounds comprising formulas (I), (II), (III), (V), (VI), (VII) (including compounds of 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 their salts, esters, solvates, optical isomers, geometric isomers or isomer salts thereof, may enhance the survival of subjects. 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 isomer salt 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 isomer salt thereof.

[0625] In one embodiment, AML includes AML with splicing factor mutations, AML with enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or AML that is not driven by FLT3 mutations but expresses IRAK4-Long.

[0626] In one embodiment, the method further comprises administering one or more adjunctive therapies to the subject, the adjunctive therapies being selected from: chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or isocitrate dehydrogenase 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, smooth receptor antagonists, including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors. ERK inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog protein (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR inhibitors, PKC and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, AuraA inhibitors, aurora kinase inhibitors, EGFR inhibitors, AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT 1. AKT 2 and / or AKT 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, and multi-kinase inhibitors.

[0627] In one embodiment, AML responds to at least one of BCL2 inhibition, BTK inhibition, CDK inhibition, and DNA methyltransferase inhibition; or AML is sensitive to anti-inflammatory glucocorticoids. In one embodiment, the adjunctive therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.

[0628] 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 refractory AML resistant to BCL2 inhibitors. In one embodiment, the AML is refractory AML resistant to venetoclax. In one embodiment, the AML is relapsed AML resistant to BCL2 inhibitors. In one embodiment, the AML is relapsed AML resistant to venetoclax. [...

Claims

1. A compound of formula (I), (II) or (III): Or its salts, esters, solvates, optical isomers, geometric isomers, isomer salts, prodrugs, or derivatives. in: A is selected from 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; R 1 R 2 R 3 R 4 and R 5 Each is independently selected from H, deuterium, halogen, hydroxyl, oxo group, -CN, -C(=O)H, -C(=O)OH, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, -C(=O)NR 31 R 32 Cycloalkyl, -O-cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl or 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, spirocycloalkyl, heterocyclic, aryl, heteroaryl or fused-ring heteroaryl are optionally substituted by one or more of the following: Deuterium, halogen, hydroxyl, oxo group, -C(=O)H, -C(=O)OH, nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, -SO3H, cycloalkyl, heterocyclic, aryl, heteroaryl, pyrrole, piperidinyl, piperazine, morpholinyl, -C(=O)-morpholin-4-yl, -C(=O)NH2, -C(=O)N(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy or C1-C7 alkyl substituted with cycloalkyl; R 6 for Or by one or more -NR 33 R 34 Substituted C3-C6 cycloalkyl groups; R 7 R 8 R 9 R 10 R 11 R 12 R 13 and R 14 Each of the following is independently selected from H, deuterium, halogen, hydroxyl, oxo group, -CN, -C(=O)H, -C(=O)OH, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl or fused-ring heteroaryl, wherein -C(=O)H, -C(=O)OH, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl or fused-ring heteroaryl is optionally substituted by 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 Independently selected from H, deuterium, halogen, hydroxyl, oxo group, -CN, formyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl, or fused-ring heteroaryl, wherein -C(=O)H, -C(=O)OH, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocycloalkyl, heterocyclic, aryl, heteroaryl or fused heteroaryl are optionally substituted by one or more halogens; R 31 and R 32 Each is independently selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more halogens; R 33 and R 34 Each is independently selected from H and C1-C6 alkyl groups; and m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5, wherein q+r+s+t is at least 1, and u+v+w+x is at least 1.

2. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (Ib-5010-WO50): Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts; in: V is N or CR 11 ; W is N or CR 12 ; X is N or CR 13 ; for R 10b Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogens. R 17b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C3-C9 heterocyclic groups, imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens. R 11 R 12 and R 13 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 14a R 14b R 15a R 15b R 16a R 16b R 18a and R 18b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and N is one of V, W, or X.

3. The compound according to claim 2, wherein at least one of (i) to (v) is applicable: (i)R 14b R 15a R 15b R 16a and R 16b Each of them is H, and R 14a For F; (ii)R 11 R 12 and R 13 If it exists, its value is H; (iii) V is CR 11 , where R 11 F is F, W is CR 12 , where R 12 Let H be a variable, and X be a variable N; (iv)R 10b Selected from H and -OCH3; and (v)R 17b Selected from 4. The compound according to claim 2 or 3, wherein the conditions are: When R 17b for At that time, R 10b For H; and When R 17b for At that time, R 11 R 12 and R 13 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

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

6. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (Id-5010-WO50): Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts; in: V is N or CR 11 ; W is N or CR 12 ; X is N or CR 13 ; for R 10d Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 18a R 18b In which the C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and The C3-C6 cycloalkyl group and the -O-(C3-C6 cycloalkyl group) therein are each optionally substituted by one or more substituents selected from C1-C6 alkyl groups and halogens; R 113d Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 18a R 18b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens. Substitution of C1-C6 alkyl groups and halogens; R 11 R 12 and R 13 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 18a and R 18b Each is independently selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; R 19a R 19b R 110a R 110b R 111a R 111b R 112a and R 112b Each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; and N is one of V, W, or X.

7. The compound according to claim 6, wherein at least one of (i) to (vi) is applicable: (i)R 19a R 19b R 110a R 110b R 111a R 111b R 112a and R 112b Each of them is H; (ii)R 19a R 19b R 110b R 111a R 111b R 112a and R 112b Each of them is H, and R 110a For F; (iii)R 11 R 12 and R 13 If it exists, its value is H; (iv) V is CR 11 , where R 11 F is F, W is CR 12 , where R 12 Let H be a variable, and X be a variable N; (v)R 10d Selected from H and -OCH3; and (vi)R 113d Selected from 8. The compound according to claim 6 or 7, wherein the conditions are: When R 113d for At that time, R 10d For H; and When R 113d for At that time, R 11 R 12 and R 13 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

9. The compound according to any one of claims 6 to 8, wherein the compound of formula (Id-5010-WO50) is selected from:

10. The compound according to claim 1, wherein the compound of formula (II) is a compound of formula (IIa-5010-WO50): Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts; in: L is N or CR 21 ; M is N or CR 22 ; Q is N or CR 23 ; for R 20a Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b In which the C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and The C3-C6 cycloalkyl group and the -O-(C3-C6 cycloalkyl group) are each optionally substituted by one or more substituents selected from C1-C6 alkyl groups and halogens; R 27a Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, spirocycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, spirocycloalkyl, -O-(C3-C6 cycloalkyl) and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens. R 21 R 22 and R 23 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 24a R 24b R 25a R 25b R 26a and R 26b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; R 28a and R 28b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and N is one of L, M, or Q.

11. The compound according to claim 10, wherein at least one of (i) to (v) is applicable: (i)R 24b R 25a R 25b R 26a and R 26b Each of them is H, and R 24a For F; (ii)R 21 R 22 and R 23 If it exists, its value is H; (iii) L is CR 21 , where R 21 Selected from F, Cl and -OCH3, M is CR 22 , where R 22 Let H be a variable and Q be a variable N; (iv)R 20a Selected from -OCH3, unsubstituted -O-(C3 cycloalkyl) and as well as (v)R 27a Selected from unsubstituted C3-C6 cycloalkyl groups, 12. The compound according to claim 10 or 11, wherein the conditions are: When R 20a For -OCH3 and R 27a When R is an unsubstituted C3 cycloalkyl group, 21 R 22 and R 23 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

13. The compound according to any one of claims 10 to 12, wherein the compound of formula (IIa-5010-WO50) is selected from:

14. The compound according to claim 1, wherein the compound of formula (II) is a compound of formula (IIb-5010-WO50): Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts; in: L is N or CR 21 ; M is N or CR 22 ; Q is N or CR 23 ; for R 20b Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), imidazolyl, triazolyl, and -C(=O)NR 28a R 28b In which the C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium, and halogens, and The C3-C6 cycloalkyl group and the -O-(C3-C6 cycloalkyl group) are each optionally substituted by one or more substituents selected from C1-C6 alkyl groups and halogens; R 27b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, spirocycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazolyl groups, triazolyl groups, and -C(=O)NR groups. 28a R 28b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted by one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, spirocycloalkyl, and -O-(C3-C6 cycloalkyl) groups are also present. Each of the C2-C6 heterocyclic groups may optionally be substituted by one or more substituents selected from -OH, C1-C6 alkyl groups, and halogens; R 21 R 22 and R 23 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; R 28a and R 28b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and N is one of L, M, or Q.

15. The compound according to claim 14, wherein at least one of (i) to (vi) is applicable: (i)R 29a R 29b R 210a R 210b R 211a R 211b R 212a and R 212b Each of them is H; (ii)R 29a R 29b R 210b R 211a R 211b R 212a and R 212b Each of them is H, and R 210a For F; (iii)R 21 R 22 and R 23 If it exists, its value is H; (iv) L is CR 21 , where R 21 Selected from F, Cl and -OCH3, M is CR 22 , where R 22 Let H be a variable and Q be a variable N; (v)R 20b Selected from -OCH3, -OCD3, unsubstituted -O-(C3 cycloalkyl) and as well as (vi)R 27b Selected from unsubstituted C3-C6 cycloalkyl groups, 16. The compound according to claim 14 or 15, wherein: When R 20b For -OCH3 and R 27b When R is an unsubstituted C3 cycloalkyl group, 21 R 22 and R 23 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

17. The compound according to any one of claims 14 to 16, wherein the compound of formula (IIb-5010-WO50) is selected from:

18. The compound according to claim 1, wherein the compound of formula (III) is a compound of formula (IIIa-5010-WO50): Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts; in: R is N or CR 31 ; T is N or CR 32 ; U is N or CR 33 ; for R 37a Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazole groups, triazolyl groups, 2-pyrrolidone groups, and -C(=O)NR groups. 38a R 38b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl) and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens. R 31 R 32 and R 33 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 34a R 34b R 35a R 35b R 36a and R 36b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; R 38a and R 38b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and N is one of R, T, or U.

19. The compound according to claim 18, wherein at least one of (i) to (iv) is applicable: (i)R 34b R 35a R 35b R 36a and R 36b Each of them is H, and R 34a For F; (ii)R 31 R 32 and R 33 If it exists, its value is H; (iii) R is CR 31 , where R 31 Let F be F and T be CR. 32 , where R 32 H is a variable, and U is a variable; and (iv)R 37a Selected from 20. The compound according to claim 18 or 19, wherein the condition is R 37a Not for 21. The compound according to any one of claims 18 to 20, wherein the compound of formula (IIIa-5010-WO50) is:

22. The compound according to claim 1, wherein the compound of formula (III) is a compound of formula (IIIb-5010-WO50): Or its salts, esters, solvates, optical isomers, geometric isomers or isomer salts; in: R is N or CR 31 ; T is N or CR 32 ; U is N or CR 33 ; for R 37b Selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, -O-(C3-C6 cycloalkyl groups), C2-C6 heterocyclic groups, imidazole groups, triazolyl groups, 2-pyrrolidone groups, and -C(=O)NR groups. 38a R 38b The C1-C6 alkyl and C1-C6 alkoxy groups are each optionally substituted with one or more substituents selected from -OH, deuterium and halogens, and the C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl) and C2-C6 heterocyclic groups are each optionally substituted with one or more substituents selected from -OH, C1-C6 alkyl and halogens. R 31 R 32 and R 33 Each is independently selected from H, C1-C6 alkoxy groups, and halogens; R 39a R 39b R 310a R 310b R 311a R 311b R 312a and R 312b Each is independently selected from H, halogen, -OH, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted by one or more halogen atoms; R 38a and R 38b Each is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens; and N is one of R, T, or U.

23. The compound according to claim 22, wherein at least one of (i) to (v) is applicable: (i)R 39a R 39b R 310a R 310b R 311a R 311b R 312a and R 312b Each of them is H; (ii)R 39a R 39b R 310b R 311a R 311b R 312a and R 312b Each of them is H, and R 310a For F; (iii)R 31 R 32 and R 33 If it exists, its value is H; (iv) R is CR 31 , where R 31 Let F be F and T be CR. 32 , where R 32 H is a variable, and U is a variable; and (v)R 37b Selected from 24. The compound according to claim 22 or 23, wherein: When R 37b for At that time, R 31 R 32 and R 33 At least one of them is present and is selected from C1-C6 alkoxy and halogen.

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

26. The compound according to any one of claims 1 to 25, wherein: (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 and not an inhibitor of FLT3; or (iii) The compound is an inhibitor of each of IRAK1, IRAK4 and FLT3.

27. A composition comprising the compound according to any one of claims 1 to 26, wherein the composition further comprises a formulation ingredient, an adjuvant, or a carrier.

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

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

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

31. The method of claim 30, wherein the hematopoietic system 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, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, and marginal zone lymphoma.

32. The method according to claim 30 or 31, wherein the disease or symptom is selected from: BCL2 inhibitor-resistant acute myeloid leukemia (AML), BCL2 inhibitor-resistant refractory acute myeloid leukemia BCL2 inhibitor resistance relapsed acute myeloid leukemia FLT3 inhibitor-resistant acute myeloid leukemia FLT3 inhibitor-resistant refractory acute myeloid leukemia, or FLT3 inhibitor resistance relapsed acute myeloid leukemia.

33. The method according to claim 28 or 29, wherein the disease or condition comprises at least one cancer selected from the following: myeloma, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer.

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

35. The method according to any one of claims 28 to 34, further comprising administering one or more adjunctive therapies to the subject, said adjunctive therapies being selected from: chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or isocitrate dehydrogenase 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, etc. CELMoD, smooth receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog protein (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 A inhibitors, aurora kinase inhibitors, EGFR inhibitors, AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT 1, AKT 2 and / or AKT 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, and multi-kinase inhibitors.

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. 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 thereof, the CDK inhibitor is selected from CDK4 / 6 inhibitor palbociclib, CDK7 inhibitor THZ1 and / or CDK9 inhibitor BAY1251152 and avecilib, or a pharmaceutically acceptable salt thereof, or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.

38. 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 a single application or in a composition.

39. 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 separately in more than one administration or in more than one composition.

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

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

42. The method of claim 41, wherein the subject's viability is increased compared to a subject receiving a therapeutically effective amount of the AML standard care treatment.

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

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

45. The method of claim 44, wherein 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 receiving a therapeutically effective amount of the AML standard care treatment.

46. ​​The method according to any one of claims 41 to 45, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 26 or the composition according to any one of claims 27 to 30 about every 6 hours, every 12 hours, every 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days or once a week.

47. The method according to any one of claims 41 to 46, further comprising administering one or more adjunctive therapies to the subject, said adjunctive therapies being selected from: chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or isocitrate dehydrogenase 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, etc. CELMoD, smooth receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog protein (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 A inhibitors, aurora kinase inhibitors, EGFR inhibitors, AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT 1, AKT 2 and / or AKT 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, and multi-kinase inhibitors.

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. 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 thereof, the CDK inhibitor is selected from CDK4 / 6 inhibitor palbociclib, CDK7 inhibitor THZ1 and / or CDK9 inhibitor BAY1251152 and avecilib, or a pharmaceutically acceptable salt thereof, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.

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

51. The method of claim 47, wherein the compound of any one of claims 1 to 26 or the composition of claim 27 is administered together with the one or more additional therapies in a single administration or in a composition.

52. The method of claim 47, wherein the compound of any one of claims 1 to 26 or the composition of claim 27 is administered separately from the one or more additional therapies in more than one administration or in more than one composition.

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