Polycyclic IRAK and FLT3 inhibitory compounds, and their use

Abstract

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

Description

[Technical Field]

[0001] Cross-reference of related applications This application is an international application claiming priority to U.S. Provisional Application No. 63 / 125,654 filed December 15, 2020, which is incorporated herein by reference in its entirety.

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

[0003] Myelodysplastic syndrome (MDS) is a malignant, sometimes fatal, hematological disorder caused by a deficiency of hematopoietic stem cells / progenitor cells, predisposing patients to acute myeloid leukemia (AML) (Corey et al., 2007; Nimer, 2008), and often progressing to chemotherapy-resistant secondary acute myeloid leukemia (sAML). Many patients with MDS die due to bone marrow failure, immunodeficiency, and / or clear progression to leukemia.

[0004] MDS is a heterogeneous disease with limited treatment options because there are no effective drugs that can provide a sustained response. Current treatment options for MDS are limited, but include allogeneic hematopoietic stem cell (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 not available to many elderly patients; instead, they receive supportive care and blood transfusions to manage disease complications. Unfortunately, MDS clones can persist in the bone marrow even after HSC transplantation, and the disease invariably progresses (Tehranchi et al., 2010). In cases of progressive disease or high-risk MDS, patients may receive immunosuppressive therapy, epigenetic modifying drugs, and / or chemotherapy (Greenberg, 2010). Despite recent advances, the majority of MDS patients experience treatment-related toxicity or relapse (Sekeres, 2010a). Overall, the effectiveness of these treatments is variable, and they typically only slightly improve life expectancy compared to supportive care. The complexity and heterogeneity of MDS, and the lack of human xenograft models, present significant challenges in identifying and evaluating novel molecular targets for this disease.

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

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

[0007] In the treatment of MDS and / or AML, there is a need to develop therapies that can inhibit adaptive resistance mechanisms to improve survival rates in AML and MDS situations. Furthermore, in AML, there is an unmet need for drugs that extend overall survival, reduce hospital stay and readmission rates, overcome acquired resistance to other treatments, and increase the success rate of hematopoietic stem cell transplantation. Additionally, there is a need for MDS treatment drugs that can slow the rate of conversion to AML and reduce transfusion dependence.

[0008] Therefore, there is a need to develop therapies and methods to effectively treat other conditions or disorders characterized by MDS and / or AML, and / or dysregulation (e.g., hyperfunction) IRAK (e.g., IRAK1 and / or 4). Furthermore, it is important to determine whether the patient is likely to respond to a particular therapy or method. Certain embodiments of this disclosure can address one or more of these issues. [Overview of the project] [Problems that the invention aims to solve]

[0009] In one embodiment, this disclosure relates to formula (I): [ka] With respect to compounds, or salts, esters, solvates, optical isomers, geometric isomers, salts of isomers, prodrugs, or derivatives thereof, in the formula, R 1 The ion is selected from H, halogen, hydroxyl, oxo, -CN, amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl is halogen, Hydro It may be substituted with one or more of the following C1-C7 alkyl groups: xy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl; R 2The is selected from H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, heteroaryl, or condensed ring heteroaryl, and the amino, O-aryl, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl is halogen, hydroxy, oxo, methyloyl ( -COH), carboxy(-CO2H), nitro(-NO2), -NH2, -NHCH3, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, condensed ring aryl, heteroaryl, condensed ring heteroaryl, or C1-C7 alkyl substituted with cycloalkyl; R 3 , R 4 , and R 5is independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and the methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl may be substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl; R 6 is [Chemical formula] and R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14Each of these is independently selected from H, halogen, hydroxyl, oxo, -CN, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 Each is independently selected from H, halogen, hydroxyl, oxo, -CN, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the aforementioned methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2 -C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1 and u+v+w+x is at least 1.

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

[0011] In one embodiment, the compound of formula (I) is formula (IIg): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; in the formula, R 20g R is selected from H and C1-C6 alkoxy; 21g These include halogens, C1-C6 alkyls, C1-C6 alkoxys, C3-C6 cycloalkyls, and -O-(C6-C 12 aryl), C3-C9 heterocyclyl, and -NR 28ga R 28gb Selected from, the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl may be substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogen;R 22g , R 23g , and R 24g Each is independently selected from H and halogen; R 25ga , R 25gb, R 26ga , R 26gb , R 27ga , and R 27gb Each of these is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, and the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more halogen atoms; R 28ga and R 28gb Each of these is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl. In one embodiment, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb One or more of are independently selected from halogens, -OH groups, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In one embodiment, R 20g H is. In one embodiment, at least one of the following (i) to (ix) applies: (i) R 20g -OCH3 and the following: [ka] (ii)R 21g t-butyl, unsubstituted C3 cycloalkyl, morpholinyl, azetidinyl, piperidinyl, isoxazolyl, Cl, -CF3, -OCH3, -O-phenyl, as follows: [ka] (wherein G is N or CH), and below: [ka] (wherein c is selected from 1 or 2); R 21g The following: [ka] And R 29gis H, isopropyl, unsubstituted C3 cycloalkyl, azetidinyl, tetrahydropyranyl-CH3, the following:

Chem.

Chem.

Chem.

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

[0013] In one embodiment, the compound of formula (I) is of formula (IIi): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, in which the following formula: [ka] The following: [ka] Selected from; R 20i R is selected from H and C1-C6 alkoxy; 21i The C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclil are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclil, respectively, may be substituted with one or more substituents selected from -OH and halogens, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogens, and the C3-C9 heterocyclil may be substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclil, -OH, -C=O, and halogens;R 22i , R 23i , and R 24i Each is independently selected from H and halogen; R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ibEach is independently selected from H, halogen, -OH, or C1-C6 alkyl. In one embodiment, R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib One or more of are independently selected from halogens, -OH, and C1-C6 alkyl groups. In one embodiment, R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib Each of these is H. In one embodiment, at least one of the following (i) to (xi) applies: (i) R 20i (ii)R 21i The following: [ka] , unsubstituted C3 cycloalkyl, see below: [ka] (wherein J is N or CH), and below: [ka] (iii)R 21i The following: [ka] And in the formula, R 220i H, -CH3, below: [ka] (iv)R 22i , R 23i, and R 24i These are H, respectively; (v)R 22i and R 24i These are F and R respectively. 23i H is; (vi)R 22i and R 24i These are H and R respectively. 23i F is; (vii) see below: [ka] The following: [ka] And R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib Each of them is H, and R 25ib is F; (viii) below: [ka] The following: [ka] And R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib Each of them is H; (ix) below: [ka] The following: [ka] And R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 28ib、 R 29ia , and R29ib Each of them is H; (x) below: [ka] The following: [ka] And R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 29ia , and R 29ib Each of them is H, and R 28ib F is; (xi) below: [ka] The following: [ka] And R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib Each of them is H, and R 27ib is F. In one embodiment, the compound is selected from the following. [ka] JPEG0007877318000041.jpg160124JPEG0007877318000042.jpg130125

[0014] In one embodiment, the compound of formula (I) is of formula (IIj): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, in which the following formula: [ka] The following: [ka] Selected from; R 20j R is selected from H and C1-C6 alkoxy; 21j The C1-C6 alkyl and C1-C6 alkoxy groups are selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl groups, where the C1-C6 alkyl and C1-C6 alkoxy groups may each be substituted with one or more substituents selected from halogens and -OH groups, and the C3-C6 cycloalkyl group may be substituted with one or more substituents selected from C1-C6 alkyl and halogen groups; R 22j , R 23j , and R 24j Each is independently selected from H and halogen. In one embodiment, at least one of the following (i) to (iv) applies: (i) R 20j (ii)R 21j (iii)R is an unsubstituted C3 cycloalkyl group; 22j , R 23j , and R 24j (iv) Below: [ka] The following: [ka] In one embodiment, the compound is selected from the following. [ka]

[0015] In one embodiment, the compound of formula (I) is of formula (IIIq): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, where R 30qR is selected from H and C1-C6 alkoxy; 31q The C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclil are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C9 heterocyclil, respectively, the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclil may be C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclil, and C6-C 12 It may be substituted with one or more substituents selected from aryl, -OH, -C=O, and halogens; R 32q , R 33q , and R 34q Each is independently selected from H and halogen. In one embodiment, at least one of the following (i) to (iv) applies: (i) R 30q (ii)R 31q The following: [ka] (wherein d is 1 or 2), and below: [ka] (wherein K is selected from N or CH); (iii)R 31q The following: [ka] And in the formula, R 35q (iv)R 32q , R 33q , and R 34q Each of these is H. In one embodiment, the compound is selected from the following. [ka] JPEG0007877318000054.jpg67124

[0016] In one embodiment, the compound of formula (I) is of formula (IIIr): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, where R 30r The C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclil are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C9 heterocyclil, respectively, the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclil may be C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclil, and C6-C 12 It may be substituted with one or more substituents selected from aryl, -OH, -C=O, and halogens; R 31r R is selected from H and C1-C6 alkoxy; 32r , R 33r , and R 34r Each is independently selected from H and halogen. In one embodiment, at least one of the following (i) to (iv) applies: (i) R 30r The following: [ka] (wherein L is N or CH) and below: [ka] (ii)R 30r The following: [ka] And in the formula, R 35r(iii)R 31r (iv)R 32r , R 33r , and R 34r Each of these is H. In one embodiment, the compound is selected from the following. [ka] JPEG0007877318000060.jpg88125

[0017] In one embodiment, the compound of formula (I) is of formula (IIIs): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, where R 30s R is selected from H and C1-C6 alkoxy; 31s The C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclil are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C9 heterocyclil, respectively, the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclil may be C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclil, and C6-C 12 It may be substituted with one or more substituents selected from aryl, -OH, -C=O, and halogens; R 32s , R 33s , and R 34s Each is independently selected from H and halogen. In one embodiment, at least one of the following (i) to (iv) applies: (i) R 30s (ii)R 31s The following: [ka] (wherein M is N or CH) and below: [ka] (iii)R 31s The following: [ka] And in the formula, R 35s (iv)R 32s , R 33s , and R 34s Each of these is H. In one embodiment, the compound is selected from the following. [ka]

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

[0019] In another embodiment, the present disclosure relates to a composition comprising a compound of any one of the formulas disclosed herein, wherein the composition further comprises a compounding component, an adjuvant, or a carrier. In one embodiment, the composition includes chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antmetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAb / immunotherapy, Plk inhibitors, MEK inhibitors, CDK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, Smoothund receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoid receptor modulators, EZH2 inhibitors, Hedgehog (Hh) inhibitors, and topoisomers. It is used in combination with one or more of the following: Ze 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, Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT1, 2, and / or 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, and multikinase inhibitors. In one embodiment, the composition is used in combination with a BCL2 inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

[0020] In another embodiment, the Disclosure relates to a method for treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of any compound of any of the formulas disclosed herein or a composition comprising any compound of any of the formulas disclosed herein. In one embodiment, the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I) and a composition comprising a formulation component, adjuvant, or carrier. In one embodiment, the disease or disorder responds to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition. In one embodiment, the administration includes 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 in an amount of about 0.005 mg / kg (subject body weight) to about 1,000 mg / kg (subject body weight). In one embodiment, the disease or disorder includes hematopoietic carcinoma. In one embodiment, the disease or disorder includes myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML). In one embodiment, the disease or disorder includes lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma. In one embodiment, the disease or disorder includes at least one cancer selected from glioblastoma polymorphoni, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by hyperactive IRAK1 and / or IRAK4, or a combination thereof.In one embodiment, the disease or disorder includes one or more inflammatory or autoimmune diseases 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, or combinations thereof. In one embodiment, the disease or disorder includes (i) MDS, MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations; or (ii) AML with splicing factor mutations, AML with enhanced expression and / or activity of IRAK4-Long compared to IRAK4-Short, and / or AML that expresses IRAK4-Long but is not promoted by FLT3 mutations. In one embodiment, MDS having a splicing factor mutation includes MDS having a splicing factor mutation in U2AF1 or SF3B1, and AML splicing factor mutation includes AML having a splicing factor mutation in U2AF1 or SF3B1. In one embodiment, the disease or disorder includes DLBCL, and the DLBCL includes the L265P MYD88 variant (ABC) subtype of DLBCL or the S219C MYD88 variant (GCB) subtype of DLBCL.In one embodiment, the method further includes chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antmetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAb / immunotherapy, Plk inhibitors, MEK inhibitors, CDK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, Smoothund receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoid receptor modulators, EZH2 inhibitors, Hedgehog (Hh) inhibitors, and topoisomerase I inhibitors. The treatment involves administering to the subject one or more additional therapeutic agents selected from 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, Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT1, 2, and / or 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, and multikinase inhibitors. In one embodiment, the method further includes administering a BCL2 inhibitor to the target. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is a BCL2 inhibitor-resistant disease or disorder. In one embodiment, the disease or disorder is a venetoclax-resistant disease or disorder. In one embodiment, the disease or disorder is a FLT3 inhibitor-resistant disease or disorder. In one embodiment, the disease or disorder is BCL2 inhibitor-resistant acute myeloid leukemia (AML).In one embodiment, the disease or disorder is venetoclax-resistant acute myeloid leukemia (AML). In one embodiment, the disease or disorder is FLT3 inhibitor-resistant acute myeloid leukemia (AML). In one embodiment, the disease or disorder is BCL2 inhibitor-resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax-resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is FLT3 inhibitor-resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is BCL2 inhibitor-resistant relapsed acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax-resistant relapsed acute myeloid leukemia (AML). In one embodiment, the disease or disorder is FLT3 inhibitor-resistant relapsed acute myeloid leukemia (AML). In one embodiment, a compound of any of the formulas disclosed herein or a composition comprising a compound of any of the formulas disclosed herein, and the one or more further therapeutic agents are administered together as a single dose or as a single composition. In one embodiment, a compound of any of the formulas disclosed herein or a composition comprising a compound of any of the formulas disclosed herein, and the one or more further therapeutic agents are administered separately as multiple doses or as multiple compositions. In one embodiment, the disease or disorder is mitigated in a subject by inhibiting at least one of IRAK1, IRAK4, and FLT3. In one embodiment, the disease or disorder is mitigated in a subject by inhibiting at least two of IRAK1, IRAK4, and FLT3. In one embodiment, the disease or disorder is mitigated in a subject by inhibiting IRAK1 and IRAK4. In one embodiment, the disease or disorder is mitigated in a subject by inhibiting IRAK1, IRAK4, and FLT3. In one embodiment, FLT3 is selected from WT FLT3, activated FLT3, and mutant FLT3. In one embodiment, the mutation FLT3 is either the D835Y mutation FLT3 or the F691L mutation FLT3. [Brief explanation of the drawing]

[0021] [Figure 1A] Figure 1A shows the concentration (nM) response of compound 106 and venetoclax to inhibition of cell viability, measured over 48 hours. The numbers in each cell represent the percentage of viable cells (Figure 1A) for each given concentration combination. Figure 1A: 10 × 10 combinations of venetoclax and compound 106 in MOLM14 (D835Y) cells. The numbers in each cell represent the response rate (%) for each given concentration combination. [Figure 1B] Figure 1B shows the concentration (nM) response of compound 106 and venetoclax to inhibition of cell viability, measured over 48 hours. The numbers in each cell represent the Delta Bliss scores (Figure 1B). Figure 1B: 10 × 10 combinations of venetoclax and compound 106 in MOLM14 (D835Y) cells. The numbers in each cell represent the Delta Bliss scores for each given concentration combination. A negative Delta Bliss score indicates that the combination of drugs is superior to either drug alone, and a larger negative Delta Bliss score indicates a greater synergistic effect.

[0022] [Figure 2A] Figure 2A shows the concentration (nM) response of compound 108 and venetoclax to inhibition of cell viability, measured over 48 hours. The numbers in each cell represent the percentage of viable cells (Figure 2A) for each given concentration combination. Figure 2A: 10 × 10 combinations of venetoclax and compound 108 in MOLM14 (D835Y) cells. The numbers in each cell represent the response rate (%) for each given concentration combination. [Figure 2B] Figure 2B shows the concentration (nM) response of compound 108 and venetoclax to inhibition of cell viability, measured over 48 hours. The numbers in each cell represent the Delta Bliss score (Figure 2B). Figure 2B: 10 × 10 combinations of venetoclax and compound 108 in MOLM14 (D835Y) cells. The numbers in each cell represent the Delta Bliss score for each given concentration combination. A negative Delta Bliss score indicates that the combination of drugs is superior to either drug alone, and a larger negative Delta Bliss score indicates a greater synergistic effect.

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

[0024] Detailed explanation of this disclosure The following related applications are incorporated herein by reference in their entirety for all purposes: U.S. Patent Application No. 62 / 414,058, Overexpression of U2AF1 as a Genetic Predictor of Activated IRAK, filed October 28, 2016; U.S. Patent Application No. 62 / 429,289, Overexpression of U2AF1 as a Genetic Predictor of Activated IRAK, filed December 2, 2016; PCT Patent Publication No. WO2018081738, Treatment of Diseases Associated with Activated IRAK, filed October 30, 2017; U.S. Patent Application No. 16 / 339,692, Treatment of Diseases Associated with Activated IRAK, filed April 4, 2019; U.S. Patent Application No. 61 / 826,211, Combination Therapy for MDS, filed May 22, 2013; PCT Patent Publication No. WO2014190163, Combination Therapy for MDS, filed May 22, 2014; U.S. Patent No. 9,168,257, Combination Therapy for MDS, published October 27, 2015; U.S. Patent No. 9,504,706, Combination Therapy for MDS, published November 29, 2016; U.S. Patent No. 9,855,273, Combination Therapy for MDS, published January 2, 2018; U.S. Patent No. 10,487,329, Methods and Compositions for the Treatment of Head and Neck Cancer, published November 26, 2019; U.S. Patent Application No. 62 / 375,965, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 17, 2016;PCT Patent Publication No. WO2018038988, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 16, 2017; U.S. Patent Application No. 16 / 326,571, COMPOUNDS, COMPOSITIONS, METHODS FOR TREATING DISEASES, AND METHODS FOR PREPARING COMPOUNDS, filed February 19, 2019; U.S. Patent Application No. 16 / 804,518, COMPOUNDS, COMPOSITIONS, METHODS FOR TREATING DISEASES, AND METHODS FOR PREPARING COMPOUNDS, filed February 28, 2020; U.S. Patent Application No. 62 / 812,948, COMPOUNDS, COMPOSITIONS, METHODS FOR TREATING DISEASES, AND METHODS FOR PREPARING COMPOUNDS, filed March 1, 2019; U.S. Patent Application No. 63 / 059,815, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 31, 2020; International Patent Application PCT / US2021 / 044089, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 31, 2021; U.S. Patent Application No. 63 / 129,895, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed December 23, 2020; and U.S. Patent Application No. 63 / 285,663, IRAK Inhibitors Combination Therapies, filed December 3, 2021.

[0025] While embodiments encompassing the general concept of the invention can take many forms, this disclosure should be considered merely illustrative, and various embodiments are described herein with the understanding that the general concept of the invention is not intended to be limited to the embodiments disclosed.

[0026] Some embodiments of the present invention include the compound of the present invention (e.g., the compound of formula (I)). Other embodiments include a composition (e.g., a pharmaceutical composition) containing the compound of the present invention. Yet another embodiment of the present invention includes a composition for treating, for example, a specific disease using the compound of the present invention. Some embodiments include a method for using the compound of the present invention (e.g., in a composition or a pharmaceutical composition) for administration and treatment. Further embodiments include a method for producing the compound of the present invention. Yet another embodiment includes a method for determining whether a particular patient may respond to treatment using the compound and composition of the present invention.

[0027] Unless otherwise specified, terms shall be understood in accordance with their conventional usage by those skilled in the art in the relevant technical field.

[0028] The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are prepared in accordance with the standard rules of valency known in the field of chemistry.

[0029] When substituents are specified in a conventional chemical formula, where they are written from left to right, they similarly encompass chemically identical substituents obtained by writing the structure from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0030] As used herein, with respect to compounds of formulas (I), (II), (III), etc., the term "bonded" means a stable covalent bond, and specific preferred bonding sites are obvious to those skilled in the art.

[0031] As used herein (unless otherwise specified), the term “alkyl” means a monovalent linear or branched hydrocarbon chain having a specified number of carbon atoms (i.e., C1-C10 means 1 to 10 carbon atoms), which may be fully saturated, monovalent or polyunsaturated, and which may contain divalent and polyvalent radicals. For example, the terms “C1-C7 alkyl” or “C1-C4 alkyl” mean a linear or branched saturated hydrocarbon group having 1 to 7 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, or 7) or 1 to 4 carbon atoms (e.g., 1, 2, 3, or 4). Examples of C1-C7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, and n-heptyl. Examples of C1-C4 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl.

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

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

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

[0035] The term “alkylene” means, unless otherwise specified, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, exemplified by -CH2CH2CH2CH2-, either by itself or as part of another substituent. Typically, the alkyl (or alkylene) group has 1 to 24 carbon atoms, and groups having 10 or fewer carbon atoms are preferred in the compounds disclosed herein. “Lower alkyl” or “lower alkylene” generally refers to shorter-chain alkyl or alkylene groups having 8 or fewer carbon atoms.

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

[0037] The term "heteroalkyl," by itself or in combination with other terms, means, unless otherwise specified, a stable, linear 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 the nitrogen and sulfur atoms may be oxidized, and the nitrogen heteroatom may be quaternized. The heteroatoms O, N, P, S, and Si may be located at any position within the heteroalkyl group or at positions where the alkyl group is bonded to the rest of the molecule. Examples, though not limited to them, include -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. For example, up to two heteroatoms may be consecutive, such as in -CH2-NH-OCH3.

[0038] Similarly, the term "heteroalkylene" means, without limitation, a divalent radical derived from a heteroalkyl group, exemplified by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-, either by itself or as part of another substituent, unless otherwise specified. In the case of a heteroalkylene group, the heteroatom may occupy one or both ends of the chain (e.g., alkylene oxy, alkylenedioxy, alkylene amino, alkylenediamino, etc.). Furthermore, in the case of alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As stated herein, when used, a heteroalkyl group includes a group bonded to the rest of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SO2R'. When “heteroalkyl” is mentioned, 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 mentioned for clarity. Therefore, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups such as -NR'R''.

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

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

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

[0042] "Arylene" and "heteroarylene" refer to divalent radicals derived from aryl and heteroaryl compounds, respectively, either alone or as part of another substituent. Thus, the term "aryl" can represent unsubstituted, monosubstituted, disubstituted, or trisubstituted monocyclic, polycyclic, biaryl, and heterocyclic aromatic groups covalently bonded at any position on the ring where a stable covalent bond can be formed, and specific preferred bonding sites are apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl). Aryl substituents can independently be halo, nitro, cyano, trihalomethyl, or C. 1-16 Alkyl, aryl C 1-16 Alkyl, C0- 16 Alkyloxy C0- 16 Alkyl, aryl C0- 16 Alkyloxy C0- 16 Alkyl, C0- 16 Alkylthio C0- 16 Alkyl, aryl C0- 16 Alkylthio C0- 16 Alkyl, C0- 16 Alkylamino C0- 16 Alkyl, aryl C0- 16 Alkylamino C0- 16 Alkyl, di(aryl C1- 16 Alkyl)amino C0- 16 Alkyl, C1- 16 Alkylcarbonyl C0- 16 Alkyl, aryl C 1-16 Alkylcarbonyl C0- 16 Alkyl, C1- 16 Alkylcarboxyl C0- 16 Alkyl, aryl C1- 16 Alkylcarboxyl C0- 16 Alkyl, C 1-16 Alkylcarbonylamino C0- 16 Alkyl, aryl C1- 16 Alkylcarbonylamino C0- 16 Alkyl,-C0- 16 Alkyl COOR4, -C0- 16alkylCONR5R6(wherein R4, R5, and R6 are independently hydrogen, C1-C) 11 Alkyl, aryl C0-C 11 Selected from alkyl groups, or R5 and R6 are bonded together to form one C 1-16 Alkyl, aryl C0-C 16 Alkyl, or C0-Cl 16 Selected from those containing or not containing alkylaryl substituents (combined with nitrogen to form a ring system containing 3 to 8 carbon atoms). The aryls include, but are not limited to, pyrazolyl and triazolyl substituents.

[0043] Simply put, the term "aryl," when used with other terms (e.g., aryloxy, arylthiooxy, arylalkyl), includes both the aryl rings and heteroaryl rings defined above. Therefore, terms such as "arylalkyl," "aralkyl," etc., are intended to include radicals (e.g., benzyl, phenethyl, pyridylmethyl, etc.) in which an aryl group is bonded to an alkyl group, and the alkyl group includes alkyl groups in which a carbon atom (e.g., a methylene group) is substituted with an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.) or a sulfur atom. Thus, terms such as "arylalkyl" (e.g., (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represent the aryl group defined above, bonded to the alkyl group defined above, having the number of carbon atoms indicated.

[0044] The terms “cycloalkyl” and “heterocycloalkyl,” also known as “heterocyclyl,” mean, either by themselves or in combination with other terms, the cyclic versions of “alkyl” and “heteroalkyl,” respectively, unless otherwise specified. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl. As used herein (unless otherwise specified), the terms “heterocycloalkyl” or “heterocyclyl” mean monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12-membered hydrocarbon rings in which one, two, three, four, five, or six carbon atoms are independently substituted by heteroatoms selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic ring system is not aromatic. Furthermore, in the case of heterocycloalkyls, the heteroatoms may occupy positions where the heterocycle is bonded to the rest of the molecule. Examples of heterocycloalkyls, though not limited to them, include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, pyrrolidinyl (e.g., pyrrolidine-1-yl, pyrrolidine-2-yl, Examples include pyrrolidine-3-yl or pyrrolidine-4-yl), piperazinyl (e.g., piperazine-1-yl, piperazine-2-yl, piperazine-3-yl, or piperazine-4-yl), piperidinyl (e.g., piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, or piperidine-4-yl), and morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl). In the case of bicyclic heterocyclines, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), the other ring is not aromatic. In the case of bicyclic heterocyclines, one or both rings may have one or more heteroatoms.In the case of bicyclic heterocyclines, one or both rings may be substituted. "Cycloalkylene" and "heterocycloalkylene" refer to divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively, either alone or as part of another substituent.

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

[0046] As used herein (unless otherwise specified), the terms "hydroxy" or "hydroxyl" mean a monovalent -OH group.

[0047] The term "acyl" means -C(O)R unless otherwise specified, 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.

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

[0049] As used herein, the term “alkylsulfonyl” means the part having the formula -S(O2)-R', where R' is the alkyl group as defined above. R' can have a specific number of carbon atoms (e.g., “C1-C4 alkylsulfonyl”).

[0050] The term "carbonyloxy" refers to a carbonyl group bonded via an oxygen crosslink.

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

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

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

[0054] As used herein (unless otherwise specified), the term “substituted” (e.g., in a substituted alkyl) means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) may be substituted by one or more nonhydrogen substituents selected from a particular set of options. Such substitution may occur at one or more positions. The term “may be substituted” means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) may be substituted, but are not required to be substituted.

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

[0056] As used herein, "size-limited substituent" or "size-limited substituent group" means, for example, a group selected from all of the substituents described above for "substituent," and each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20Each alkyl group is an alkyl group, and each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2-20 membered ring heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C4-C8 cycloalkyl group, and each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 4-8 membered ring heterocycloalkyl group.

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

[0058] When used in the context of numbers, the term "approximately" indicates a range of + / - 10% of the number unless otherwise specified.

[0059] Some compounds of the present invention may have one or more chiral centers, and any one of the one or more chiral centers may exist in an optically active racemic form and be isolated. Some compounds may exhibit polymorphism. Compounds of the present invention (e.g., formula I) encompass any optically active form, racemate, stereoisomer, polymorph, or mixture thereof. If a chiral center does not provide an indicator of its stereochemistry in the chemical structure (i.e., R or S), it is considered to represent R, S, or a racemate.

[0060] As used herein, the term “sample” encompasses samples obtained from a subject or patient. Such samples may 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., leukocytes), circulating cells (e.g., stem cells or endothelial cells in the blood), tissue, core or fine-needle biopsy samples, cell-containing fluids, free suspended nucleic acids, urine, feces, peritoneal fluid, and pleural fluid, tears, or cells derived therefrom. Samples may also include tissue sections such as frozen or fixed sections taken for histological purposes, or microanalyzed cells or their extracellular components. The sample to be analyzed may be tissue material derived from a tissue biopsy, obtained by aspiration or perforation, excision, or other surgical methods resulting in biopsy or excised cell material. Such samples may include cells obtained from a subject or patient. In some embodiments, the sample is a bodily fluid including, for example, blood fluid, serum, mucus, plasma, lymph, ascites, gynecological fluids, or urine, but is not limited to these fluids. In some embodiments, the sample may be a non-invasive sample such as, for example, a saline swish, a buccal scrape, or a buccal swab.

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

[0062] As used herein, the term “assessing” includes any form of measurement and includes determining whether or not an element is present. The terms “determining,” “measuring,” “evaluating,” “assessing,” “analyzing,” and “assaying” are interchangeable and may include quantitative and / or qualitative determinations.

[0063] As used herein, the term “monitoring” in relation to cancer types means a method or process for determining the severity or extent of a cancer type, or for stratifying cancer types based on the risk and / or probability of death. In some embodiments, monitoring relates to a method or process for determining the therapeutic effect of a treatment being administered to a patient.

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

[0065] As used herein, the term “high-risk clinical trial” means a clinical trial in which the investigational drug carries “more than minimal risk” (as defined by the terminology used by the Institutional Review Board, i.e., the IRB). In some embodiments, a high-risk clinical trial is a clinical trial.

[0066] As used herein, the term “low-risk clinical trial” means a clinical trial in which the risk of the investigational drug is “minimal” (as defined in the terminology used by the IRB). In some embodiments, a low-risk clinical trial is a clinical trial that is not a clinical trial. In some embodiments, a low-risk clinical trial involves the use of a monitor or clinical practice process. In some embodiments, a low-risk clinical trial is an observational clinical trial.

[0067] As used herein, unless otherwise specified and the context of a particular use makes clear, the terms “modulated” or “modulation,” “regulated” or “regulation,” and “differentially regulated” may mean both upregulation (i.e., activation or stimulation by, for example, stimulation or enhancement) and downregulation (i.e., inhibition or suppression by, for example, antagonism, reduction, or inhibition).

[0068] As used herein, the term “subject” means any suitable (e.g., therapeutic) 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 may be a mammalian pediatric patient. In the method, a pediatric patient is a mammalian (e.g., preferably human) patient under 18 years of age, while an adult patient is 18 years of age or older.

[0069] When used herein, the term “to treat” (and its variations, e.g., “to treat,” “to treat,” “treating,” etc.) is considered in its broadest context unless otherwise specified, and means to obtain the desired pharmacological and / or physiological effect. In particular, for example, the term “to treat” may not necessarily imply or require that the animal be treated until it is fully recovered. Thus, “to treat” includes improvement of symptoms, mitigation of symptoms or effects associated with a condition, reduction of the severity of a condition, or prevention of symptoms, prophylactic improvement of symptoms, or reduction of the risk of developing a particular condition. In some embodiments, “treatment” may not require or include prevention. When used herein, the statement that an animal is “treating” includes, but is not limited to, prophylactic and therapeutic measures. The effect may be prophylactic in that it completely or partially prevents the disease or its symptoms, and / or therapeutic in that it partially or completely cures the disease and / or any side effects that may result from such disease. As used herein, “treatment” encompasses any treatment of a disease in a subject, preferably a mammal (e.g., human), and may include one or more of the following: (a) preventing the onset of the disease in a subject that may be susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, i.e., preventing its onset; and (c) alleviating the disease, i.e., causing regression or elimination of the disease, and / or reducing one or more symptoms of the disease. In certain embodiments of methods such as a condition or disorder characterized by dysregulated IRAK expression or dysregulated (e.g., hyperactive) IRAK-mediated signaling pathways, treatment may be or may include reducing such expression or signaling. “Treatment” may also encompass the delivery of a drug or administration of a therapeutic agent to provide a pharmacological effect even in the absence of a disease or condition. Any of the compositions described herein (e.g., pharmaceutical compositions) may be used to treat a suitable subject.

[0070] "Therapeutic effective dose" means an amount effective in achieving the desired and / or beneficial effect. The effective dose may be administered in one or more doses. In the above method, the therapeutic effective dose is an appropriate amount for treating the indication. Treating the indication means achieving any desired effect, such as mitigating, improving, stabilizing, reversing, slowing, or delaying disease progression, improving quality of life, or extending lifespan. Such achievement may be measured by any preferred method, such as measuring tumor size or blood cell count, or any other preferred measurement.

[0071] As used herein, the terms “marker” or “biomarker” mean, for example, biomolecules such as nucleic acids, peptides, proteins, and hormones whose presence or concentration can be detected and correlated with known conditions, such as disease. They can also be used to mean differentially expressed genes whose expression patterns can be used as part of a predictive, prognostic, or diagnostic process in healthy or diseased states, or in methods for identifying useful therapeutic or preventive measures.

[0072] As used herein, mRNA "isoform" refers to an alternative transcript of a particular mRNA or gene. This term includes premRNA, immature mRNA, mature mRNA, cleaved or truncated, shortened or abnormal mRNA, modified mRNA (including, for example, any residue modification, capping variants, polyadenylation variants, etc.).

[0073] "Antibody" or "antibody peptide" means an intact antibody or its binding fragment that competes with the intact antibody for specific binding, and this definition also includes monoclonal and polyclonal antibodies. Binding fragments are produced by recombinant DNA technology or by enzymatic or chemical cleavage of an intact 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. For example, an antibody substantially inhibits the adhesion of a receptor to a counterreceptor if an excess of the antibody reduces the amount of receptor that binds to the counterreceptor by at least about 20%, 40%, 60%, or 80%, or more typically, more than about 85% (as measured by an in vitro competitive binding assay).

[0074] Embodiments of the present invention described herein include compounds of the present invention (e.g., compounds of formula (I), such as compounds of formula (II) and formula (III)). Other embodiments include compositions (e.g., pharmaceutical compositions) containing compounds of the present invention. Yet another embodiment of the present invention includes compositions (e.g., pharmaceutical compositions) for treating, for example, a particular disease using compounds of the present invention. Some embodiments include methods for using compounds of the present invention (e.g., in a composition or pharmaceutical composition) for administration and treatment (e.g., a disease such as cancer or a blood disorder). Some embodiments include methods for determining whether a patient is suitable for a particular treatment or can respond favorably to a particular treatment. Further embodiments include methods for producing compounds of the present invention. Further embodiments of the present invention are also described herein.

[0075] Compositions comprising compounds and pharmaceutical compositions Some embodiments of the present invention are given by formula (I-5008): [ka] The compound comprises a compound having the structure described herein, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. In some embodiments, the compound is a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative of formula (I-5008). In some embodiments, the compound is not an ester, not a solvate, and not a prodrug.

[0076] In an exemplary embodiment, R 1 , R 2 , R 3 , R 4 , and R 5 The following are independently selected from H, halogen, hydroxyl, oxo, -CN, amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the aforementioned amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl The teloaryl may be substituted with one or more of the following: halogen, hydroxy, oxo, methanolyyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl.

[0077] In some embodiments, R 1This can be H, halogen, hydroxyl, oxo, -CN, amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl (the amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be halogen, hydroxyl It may be substituted with one or more of the following: roxy, oxo, methanoyl(-COH), carboxy(-CO2H), nitro(-NO2), -NH2, -NHCH3, -N(CH3)2, cyano(-CN), ethinyl(-CCH), propynyl, sulfo(-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl);R 2This can be H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, heteroaryl, or condensed ring heteroaryl (the amino, O-aryl, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be halogen, hydroxy, oxo, methyloyl (-COH), carboxy(-CO2H), nitro(-NO2), -NH2, -NHCH3, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, condensed ring aryl, heteroaryl, condensed ring heteroaryl, or C1-C7 alkyl substituted with cycloalkyl; R 3 , R 4 , and R 5This can be H, halogen, hydroxyl, oxo, -CN, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl (wherein the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl is halogen, hydroxyl (May be substituted with one or more C1-C7 alkyl groups substituted with oxo, methanoyl(-COH), carboxy(-CO2H), nitro(-NO2), -NH2, -NHCH3, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl).

[0078] R 6 It can be the following: [ka]

[0079] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14This can be H, halogen, hydroxyl, oxo, -CN, methylanoyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl (the methylanoyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens);R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 This can be H, halogen, hydroxy, oxo, -CN, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl (the aforementioned methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2- C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x can be 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1 and u+v+w+x is at least 1.

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

[0081] In some embodiments, R 2 The first element is H, halogen, hydroxyl, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, condensed ring aryl, heteroaryl, or condensed ring heteroaryl, and the first element is O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, condensed ring aryl, heteroaryl, or condensed ring heteroaryl, and the first element is O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkoxy, heterocyclyl, aryl, heteroaryl, condensed ring aryl, condensed ring heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or a C1-C7 alkyl substituted with a cycloalkyl. In some embodiments, R 2is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, condensed ring aryl, heteroaryl, or condensed ring heteroaryl, and the O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more of halogen, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or a C1-C7 alkyl substituted with a cycloalkyl. In some embodiments, R 2 is H, Cl, hydroxy, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -OCHF2, -OPh, -CF3, -CHF2, unsubstituted C1-C7 alkyl, substituted amino, substituted C1-C7 alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted condensed ring heteroaryl, or unsubstituted condensed ring heteroaryl. In some embodiments, R 2 It is not H.

[0082] In some embodiments, R 3is H, halogen, hydroxyl, -CN, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy may be substituted with one or more of halogen, hydroxyl, methanolyyl(-COH), carboxy(-CO2H), nitro(-NO2), -NH2, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl. In some embodiments, R 3 is H, halogen, hydroxyl, -CN, methyl, -CF3, or methoxy.

[0083] In some embodiments, R 4 is H, halogen, hydroxyl, -CN, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy may be substituted with one or more of halogen, hydroxyl, methanolyyl(-COH), carboxy(-CO2H), nitro(-NO2), -NH2, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl. In some embodiments, R 4 is H, halogen, hydroxyl, -CN, methyl, -CF3, or methoxy.

[0084] In some embodiments, R5 is H, halogen, hydroxyl, -CN, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy may be substituted with one or more of halogen, hydroxyl, methanolyyl(-COH), carboxy(-CO2H), nitro(-NO2), -NH2, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl. In some embodiments, R 5 is H, halogen, hydroxyl, -CN, methyl, -CF3, or methoxy.

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

[0086] In some embodiments, R 6 A chiral center is present at the bonded carbon. In some embodiments, the chiral center is an R-chiral center. In some embodiments, the chiral center is an S-chiral center. In certain embodiments, the chiral center can be represented by the following bond: [ka] As those skilled in the art will understand, if the chiral center can be located at other positions in the compound relating to formula (I), then the straight bond described may also be as follows: [ka]

[0087] In some embodiments, R 6 The following applies: [ka]

[0088] In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 Each is independently selected from H, halogen, hydroxyl, oxo, -CN, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and is one of the aforementioned methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl is substituted with one or more halogens, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl C1-C7 alkyl, however R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14At least one of them is not 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 Each is independently selected from H, halogen, hydroxyl, oxo, -CN, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the aforementioned methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl The alkyl group may be substituted with one or more halogens, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl groups. In some embodiments, m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1 and u+v+w+x is at least 1.

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

[0090] In one embodiment, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 At least one of 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 these is H if it exists.

[0091] In some embodiments, R 6 The following applies: [ka]

[0092] In some embodiments, R 6 The following applies: [ka]

[0093] Some embodiments of the present invention include compounds having a structure according to the following formula (I). [ka] In the formula, from Y to R 6 A wave-like connection to, i.e., the following: [ka] In some cases, R 6 This indicates the presence of a chiral center at the bonded carbon. In some embodiments, R 6 When a chiral center is present on the bonded carbon, the wavy bond can represent an R-chiral center, an S-chiral center, or a racemic mixture. In specific embodiments, see below: [ka] The following: [ka] It can be as follows. As those skilled in the art will understand, if the chiral center can be located at other positions in the compound relating to formula (I), the direct bond shown can also be as follows: [ka]

[0094] In some embodiments, R 6 This is (Ia), which gives the structure of equation (II) below. [ka]

[0095] In some embodiments relating to formula (II), m is 0 or 1, n is 0 or 1, o is 0 or 1, and p is 0 or 1.

[0096] In some embodiments, R 7 , R 8 , R 9 , and R 10 is H, and R 11 , R 12 , R 13 , and R 14 At least one of them is not H, and / or R 11 , R 12 , R 13 , and R 14 is H, and R 7 , R 8 , R 9 , and R 10 At least one of them is not H. In a specific embodiment, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 R is independently selected from H, halogen, hydroxyl, oxo, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl, wherein the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spirocondensed cycloalkyl may be substituted with one or more halogens. In some embodiments, R 7 , R 8 , R 9 , and R 10 is H, and R 11 , R 12 , R 13 , and R 14At least one of is a halogen, hydroxyl, oxo, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl, wherein the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spirocondensed cycloalkyl may be substituted with one or more halogens. In some embodiments, R 11 , R 12 , R 13 , and R 14 is H, and R 7 , R 8 , R 9 , and R 10 At least one of is a halogen, hydroxyl, oxo, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl, wherein the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spirocondensed cycloalkyl may be substituted with one or more halogens. In some embodiments, R 7 , R 8 , R 9 , and R 10 At least one of them is a halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl. In some embodiments, R 7 , R 8 , R 9 , and R 10 At least one of them is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spirocondensed cyclopropyl, spirocondensed cyclobutyl, or spirocondensed cyclopentyl. In some embodiments, R 7 and R 8 Both or R 9 and R 10 Both are F, or R 7 and R 8 Both or R 9 and R 10Both are methyl. In some embodiments, R 11 , R 12 , R 13 , and R 14 At least one of them is a halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl. In some embodiments, R 11 , R 12 , R 13 , and R 14 At least one of them is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spirocondensed cyclopropyl, spirocondensed cyclobutyl, or spirocondensed cyclopentyl. In some embodiments, R 11 and R 12 Both or R 13 and R 14 Both are F, or R 11 and R 12 Both or R 13 and R 14 Both are methyl.

[0097] In addition to the embodiment in which the compound has the structure of formula (II), the compound may have a structure relating to any of (IIa) to (IIe), wherein the formulas V, W, X, Y, and Z are independently R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , or R 14 It can represent that at least one of V, W, X, Y, and Z is not H. [ka] TIFF0007877318000080.tif130124

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

[0099] In one embodiment, R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb One or more of are independently selected from halogens, -OH groups, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In another embodiment, R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb Each of these is H.

[0100] In one embodiment, R 20f In another embodiment, R 20fis not H. In one embodiment, R 20f is a halogen. In one embodiment, R 20f In another embodiment, R 20f is an unsubstituted C1-C6 alkoxy. In one embodiment, R 20f The following applies: [ka] In another embodiment, R 20f is a C1-C6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20f The following applies: [ka] In another embodiment, R 21g is a C1-C6 alkyl group substituted with one or more -OH groups. In one embodiment, R 20f The following applies: [ka] In another embodiment, R 20f is a C3-C6 cycloalkyl group. In one embodiment, R 20f is an unsubstituted C3 cycloalkyl. In one embodiment, R 20f The following applies: [ka]

[0101] In one embodiment, R 21f , R 22f , and R 23f Each of these is H. In another embodiment, R 21f and R 23f Each of them is independently a halogen, and R 22f H is H. In one embodiment, R 21f and R 23f These are F and R respectively. 22f H is H. In one embodiment, R 21f and R 23f These are H and R respectively.22f is a halogen. In one embodiment, R 21f and R 23f These are H and R respectively. 22f It is F.

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

[0103] In one embodiment, the compound of formula (IIf) has one or more stereocenters. In one embodiment, the compound of formula (IIf) has the following part: [ka] However, the rest of formula (IIf) contains a stereocenter at the site of bonding. In one embodiment, the compound of formula (IIf) is R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and / or R 26fb It contains one or more stereocenters. In one embodiment, the compound of formula (IIf) is R 20f It includes the center of the solid.

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

[0105] In one embodiment, the compound of formula (II) is formula (IIg): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, During the ceremony: R 20g It is selected from H and C1-C6 alkoxy; R 21g These include halogens, C1-C6 alkyls, C1-C6 alkoxys, C3-C6 cycloalkyls, and -O-(C6-C 12 aryl), C3-C9 heterocyclyl, and -NR 28ga R 28gbSelected from the above, the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogens, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogens, and the C3-C9 heterocyclyl may be substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogens; R 22g , R 23g , and R 24g Each is independently selected from H and halogen; R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of these is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, and the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more halogen atoms; R 28ga and R 28gb Each of these is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0106] In one embodiment, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb One or more of are independently selected from halogens, -OH groups, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups. In another embodiment, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of these is H.

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

[0108] In one embodiment, R 21g is a halogen. In one embodiment, R 21g is Cl. In one embodiment, R 21g is an unsubstituted C1-C6 alkyl group. In one embodiment, R 21g is t-butyl. In another embodiment, R 21g is a C1-C6 alkyl group substituted with one or more F and / or -OH groups. In one embodiment, R 21g The following: [ka] Selected from. In another embodiment, R 21g is an unsubstituted C1-C6 alkoxy. In one embodiment, R 21g is -OCH3. In another embodiment, R 21g is a C1-C6 alkoxy substituted with one or more halogen atoms. In another embodiment, R 21g is -O-(C6-C 12 It is R. In one embodiment, 21g is -O-phenyl. In another embodiment, R 21g is an unsubstituted C3-C6 cycloalkyl. In one embodiment, R 21g is an unsubstituted C3 cycloalkyl. In one embodiment, R 21g is a C3 cycloalkyl substituted with one or more fluorine atoms. In one embodiment, R 21g The following: [ka] In another embodiment, R 21g is an unsubstituted C3-C9 heterocycline. In one embodiment, R21g These include morpholinyl, acetyldinyl, piperidinyl, isoxazolyl, pyrazolyl, and the following: [ka] (wherein G is N or CH), and below: [ka] (wherein c is 1 or 2) is selected from. In another embodiment, R 21g is a C3-C9 heterocyclyl substituted with one or more substituents selected from C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocyclyl, -OH, and halogen. In one embodiment, R 21g The following: [ka] And in the formula, R 29g is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, and the C1-C6 alkyl and C3-C6 cycloalkyl may each be substituted with one or more halogens and / or -OH. In one embodiment, R 21g The following: [ka] And in the formula, R 29g H is H. In one embodiment, R 21g The following: [ka] And in the formula, R 29g is an unsubstituted C1-C6 alkyl group. In one embodiment, R 21g The following: [ka] And in the formula, R 29g is selected from -CH3 and isopropyl. In one embodiment, R 21g The following: [ka] And in the formula, R 29g is a C1-C6 alkyl group substituted with one or more -OH groups and / or F groups. In one embodiment, R 21g The following: [ka] And in the formula, R 29g The following: [ka] Selected from. In another embodiment, R 21g The following: [ka] And in the formula, R 29g R is selected from unsubstituted C3 cycloalkyl, azetidinyl, and tetrahydropyranyl. In another embodiment, R 21g The following: [ka] In the formula, a is 1, 2, or 3, G is N or CH, and each X is independently a halogen. In one embodiment, R 21g The following: [ka] Selected from. In another embodiment, R 21g The following: [ka] In the formula, b is 0, 1, 2, 3, 4, 5, or 6, c is 1 or 2, and each R 220g These are independently C1-C6 alkyl groups. In one embodiment, R 21g The following: [ka] In another embodiment, R 21g is an isoxazolyl substituted with a C1-C6 alkyl group. In one embodiment, R 21g is a monosubstituted isoxazolyl with -CH3. In another embodiment, R 21g -NR 28ga R 28gb And in the formula, R 28ga H is R 28gb -Selected from CH3, cyclobutyl, and cyclohexyl. In another embodiment, R 21g -NR 28ga R 28gb And in the formula, R 28ga and R 28gb Each of these is independently a C1-C6 alkyl group. In one embodiment, R 21g -NR 28ga R 28gb And R 28ga and R 28gb These are -CH3, respectively.

[0109] In one embodiment, R 22g , R 23g , and R 24g These are H, respectively. In one embodiment, R 22g and R 24g Each of them is independently a halogen, and R 23g H is H. In one embodiment, R 22g and R 24g These are F and R respectively. 23g H is H. In one embodiment, R 22g and R 24g These are H and R respectively. 23g is a halogen. In one embodiment, R 22g and R 24g These are H and R respectively. 23g It is F.

[0110] In one embodiment, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gbEach of these is H. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25ga and / or R 25gb is a halogen. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25ga is F. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25ga and R 25gb Each of these is F. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25ga and / or R 25gb is a C1-C6 alkyl group. In one embodiment, R 26ga , R 26gb , R 27ga , and R 27gb These are H and R respectively. 25ga and R 25gb These are -CH3, respectively. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25ga In another embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25ga R is selected from substituted C1-C6 alkyl and -OH. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25gais -OH. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25ga -CF3 and the following: [ka] Selected from. In another embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25ga is an unsubstituted C1-C6 alkoxy. In one embodiment, R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of them is H, and R 25ga It is -OCH3.

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

[0112] In one embodiment, R 25ga , R 25gb , R 26ga , and R 26gb Each of them is H, and R 27ga and R 27gb Each of them is an unsubstituted C1-C6 alkyl. In one embodiment, R 25ga , R 25gb , R 26ga , and R 26gb Each of them is H, and R27ga and R 27gb Each of these is -CH3.

[0113] In one embodiment, the compound of formula (IIg) contains one or more stereocenters. In one embodiment, the compound of formula (IIg) is R 21g It contains a stereocenter. In one embodiment, the compound of formula (IIg) has the following part: [ka] However, the rest of formula (IIg) contains a stereocenter at the site of attachment. In one embodiment, the compound of formula (IIg) is R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and / or R 27gb It contains one or more solid centers.

[0114] In one embodiment, the compound of formula (IIg) is selected from the following. [ka] TIFF0007877318000109.tif142125TIFF0007877318000110.tif155125TIFF0007877318 000111.tif152124TIFF0007877318000112.tif148124JPEG0007877318000113.jpg63125

[0115] In one embodiment, the compound of formula (II) is of formula (IIh): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, During the ceremony, R 20h It is selected from H and C1-C6 alkoxy; R 21hThe C1-C6 alkyl group is selected from C1-C6 alkyl groups, C3-C6 cycloalkyl groups, and C3-C9 heterocyclil groups, wherein the C1-C6 alkyl group may be substituted with one or more substituents selected from -OH groups and halogens, and the C3-C6 cycloalkyl group and C3-C9 heterocyclil group may each be substituted with one or more substituents selected from C1-C6 alkyl groups, -OH groups, and halogens; R 22ha , R 22hb , R 23ha , and R 23hb Each of these is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl may be substituted with one or more halogen atoms; R 24h , R 25h , and R 26h Each of these is independently selected from H and halogen.

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

[0117] In one embodiment, R 21h is a C3-C9 heterocycline substituted with one or more substituents selected from C1-C6 alkyl, -OH, and halogen. In one embodiment, R 21h is a pyrazolyl substituted with C1-C6 alkyl and F. In one embodiment, R 21h The following: [ka] It is pyrazolyl substituted with R. In one embodiment, R 21h The following applies: [ka]

[0118] In one embodiment, R 22ha , R 22hb , R 23ha , and R 23hb One or more of are independently substituted C1-C6 alkyl groups. In another embodiment, R22ha , R 22hb , R 23ha , and R 23hb Each of these is H. In one embodiment, R 22ha , R 22hb Each of them is H, and R 23ha and / or R 23hb is a C1-C6 alkyl group. In one embodiment, R 22ha , R 22hb , and R 23ha Each of them is H, and R 23hb In another embodiment, R 22ha and R 22hb Each of them is H, and R 23ha and R 23hb Each of these is -CH3.

[0119] In one embodiment, R 24h , R 25h , and R 26h These are H, respectively. In one embodiment, R 24h and R 26h Each of them is independently a halogen, and R 25h H is H. In one embodiment, R 24h and R 26h These are F and R respectively. 25h H is H. In one embodiment, R 24h and R 26h These are H and R respectively. 25h is a halogen. In one embodiment, R 24h and R 26h These are H and R respectively. 25h It is F.

[0120] In one embodiment, the compound of formula (IIh) contains one or more stereocenters. In one embodiment, the compound of formula (IIh) is R 21h It contains a stereocenter. In one embodiment, the compound of formula (IIh) has the following part: [ka] However, the part of equation (IIh) that joins to the rest of the equation contains a stereocenter. In one embodiment, R22ha , R 22hb , R 23ha , and / or R 23hb One or more of them contain a stereocenter.

[0121] In one embodiment, the compound of formula (IIh) is as follows.

Chemical formula

[0122] In one embodiment, the compound of formula (II) is of formula (IIi):

Chemical formula

Chemical formula

Chemical formula

[0123] In one embodiment, R 25ia 、R 25ib 、R 26ia 、R 26ib 、R 27ia 、R 27ib 、R 28ia 、R 28ib 、R 29ia 、及びR 29ib one or more of are independently selected from halogen, -OH, and C1-C6 alkyl. In another embodiment, R 25ia 、R 25ib 、R 26ia 、R 26ib 、R 27ia 、R 27ib 、R 28ia 、R 28ib 、R 29ia 、及びR 29ib each is H.

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

[0125] In one embodiment, R 21i ​​​​​​​​​​​​21i is an unsubstituted C3 cycloalkyl. In one embodiment, R 21i is a C3 cycloalkyl substituted with C1-C6 alkyl. In one embodiment, R 21i The following: [ka] In one embodiment, R 21i is a C3 cycloalkyl substituted with one or more C1-C6 alkyls and one or more fluorine atoms. In one embodiment, R 21i The following: [ka] In another embodiment, R 21i is an unsubstituted C3-C9 heterocycline. In one embodiment, R 21i is pyrazolyl. In one embodiment, R 21i The following: [ka] In the formula, J is N or CH. In another embodiment, R 21i is a C3-C9 heterocyclyl substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, -C=O, and halogen. In one embodiment, R 21i This is a monosubstituted pyrrolidinyl with -C=O. In one embodiment, R 21i The following: [ka] In one embodiment, R 21i The following: [ka] And in the formula, R 220iis selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, and the C1-C6 alkyl and C3-C6 cycloalkyl may each be substituted with one or more halogens and / or -OH. In one embodiment, R 21i The following: [ka] And in the formula, R 220i H is H. In one embodiment, R 21i The following: [ka] And in the formula, R 220i is an unsubstituted C1-C6 alkyl group. In one embodiment, R 21i The following: [ka] And in the formula, R 220i is -CH3. In one embodiment, R 21i The following: [ka] And in the formula, R 220i is a C1-C6 alkyl group substituted with one or more -OH groups and / or F groups. In one embodiment, R 21i The following: [ka] And in the formula, R 220i The following: [ka] Selected from. In another embodiment, R 21i The following: [ka] And in the formula, R 220i It is an unsubstituted C3 cycloalkyl group.

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

[0127] In one embodiment, the following:

Chemical Formula

Chemical Formula

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

[0129] In one embodiment, the compound of formula (IIi) contains one or more stereocenters. In one embodiment, the compound of formula (IIi) is R 20i It contains a stereocenter. In one embodiment, the compound of formula (IIi) is R 21i It contains a stereocenter. In one embodiment, the compound of formula (IIi) has the following part: [ka] However, the part of equation (IIi) that joins to the rest of the equation includes a stereocenter. In one embodiment, R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and / or R 29ib If the value is 1 or greater, it includes the center of the solid.

[0130] In one embodiment, the compound of formula (IIi) is selected from the following. [ka] JPEG0007877318000141.jpg160124JPEG0007877318000142.jpg130125

[0131] In one embodiment, the compound of formula (II) is formula (IIj): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, In the formula, see below: [ka] The following: [ka] Selected from; R 20j It is selected from H and C1-C6 alkoxy; R 21j The C1-C6 alkyl and C1-C6 alkoxy groups are selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl groups, respectively, and the C1-C6 alkyl and C1-C6 alkoxy groups may each be substituted with one or more substituents selected from halogens and -OH groups, and the C3-C6 cycloalkyl group may be substituted with one or more substituents selected from C1-C6 alkyl and halogen groups. R 22j , R 23j , and R 24j Each of these is independently selected from H and halogen.

[0132] In one embodiment, R 20j In another embodiment, R 20j is a C1-C6 alkoxy which may be substituted. In one embodiment, R 20j is an unsubstituted C1-C6 alkoxy. In one embodiment, R 20j It is -OCH3.

[0133] In one embodiment, R 21jis a C3-C6 cycloalkyl which may be substituted. In one embodiment, R 21j is a C3 cycloalkyl which may be substituted. In one embodiment, R 21j It is an unsubstituted C3 cycloalkyl group.

[0134] In one embodiment, R 22j , R 23j , and R 24j These are H, respectively. In one embodiment, R 22j and R 24j Each of them is independently a halogen, and R 23j is H. In one embodiment, R 22j and R 24j These are F and R respectively. 23j is H. In one embodiment, R 22j and R 24j These are H and R respectively. 23j is a halogen. In one embodiment, R 22j and R 24j These are H and R respectively. 23j It is F.

[0135] In one embodiment, the following: [ka] The following: [ka] That is the case.

[0136] In one embodiment, the compound of formula (IIj) contains one or more stereocenters. In one embodiment, the compound of formula (IIj) is R 21j It contains a stereocenter. In one embodiment, the compound of formula (IIj) has the following part: [ka] However, the point where it joins to the rest of equation (IIj) contains a stereocenter.

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

[0138] In some embodiments, R 6 This is (Ib), which gives the structure of equation (III) below. [ka]

[0139] In some embodiments relating to equation (III), q, r, s, t, u, v, w, and x are independently 0, 1, or 2. In some embodiments, q is 0 or 1, r is 0 or 1, s is 0 or 1, t is 0 or 1, u is 0 or 1, v is 0 or 1, w is 0 or 1, and x is 0 or 1.

[0140] In some embodiments, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 R is independently selected from H, halogen, hydroxyl, oxo, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl, wherein the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spirocondensed cycloalkyl may be substituted with one or more halogens. In some embodiments, R 15 , R 16 , R 17 , R18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 If 1 or more of these is H, then 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 All of these are H.

[0141] In addition to the embodiment in which the compound has the structure of formula (III), the compound may have any of the following structures (IIIa) to (IIIp). [ka] JPEG0007877318000152.jpg192125JPEG0007877318000153.jpg196125TIFF00078773180 00154.tif214144TIFF0007877318000155.tif195125TIFF0007877318000156.tif131124

[0142] In one embodiment, the compound of formula (III) is formula (IIIq): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, During the ceremony, R 30q It is selected from H and C1-C6 alkoxy; R 31q The C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclil are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C9 heterocyclil, respectively, C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogen, and C3-C9 heterocyclil may be substituted with C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclil, and C6-C 12 It may be substituted with one or more substituents selected from aryl, -OH, -C=O, and halogens; R 32q , R 33q , and R 34q Each of these is independently selected from H and halogen.

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

[0144] In one embodiment, R 31q is an unsubstituted C3-C9 heterocycline. In one embodiment, R 31q is pyrazolyl. In one embodiment, R 31q The following: [ka] (In the formula, K is either N or CH), see below: [ka] (wherein d is 1 or 2) is selected from. In one embodiment, R 31q The following: [ka] (wherein d is 2) In another embodiment, R 31qThese are C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, and C6-C 12 It is a C3-C9 heterocyclyl substituted with one or more substituents selected from aryl, -OH, -C=O, and halogen. In one embodiment, R 31q The following: [ka] And in the formula, R 35q H, unsubstituted C1-C6 alkyl, unsubstituted C6-C 12 Selected from aryls and unsubstituted C3-C9 heterocyclines. In one embodiment, R 31q The following: [ka] And in the formula, R 35q is H. In one embodiment, R 31q The following: [ka] And in the formula, R 35q R is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranil. In another embodiment, R 31q is an isoxazolyl substituted with a C1-C6 alkyl group. In one embodiment, R 31q is a monosubstituted isoxazolyl with -CH3. In one embodiment, R 31q The following: [ka] In another embodiment, R 31q The following: [ka] In the formula, e is 1, 2, or 3, K is N or CH, and each X is independently a halogen. In one embodiment, R 31q The following applies: [ka]

[0145] In one embodiment, R 32q , R 33q , and R 34q These are H, respectively. In one embodiment, R 32q and R 34q Each of them is independently a halogen, and R 33q is H. In one embodiment, R 32q and R 34q These are F and R respectively. 33q i is H. In one embodiment, R 32q and R 34q These are H and R respectively. 33q is a halogen. In one embodiment, R 32q and R 34q These are H and R respectively. 33q It is F.

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

[0147] In one embodiment, the compound of formula (IIIq) is selected from the following. [ka] JPEG0007877318000168.jpg97125

[0148] In one embodiment, the compound of formula (III) is formula (IIIr): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, During the ceremony, R 30rThe C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclil are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C9 heterocyclil, respectively, the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclil may be C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclil, and C6-C 12 It may be substituted with one or more substituents selected from aryl, -OH, -C=O, and halogens; R 31r Selected from H and C1-C6 alkoxy; R 32r , R 33r , and R 34r Each of these is independently selected from H and halogen.

[0149] In one embodiment, R 30r is an unsubstituted C3-C9 heterocycline. In one embodiment, R 30r is an unsubstituted pyrazolyl. In one embodiment, R 30r The following: [ka] (In the formula, L is either N or CH), see below: [ka] (wherein f is 1 or 2) is selected from. In one embodiment, R 30r The following: [ka] (wherein f is 2) In another embodiment, R 30r These are C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, and C6-C 12It is a C3-C9 heterocyclyl substituted with one or more substituents selected from aryl, -OH, -C=O, and halogen. In one embodiment, R 30r The following: [ka] And in the formula, R 35r H, unsubstituted C1-C6 alkyl, unsubstituted C6-C 12 Selected from aryls and unsubstituted C3-C9 heterocyclines. In one embodiment, R 30r The following: [ka] (In the formula, R 35r In one embodiment, R 30r The following: [ka] And in the formula, R 35r R is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranil. In another embodiment, R 30r is an isoxazolyl substituted with a C1-C6 alkyl group. In one embodiment, R 30r is a monosubstituted isoxazolyl with -CH3. In one embodiment, R 30r The following: [ka] In another embodiment, R 30r The following: [ka] In the formula, g is 1, 2, or 3, L is N or CH, and each X is independently a halogen. In one embodiment, R 30r The following: [ka] That is the case.

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

[0151] In one embodiment, R 32r , R 33r , and R 34r These are H, respectively. In one embodiment, R 32r and R 34r Each of them is independently a halogen, and R 33r is H. In one embodiment, R 32r and R 34r These are F and R respectively. 33r is H. In one embodiment, R 32r and R 34r These are H and R respectively. 33r is a halogen. In one embodiment, R 32r and R 34r These are H and R respectively. 33r It is F.

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

[0153] In one embodiment, the compound of formula (IIIr) is selected from the following. [ka] JPEG0007877318000180.jpg86125

[0154] In one embodiment, the compound of formula (III) is: [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, During the ceremony, R 30s It is selected from H and C1-C6 alkoxy; R 31sThe C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclil are selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C9 heterocyclil, respectively, the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclil may be C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclil, and C6-C 12 It may be substituted with one or more substituents selected from aryl, -OH, -C=O, and halogens; R 32s , R 33s , and R 34s Each of these is independently selected from H and halogen.

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

[0156] In one embodiment, R 31s is an unsubstituted C3-C9 heterocycline. In one embodiment, R 31s is pyrazolyl. In one embodiment, R 31s The following: [ka] (In the formula, M is either N or CH), see below: [ka] (wherein h is 1 or 2) is selected from. In one embodiment, R 31s The following: [ka] (wherein h is 2) In another embodiment, R 31s These are C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, and C6-C 12It is a C3-C9 heterocyclyl substituted with one or more substituents selected from aryl, -OH, -C=O, and halogen. In one embodiment, R 31s The following: [ka] And in the formula, R 35s H, unsubstituted C1-C6 alkyl, unsubstituted C6-C 12 Selected from aryls and unsubstituted C3-C9 heterocyclines. In one embodiment, R 31s The following: [ka] (In the formula, R 35s In one embodiment, R 31s The following: [ka] And in the formula, R 35s R is selected from -CH3, isopropyl, phenyl, azetidinyl, and tetrahydropyranil. In another embodiment, R 31s is an isoxazolyl substituted with a C1-C6 alkyl group. In one embodiment, R 31s is a monosubstituted isoxazolyl with -CH3. In one embodiment, R 31s The following: [ka] In another embodiment, R 31s The following: [ka] In the formula, i is 1, 2, or 3, M is N or CH, and each X is independently a halogen. In one embodiment, R 31s The following applies: [ka]

[0157] In one embodiment, R 32s , R 33s , and R 34s These are H, respectively. In one embodiment, R 32s and R 34s Each of them is independently a halogen, and R 33s is H. In one embodiment, R 32s and R 34s These are F and R respectively. 33s is H. In one embodiment, R 32s and R 34s These are H and R respectively. 33s is a halogen. In one embodiment, R 32s and R 34s These are H and R respectively. 33s It is F.

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

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

[0160] In some embodiments, the compound of formula (I), such as the compound of formula (II) or formula (III), may be any of the compounds specified in Tables 1 to 15, from compound 1 to 137. In some embodiments, the compound may be compound 1, compound 9, compound 19, compound 20, compound 21, compound 26, compound 31, compound 38, compound 45, compound 56, compound 60, compound 61, compound 62, compound 63, compound 81, compound 84, compound 96, compound 97, or compound 99.

[0161] In some embodiments, the compound of formula (I), such as the compound of formula (II) or formula (III), may be in the form of a salt, optical and geometric isomers, and salts of isomers. In other embodiments, the compound may be in the form of an uncharged molecule, a component of a molecular complex, or various forms such as, but not limited to, a non-irritating, pharmacologically acceptable salt, such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some cases, in the case of a salt of an acidic compound, the salt may contain a metal, amine, or organic cation (e.g., a quaternary ammonium). In yet another embodiment, a simple derivative of the compound (e.g., an ether, ester, or amide) may be used that has desirable retention and release properties but is readily hydrolyzed by the pH of the body, enzymes, or other suitable means.

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

[0163] In some embodiments, the compounds disclosed herein have a chiral center and can exist as racemates, racemic mixtures, and individual enantiomers or diastereoisomers, and all isomeric forms and mixtures thereof are intended for use in the compounds and methods described herein. The compounds intended for use in the compounds and methods described herein do not include compounds known in the art to be unstable and unsynthesizable and / or unisolated.

[0164] Compounds disclosed herein may also contain one or more atomic isotopes in unnatural proportions among the atoms constituting such compounds. For example, such compounds may contain tritium ( 3 H), Iodine-125( 125 I), or carbon-14 ( 14 They can be radioactively labeled with radioactive isotopes such as C). All isotopic varieties of the compounds disclosed herein, whether radioactive or not, are included within the intended range.

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

[0166] In some embodiments, the compounds intended herein may be provided in the form of prodrugs. The term “prodrug” means a compound that can be converted in vivo to the compounds described herein (e.g., bioactive compounds). Prodrugs may be useful for a variety of reasons known in the art, such as ease of administration, for example, by improving bioavailability in oral administration. Prodrugs may also have improved solubility in pharmaceutical compositions than bioactive compounds. Examples of prodrugs, though not limited to them, include compounds that are administered as esters (i.e., “prodrugs”) that promote permeability across cell membranes where water solubility is disadvantageous for mobility, but are metabolically hydrolyzed intracellularly to an active carboxylic acid where water solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985), which are incorporated herein by reference for the limited purpose of describing the procedures and preparation of suitable prodrug derivatives.

[0167] Certain compounds disclosed herein may exist in solvated forms, including hydrated forms, as well as in non-solvated forms. Generally, the solvated forms are equivalent to the non-solvated forms and fall within the range of the intended compounds. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods intended herein and are intended to fall within the scope of the disclosure herein.

[0168] In certain embodiments, one or more compounds of the Disclosure (e.g., formula (I)) may be part of a composition in amounts of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, It can be at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, or about 99.99% or less, about 0.0001% to about 99%, about 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75% in weight of the total composition.

[0169] In some embodiments, one or more compounds of the Disclosure (e.g., formula (I)) are present in amounts of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, and less They can be purified or isolated in amounts of approximately 75%, at least approximately 90%, at least approximately 95%, at least approximately 99%, at least approximately 99.99%, approximately 75% or less, approximately 90% or less, approximately 95% or less, approximately 99% or less, approximately 99.99% or less, approximately 0.0001% to approximately 99%, approximately 0.0001% to approximately 50%, approximately 0.01% to approximately 95%, approximately 1% to approximately 95%, approximately 10% to approximately 90%, or approximately 25% to approximately 75%.

[0170] Method for preparing the compound of formula (I) Some embodiments of this disclosure include methods for preparing compounds of formula (I). In certain embodiments, compounds of formula (I) can be prepared by comprising one or more steps described in Examples 1 to 25 of this specification. The synthetic routes shown and described in Examples 1 to 25 can be used, for example, to prepare compounds 1 to 137 shown in Tables 1 to 15, and structurally related compounds.

[0171] Pharmaceutical compositions and preparations Some embodiments of this disclosure include compositions comprising one or more compounds of this disclosure (e.g., formula (I)). In certain embodiments, the composition is a pharmaceutical composition, such as one suitable for administration to animals (e.g., mammals, primates, monkeys, humans, dogs, cats, pigs, mice, rabbits, rats, etc.). In some embodiments, a pharmaceutical composition is provided comprising a compound disclosed herein and a pharmaceutically acceptable excipient. The compound may be any of the compounds of formula (I) to (III) disclosed herein, the compounds shown in Tables 1 to 16, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. In some embodiments, the compound is shown in any of Tables 1 to 16 herein.

[0172] Further embodiments of the present disclosure relate to compositions comprising the compound. In some embodiments, the amount of the compound can be about 0.0001% (as weight of the total composition) to about 99%. In some embodiments, the composition may further include formulation components, adjuvants, or carriers. In some embodiments, the composition may further include a BCL2 inhibitor. In some embodiments, the composition may be used in combination with a second composition comprising a BCL2 inhibitor. In some embodiments, the BCL2 may be venetoclax, or a salt, isomer, derivative, or analog thereof.

[0173] The term “pharmaceutically acceptable salt” is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. Where a compound disclosed herein contains a relatively acidic functional group, a neutral form of such compound can be obtained by contacting the base-addition salt with a sufficient amount of the desired base in a neat or suitable inert solvent. Examples of pharmaceutically acceptable base-addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salts, or similar salts. Where a compound disclosed herein contains a relatively basic functional group, an acid-addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid in a neat or suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, bicarbonate, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Also included are salts of amino acids such as alginic acid, 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). Certain compounds disclosed herein possess both basic and acidic functionalities that enable the conversion of the compound into either a base or an acid addition salt.

[0174] The compounds disclosed herein may exist as salts with pharmaceutically acceptable acids, etc. Therefore, the compounds intended herein include such salts. Examples of such salts include hydrochlorides, hydrobroms, sulfates, methanesulfons, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0175] The neutral form of the compound is preferably regenerated by conventional methods, such as contacting the salt with a base or acid and isolating the parent compound. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0176] pharmaceutically acceptable salts of the compounds having basic or acidic groups in their structure are also included within the range of compounds intended herein. When acidic substituents such as -NHSO3H, -COOH, and -P(O)(OH)2 are present, ammonium, sodium, potassium, calcium salts, etc., may be formed for use as dosage forms. Basic groups such as amino or basic heteroaryl radicals, or acidic salts such as pyridyl and hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, and p-toluenesulfonate can be used as dosage forms.

[0177] Furthermore, in embodiments where R-COOH is present, pharmaceutically acceptable esters may be used (e.g., methyl, ethyl, tert-butyl, pivaloyloxymethyl, etc.), and esters known in the art may be used to modify solubility or hydrolysis properties for use as a sustained-release formulation or prodrug formulation.

[0178] In some cases, the pharmaceutical composition is non-toxic, causes no side effects, or both. In some embodiments, it may exhibit specific side effects (e.g., it may harm patients or exhibit some degree of toxicity or adverse effects in some patients).

[0179] In some embodiments, one or more compounds of the present disclosure (e.g., formula (I)) may be part of a pharmaceutical composition in amounts of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, The amount may be at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, or about 99.99% or less, about 0.001% to about 99%, about 0.001% to about 50%, about 0.1% to about 99%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%. In some embodiments, the pharmaceutical composition may be in a dosage form suitable for a route of administration such as topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, cutaneous, nasal, vaginal, or ocular. In other embodiments, the pharmaceutical composition may be in a dosage form suitable for parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. The pharmaceutical composition may be, for example, a tablet, capsule, pill, powder, suspension, emulsion, solution, gel (including hydrogel), paste, ointment, cream, poultices, liquid medicine, delivery device, suppositories, enemas, injections, implants, sprays, aerosols, or other suitable forms.

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

[0181] In some embodiments, the tablets contain the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for tablet production. These excipients may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate; (2) granulating and disintegrating agents such as corn starch or alginic acid; (3) binders such as starch, gelatin, or acacia; and (4) lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or coated with known techniques that provide a sustained action over a longer period by delaying breakdown and absorption in the gastrointestinal tract. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used.

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

[0183] The compounds disclosed herein may be administered parenterally for in vivo application by injection or by gradual perfusion over time, in the form of free compounds or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts. Administration may be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavitary, or percutaneous. In in vitro studies, the compounds may be added or dissolved in a suitable bioacceptable buffer and added to cells or tissues.

[0184] In powder formulations, the carrier is a micronized solid in a mixture with the micronized active ingredient. In tablets, the active ingredient is mixed in an appropriate ratio with a carrier having the required binding properties and compressed into the desired shape and size.

[0185] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting-point wax, and cocoa butter. The term “formulation” is intended to include formulations of the active compound, with or without other carriers, that include an encapsulating material as a carrier providing a capsule in which the active ingredient is surrounded by a carrier to which it associates. Similarly, cachets and lozenges are also included. Suitable solid formulations for oral administration include tablets, powders, capsules, pills, cachets, and lozenges.

[0186] To prepare suppositories, first, a low-melting-point wax, such as a mixture of fatty acid glycerides or cocoa butter, is melted and the active ingredient is uniformly dispersed by stirring. Then, the molten, homogeneous mixture is poured into a mold of a suitable size and solidified by cooling.

[0187] Liquid formulations include solutions, suspensions, and emulsions, such as water or a water / propylene glycol solution. For injectable formulations, liquid formulations can be formulated as a solution in an aqueous polyethylene glycol solution.

[0188] Where parenteral administration is required or desired, particularly suitable mixtures for the compounds disclosed herein are injectables, sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions, or implants (including suppositories). These suspensions can be formulated according to known methods using the aforementioned suitable dispersants or wetting agents and suspensions. Sterile injectables may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Available, acceptable vehicles, carriers, and solvents are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils have conventionally been used as solvents or suspension media. For this purpose, any brand of fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectables. In particular, parenteral administration carriers include aqueous solutions of dextrose, physiological saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, and polyoxyethylene block polymers. Ampoules are convenient unit doses. The compounds disclosed herein may 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 Ed., Mack Pub. Co., Easton, PA) and WO96 / 05309, both of which are incorporated herein by reference.

[0189] In some embodiments, formulations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcohol / aqueous solutions, emulsions, or suspensions (including saline and buffer media). Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents (e.g., sterile water, alcohol, glycerol, and polyhydric alcohols). Vehicles for intravenous administration include fluids and nutritional supplements. Vehicles for parenteral administration include sodium chloride solution, Ringer's dextrose, dextrose, and sodium chloride, while intravenous Ringer's lactate vehicles include fluids and nutritional supplements, electrolyte supplements (e.g., Ringer's dextrose-based ones), etc. Preservatives and other additives, such as antimicrobial agents, antioxidants, chelating agents, growth factors, and inert gases, may also be present.

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

[0191] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and, if necessary, adding appropriate colorants, flavors, stabilizers, and thickeners. Aqueous suspensions suitable for oral use can be prepared by dispersing micronized active ingredients in water with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Aqueous suspensions typically contain the active ingredient mixed with excipients suitable for the preparation of aqueous suspensions. Such excipients may be dispersants or wetting agents that are (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, or acacia gum; (2) (a) naturally occurring phosphatides such as lecithin; (b) condensates of alkylene oxides and fatty acids, e.g., polyoxyethylene stearate; (c) condensates of ethylene oxides and long-chain aliphatic alcohols, e.g., heptadecaethyleneoxycetanol; (d) condensates of ethylene oxides and hexitols such as partial esters derived from fatty acids and polyoxyethylene sorbitol monooleate; or (e) condensates of ethylene oxides and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate).

[0192] This also includes solid formulations intended to be converted into liquid formulations for oral administration immediately before use. Such liquid formulations include solutions, suspensions, and emulsions. These formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0193] The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form is packaging containing the preparation in individual doses, such as packaged preparations, packaged tablets, capsules, and powders in vials or ampoules. Alternatively, the unit dosage form may be the capsule, tablet, cache, or lozenge itself, or a package containing an appropriate number of any of these.

[0194] In some embodiments, the pharmaceutical composition may contain one or more formulary ingredients. “Formulary ingredient” is not limited to any suitable ingredient (e.g., suitable for a drug, suitable for a drug dosage, suitable for the timing of drug release, suitable for a disease, suitable for a pathological condition, or suitable for a delivery route), but may include water (e.g., boiling water, distilled water, filtered water, pyrogen-free water, or water containing chloroform), sugars (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made from them), ethanol, glycerol, glycol (e.g., propylene glycol), acetone, ether, DMSO, surfactant (e.g., Examples of suitable ingredients include anionic surfactants, cationic surfactants, amphoteric surfactants, or nonionic surfactants (e.g., polysorbates), oils (e.g., animal oils, vegetable oils (e.g., coconut oil or peanut oil), mineral oils), oil derivatives (e.g., ethyl oleate, glyceryl monostearate, or hydrogenated glycerides), excipients, preservatives (e.g., vitamins (e.g., A, E, or C), selenium, retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens (e.g., methylparaben or propylparaben)), or any combination thereof.

[0195] In certain embodiments, a pharmaceutical composition may be formulated to release an active ingredient (e.g., one or more compounds of the disclosure, such as formula (I)) immediately after administration, at a substantially predetermined time after administration, or at a time after administration. Such formulations include, for example, controlled-release formulations such as various controlled-release compositions and coatings.

[0196] Other formulations (e.g., formulations of pharmaceutical compositions) may, in certain embodiments, include those in which a drug (or controlled-release formulation) is incorporated into food, foodstuffs, animal feed, or beverages.

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

[0198] Viscosity higher than that of a simple aqueous solution may be desirable to reduce variations during dispensing of the formulation, to decrease the physical separation of components in the suspension or emulsion of the formulation, and / or to improve the formulation. Such viscosity building agents 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. Such agents are typically used in amounts of about 0.01% to about 2% by weight.

[0199] The compositions disclosed herein may further include components for providing sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and micronized drug carrier substrates. These components are described in more detail in U.S. Patent No. 4,911,920; No. 5,403,841; No. 5,212,162; and No. 4,861,760. The entire contents of these patents are incorporated herein by reference for any purpose.

[0200] A variety of pharmaceutical compositions useful for improving specific diseases and disorders are provided. A pharmaceutical composition according to one embodiment is prepared by formulating the compounds disclosed herein, either alone or in combination with other pharmaceutical agents, in the form of free compounds or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts, suitable for administration to a subject, using carriers, excipients, and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol and solvents (e.g., sterile water, alcohol, glycerol, and polyhydric alcohols). Vehicles for intravenous administration include body fluids and nutritional supplements.

[0201] A variety of pharmaceutical compositions useful for improving specific diseases and disorders are provided. A pharmaceutical composition according to one embodiment is prepared by formulating the compounds disclosed herein, either alone or in combination with other pharmaceutical agents, in the form of free compounds or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts, suitable for administration to a subject, using carriers, excipients, and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol and solvents (e.g., sterile water, alcohol, glycerol, and polyhydric alcohols). Vehicles for intravenous administration include body fluids and nutritional supplements.

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

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

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

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

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

[0207] In some embodiments, the subject is susceptible to AML and / or MDS, and / or the method prevents or improves future AML and / or MDS. In some embodiments, the method is performed after one or more occurrences of myelodysplastic syndrome, myeloproliferative disorder, exposure to chemicals, exposure to ionizing radiation, or cancer treatment.

[0208] In some embodiments, the method further comprises administering a composition comprising a BCL2 inhibitor, or at least one of the compositions comprising the compound further comprises a BCL2 inhibitor. In some embodiments, the compound and the BCL2 inhibitor may be administered together or separately in one or more doses of one or more compositions. In some embodiments, the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0209] In some embodiments, the method further comprises administering one or more therapeutic agents selected from one or more chemotherapy regimens, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antmetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAb / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, Smound receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof. In some embodiments, the DNA methyltransferase / hypomethylating agent comprises azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a constant molar ratio of 5:1); and the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, and b The following are included: luproic acid and / or prasinostat; the purine nucleoside analog (antmetabolite) comprises fludarabine, cladribine and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor comprises ivosidenib and / or enasidenib; the antibody drug conjugate comprises anti-CD33 (e.g., Ac225-lintuzumab, vadasutuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-A pamistamab) is included; the mAb / immunotherapy comprises anti-CD70 (e.g., ARGX-110, xatuzumab), bispecific antibodies (e.g., floteuzumab (CD123×CD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (maglorimab)); the Plk inhibitor comprises volasertib and / or rigosatib; the MEK inhibitor comprises trametinib, cobi The CDK9 inhibitor comprises methinib, selumetinib, pimacertib, and / or refametinib; the CDK9 inhibitor comprises arbocidib and / or borciclib; the CDK8 inhibitor comprises SEL120; the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activator comprises APR-246 (Eprenetapt); the smoothed receptor antagonist comprises glass-de-gib; the ERK inhibitor comprises urixerutinib, S The PI3K inhibitors include CH772984, laboxertinib, MK-8353, and / or VTX-11e, comprising ERK2 / MAPK1 inhibitors or ERK1 / MAPK3 inhibitors; the PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, reniolisib (CDZ-173), piraralisib (XL147, SAR245408), and / or vimiralisib (PQR-309); the mTOR inhibitors include vimiralisib (PQR-309), sapanicertib (TAK-228, INK-128), ridafololimus (MK-86 69, AP-23573), everolimus, viscertib (AZD2014); the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricolinant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor comprises tazemettostat.

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

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

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

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

[0214] In some embodiments, the subject is susceptible to AML and / or MDS, and / or the method prevents or improves future AML and / or MDS. In some embodiments, the method is performed after one or more occurrences of myelodysplastic syndrome, myeloproliferative disorder, exposure to chemicals, exposure to ionizing radiation, or treatment of cancer. In some embodiments, the method further comprises the administration of a composition comprising a BCL2 inhibitor, or at least one of the compositions comprising a compound according to any one of claims 1 to 39 further comprises a BCL2 inhibitor. In some embodiments, the compound according to any one of claims 1 to 39 and the BCL2 inhibitor may be administered together or separately in one or more doses of one or more compositions. In some embodiments, the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0215] In some embodiments, the method further comprises administering one or more therapeutic agents selected from one or more chemotherapy regimens, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antmetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAb / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, Smound receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof. In some embodiments, the DNA methyltransferase / hypomethylating agent comprises azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a constant molar ratio of 5:1); and the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, and b The following are included: luproic acid and / or prasinostat; the purine nucleoside analog (antmetabolite) comprises fludarabine, cladribine and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor comprises ivosidenib and / or enasidenib; the antibody drug conjugate comprises anti-CD33 (e.g., Ac225-lintuzumab, vadasutuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-A pamistamab) is included; the mAb / immunotherapy comprises anti-CD70 (e.g., ARGX-110, xatuzumab), bispecific antibodies (e.g., floteuzumab (CD123×CD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (maglorimab)); the Plk inhibitor comprises volasertib and / or rigosatib; the MEK inhibitor comprises trametinib, cobi The CDK9 inhibitor comprises methinib, selumetinib, pimacertib, and / or refametinib; the CDK9 inhibitor comprises arbocidib and / or borciclib; the CDK8 inhibitor comprises SEL120; the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activator comprises APR-246 (Eprenetapt); the smoothed receptor antagonist comprises glass-de-gib; the ERK inhibitor comprises urixerutinib, S The PI3K inhibitors include CH772984, laboxertinib, MK-8353, and / or VTX-11e, comprising ERK2 / MAPK1 inhibitors or ERK1 / MAPK3 inhibitors; the PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, reniolisib (CDZ-173), piraralisib (XL147, SAR245408), and / or vimiralisib (PQR-309); the mTOR inhibitors include vimiralisib (PQR-309), sapanicertib (TAK-228, INK-128), ridafololimus (MK-86 69, AP-23573), everolimus, viscertib (AZD2014); the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricolinant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor comprises tazemettostat.

[0216] In addition to their ability to inhibit IRAK, IRAK inhibitors have been shown to exhibit selectivity for multiple kinases. In some embodiments, compounds described herein relating to formula (I), such as compounds 1 to 137 listed in Tables 1 to 15, exhibit inhibitory activity against one or more kinases, such as interleukin-1 receptor-related kinase (IRAK) and FMS-like tyrosine kinase 3 (FLT3). Inhibitory effects on one or more kinases, such as IRAK and FLT3, but not limited to, enable the treatment and / or prevention of diseases in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cattle, primates, rodents, monkeys, rabbits, mice, rats, and humans) using the compounds of the Disclosure (e.g., formula (I)), including hematopoietic cancers (e.g., hematopoietic cancers), MDS, AML, myeloproliferative disorders, and diseases associated with mutations in IRAK1, IRAK4, and / or FLT3 (e.g., mutations in the near-membrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations).

[0217] In some embodiments, the compounds of the present disclosure can inhibit one or more activities of FLT3, mutations of FLT3 (e.g., mutations in the near-membrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, intra-FLT3 tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), IRAK4 (interleukin-1 receptor-related kinase 4), isoforms of IRAK4, mutations of IRAK4, IRAK1 (interleukin-1 receptor-related kinase 1), isoforms of IRAK1, and / or mutations of IRAK1. In some embodiments, the compounds of the present disclosure can inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the near-membrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, intra-FLT3 tandem mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and may inhibit one or more of IRAK4, isoforms of IRAK4, mutations of IRAK4, IRAK1, isoforms of IRAK1, or mutations of IRAK1. In some embodiments, the compounds of the Disclosure may inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the near-membrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, intra-FLT3 tandem mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and may also inhibit one or both of IRAK4 and IRAK1, or their isoforms or mutations. In some embodiments, the compounds of the Disclosure may inhibit FLT3 in combination with IRAK4, in combination with IRAK1, or in combination with both IRAK4 and IRAK1.

[0218] In some embodiments, the compound exhibits inhibitory activity against IRAK and / or FLT-3, with activity of 1 μM or greater, 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 greater. In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3, with activity ranging from 0.1 nM to 1 nM, for example, about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 nM. In some embodiments, the compounds described herein exhibit inhibitory activity against IRAK and / or FLT-3, with activity of 0.1 μM or less, for example, about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. A range of values ​​is also intended, using any combination of the values ​​described herein as upper and / or lower limits, for example, but not limited to, 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM. In some embodiments, the inhibitory activity is in the range of approximately 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or even 500-1000 μM.For quantification purposes, it is understood that terms such as “activity,” “inhibitory activity,” “biological activity,” “IRAK activity,” “IRAK1 activity,” “IRAK4 activity,” and “FLT-3 activity” in the context of the inhibitory compounds disclosed herein can be quantified by various methods known in the art. Unless otherwise specified, when used herein, such terms are used in the conventional sense of IC. 50 (That is, the concentration required to achieve 50% inhibition (half-maximal inhibition)).

[0219] In some embodiments, the hematopoietic cancers that can be treated in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cattle, primates, rodents, monkeys, rabbits, mice, rats, and humans) using the compounds of the Disclosure (e.g., formula (I)) include, but are not limited to, hematopoietic cancers and cancers of myeloid blood cells, cancers whose risk of development is increased by other blood disorders, cancers whose risk of development is increased by exposure to chemicals (e.g., anticancer treatment or occupational exposure to chemicals), cancers whose risk of development is increased by ionizing radiation (e.g., anticancer therapy), cancers progressing from myelodysplastic syndromes, cancers progressing from myeloproliferative disorders, and B-cell cancers.

[0220] In some embodiments, the hematopoietic cancers that can be treated include, but are not limited to, MDS, AML, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., ABC DLBCL with MYD88 mutation (e.g., L265P)), follicular lymphoma, or marginal zone lymphoma, or combinations thereof.

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

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

[0223] In certain embodiments, the compounds of the Disclosure (e.g., formula (I)) can be used to treat MDS in subjects (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans), including, but not limited to, MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, MDS with mutations in isocitrate dehydrogenase 2, and refractory hematopoiesis with monocytic dysplasia. This includes cytopenia (e.g., refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia with polycytic lineage dysplasia (e.g., refractory cytopenia with polycytic lineage dysplasia and ring sideroblasts, animal / human with pathological changes not limited to erythrocytes such as marked leukocyte and platelet progenitor (megakaryocyte) dysplasia), refractory anemia with excess blast cells I and II, 5q syndrome, megakaryocytic dysplasia with fibrosis, and childhood refractory cytopenia. In some embodiments, treatable MDSs include, but are not limited to, hereditary MDS, MDS with increased risk due to hereditary predisposition, MDS with increased risk due to other blood disorders, MDS with increased risk due to exposure to chemicals, MDS with increased risk due to ionizing radiation, MDS with increased risk due to cancer treatment (e.g., a combination of radiation and radioactive alkylating agents such as busulfan, nitrosourea, or procarbazine (latency period of 5-7 years) or DNA topoisomerase inhibitors), MDS progressing from acquired aplastic anemia and Fanconi anemia after immunosuppressive therapy, MDS with increased risk due to splicing factor mutations, MDS with increased risk due to isocitrate dehydrogenase 1 mutations, and MDS with increased risk due to isocitrate dehydrogenase 2 mutations. The animals that can be treated include, but are not limited to, mammals, rodents, primates, monkeys (e.g., macaques, rhesus monkeys, pig-tailed macaques), humans, dogs, cats, pigs, birds (e.g., chickens), cattle, mice, rabbits, and rats. In the above method, the term "subject" may mean both human and non-human subjects.In some settings, the subjects in question require treatment (e.g., showing signs of diseases such as MDS, AML, cancer, autoimmune diseases, inflammatory conditions, or low blood cell counts).

[0224] In some embodiments, MDSs that can be treated with a compound of the Disclosure (e.g., formula (I)) in a subject (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cattle, primates, rodents, monkeys, rabbits, mice, rats, and humans) include, but are not limited to, MDSs that can be treated by inhibiting one or more of the following: FLT3 (e.g., using an FLT3 inhibitor), mutations of FLT3 (e.g., using an FLT3 mutation inhibitor), IRAK4 (e.g., using an IRAK4 inhibitor), mutations of IRAK4 (e.g., using an IRAK4 mutation inhibitor), IRAK1 (e.g., using an IRAK1 inhibitor), and / or mutations of IRAK1 (e.g., using an IRAK1 mutation inhibitor). In some embodiments, treatable MDSs include, but are not limited to, MDSs that can be treated by inhibiting IRAK4 (or its mutations), MDSs that can be treated by inhibiting IRAK1 (or its mutations), or MDSs that can be treated by inhibiting both IRAK4 (or its mutations) and IRAK1 (or its mutations). In some embodiments, treatable MDSs include, but are not limited to, MDSs that can be treated by inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 makes it possible to treat tumors with FLT3 mutations that may be resistant to or may become resistant to FLT3 inhibitors due to adaptive resistance mechanisms caused by IRAK, for example.In some embodiments, the MDS that can be treated is characterized by an MDS in which the expression and / or activity of IRAK4-Long is enhanced compared to IRAK4-Short, and / or the MDS is characterized by the expression of IRAK4-Long, which is not caused by an FLT3 mutation, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.”). Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5 (Both of these are incorporated herein by reference).

[0225] In some embodiments, the compounds of the Disclosure (e.g., formula (I)) can be used to treat AML in subjects (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cattle, primates, rodents, monkeys, rabbits, mice, rats, and humans), including, but not limited to, hereditary AML, AML with increased risk due to genetic predisposition, and one or more recurrent genetic abnormalities (e.g., those with the following inversions or translocations, e.g., MLLT3 / MLL ("MLL"), a translocation between chromosome 9 and chromosome 11, AML with a translocation between chromosome 8 and chromosome 21, and a translocation of chromosome 16). AML with inversion, AML with translocation between chromosome 9 and 11, APL (M3) with translocation between chromosome 15 and 17, AML with translocation between chromosome 6 and 9, AML with translocation or inversion on chromosome 3, etc.), AML with translocation between chromosome 1 and 22, AML with myelodysplasia-related changes, AML associated with past chemotherapy or radiotherapy (e.g., alkylating agent-related AML, topoisomerase II inhibitor-related AML, etc.), AML not otherwise classified (those not falling into the above categories (similar to FAB classification); for example, minimally differentiated AML (AML minimally differentiated) (M0), AML with minimal maturation (AML with minimal maturation) (M1), mature AML (AML with Maturation (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroblastic leukemia (M6), acute megakaryoblastic leukemia (M7), acute basophilic leukemia, acute panmyelopathy with fibrosis, etc.), myeloid sarcoma (also known as granulocytic sarcoma, chlorotoma, or extramedullary myeloblastoma), undifferentiated and biphenotypic acute leukemia (also known as mixed phenotypic acute leukemia), AML with increased risk due to other hematological disorders, AML with increased risk due to exposure to chemicals, AML with increased risk due to ionizing radiation, AML progressing from myelodysplastic syndrome, AML progressing from myeloproliferative disorders, AML with increased risk due to FLT3 mutations, AML with increased risk due to FLT3 mutations in the near-membrane region of FLT3, AML with increased risk due to internal tandem duplication FLT3 mutations in the near-membrane region of FLT3,This includes 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, AML with increased risk due to FLT3 mutation R834Q, and so on. In some embodiments, treatable AML includes AML that can be treated by inhibiting one or more of the following: FLT3 (e.g., using an FLT3 inhibitor), mutations of FLT3 (e.g., using an FLT3 mutation inhibitor), IRAK4 (e.g., using an IRAK4 inhibitor), mutations of IRAK4 (e.g., using an IRAK4 mutation inhibitor), IRAK1 (e.g., using an IRAK1 inhibitor), and / or mutations of IRAK1 (e.g., using an IRAK1 mutation inhibitor). In certain 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 both 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 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 makes it possible to treat tumors with FLT3 mutations that may be resistant to or may become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms caused by IRAK. In some embodiments, the treatable AML is characterized by AML in which the expression and / or activity of IRAK4-Long is enhanced compared to IRAK4-Short, and / or the AML is characterized by expressing IRAK4-Long but not caused by an FLT3 mutation, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (for example,U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5 (Both of these are incorporated herein by reference).

[0226] In some embodiments, hematopoietic cancers that can be treated with a compound of the Disclosure (e.g., formula (I)) in a subject (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cattle, primates, rodents, monkeys, rabbits, mice, rats, and humans) include, but are not limited to, hematopoietic cancers (e.g., MDS, AML, DLBCL, etc.) that can be treated by inhibiting one or more of FLT3 (e.g., using an FLT3 inhibitor), mutations of FLT3 (e.g., using an FLT3 mutation inhibitor), IRAK4 (e.g., using an IRAK4 inhibitor), isoforms of IRAK4, mutations of IRAK4 (e.g., using an IRAK4 mutation inhibitor), IRAK1 (e.g., using an IRAK1 inhibitor), isoforms of IRAK1, or mutations of IRAK1 (e.g., using an IRAK1 mutation inhibitor) (e.g., reducing their activity or expression). In certain embodiments, the hematopoietic cancers that can be treated include, but are not limited to, cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK4 (or its mutations); hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK1 (or its mutations); or hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations), IRAK4 (or its isoform or mutations), and IRAK1 (or its isoform or mutations). In some embodiments, the hematopoietic cancers that can be treated include, but are not limited to, hematopoietic cancers that can be treated by inhibiting IRAK4, IRAK1, or FLT3 together with both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 makes it possible to treat tumors with FLT3 mutations that may be resistant to or could become resistant to FLT3 inhibitors, for example, through adaptive resistance mechanisms induced by IRAK.In some embodiments, the hematopoietic malignancies that can be treated are hematopoietic malignancies in which the expression and / or activity of IRAK4-Long is enhanced compared to IRAK4-Short, and / or the hematopoietic malignancies are characterized by being hematopoietic malignancies that express IRAK4-Long but are not caused by an FLT3 mutation, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.”). Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5 (Both of these are incorporated herein by reference).

[0227] In some embodiments, the cancers that can be treated include, but are not limited to, glioblastoma polymorphoni, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, as well as combinations thereof, which can be treated by inhibiting FLT3 with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 with IRAK4, IRAK1, or both IRAK4 and IRAK1 makes it possible to treat tumors with FLT3 mutations that may be resistant to or may become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms induced by IRAK. In some embodiments, the cancers that can be treated are characterized by enhanced expression and / or activity of IRAK4-Long compared to IRAK4-Short, and / or the cancer is characterized by expressing IRAK4-Long but not caused by an FLT3 mutation, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g., U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.”) Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5 (Both of these are incorporated herein by reference).

[0228] In some embodiments, inflammatory and autoimmune diseases that can be treated are characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling, including, but not limited to, chronic inflammation (i.e., 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. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 makes it possible to treat inflammatory and autoimmune diseases having FLT3 mutations that may be resistant to or may become resistant to FLT3 inhibitors, for example, by adaptive resistance mechanisms caused by IRAK. In some embodiments, the cancers that can be treated are inflammatory and autoimmune diseases in which the expression and / or activity of IRAK4-Long is enhanced compared to IRAK4-Short, and / or the inflammatory and autoimmune diseases are characterized by being inflammatory and autoimmune diseases that express IRAK4-Long but are not caused by FLT3 mutations, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (see, for example, U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0229] In relation to the treatment of MDS (for example, MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations), treatment may include, but is not limited to, prophylactic and therapeutic treatments. Therefore, treatment is not limited to, but includes: prevention of MDS (e.g., MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2); reduction of the risk of MDS (e.g., MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2); alleviation or reduction of symptoms of MDS (e.g., MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2); induction of a bodily response to MDS (e.g., MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2); Inhibition of the onset or progression of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); Inhibition or prevention of the onset of symptoms associated with MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2) Reduction in the severity of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) or one or more symptoms associated with MDS (e.g., increased blood cell count); remission of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations);Remission of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations); prevention of relapse of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); or prevention of relapse of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) in animals / humans with intrinsic or acquired resistance to other MDS treatments. In some embodiments, the treatment does not include prophylactic treatment of MDS (e.g., prevention or improvement of future MDS).

[0230] In relation to the treatment of hematopoietic cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin 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), treatment may include, but is not limited to, prophylactic and therapeutic treatments. Therefore, treatment is not limited to, but includes: cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL Prevention of MYD88 mutations, follicular lymphoma, marginal zone lymphoma, and combinations thereof; cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL Reducing the risk of cancer (e.g., MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); alleviating or reducing the symptoms of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin 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);Induction of a physical response to cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin 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); induction of a physical response to cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL Inhibition of the onset or progression of cancer (such as MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL Inhibition or prevention of the onset of symptoms associated with MYD88 mutations, follicular lymphoma, or marginal zone lymphoma, and combinations thereof; cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL Reduction in the severity of cancer (e.g., MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); recovery from one or more symptoms associated with cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof) or cancer (e.g., reduction in tumor size);Cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL) Remission of cancers (such as MYD88 mutations, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); prevention or minimization of FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations) for cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL Remission of MYD88 mutations (such as follicular lymphoma, marginal zone lymphoma, or combinations thereof); remission of acute myeloid leukemia by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutation or D835Y mutation); cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL Prevention of relapse of cancer (e.g., MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof) in animals / humans with intrinsic or acquired resistance to other cancer treatments (e.g., with some FLT3 inhibitors or MLL); prevention of relapse of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof)Or prevention of relapse of acute myeloid leukemia in animals / humans with intrinsic or acquired resistance to other cancer treatments (e.g., with certain FLT3 inhibitors or MLL). In some embodiments, the treatment does not include prophylactic treatment of cancer (e.g., prevention or improvement of future cancer).

[0231] The treatment of the subject can be carried out using any suitable method of administration (e.g., the methods disclosed herein) and any suitable amount of the compound of the Disclosure (e.g., formula (I)). In some embodiments, the treatment method includes treating animal or human MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations). In some embodiments, the treatment method includes treating hematopoietic cancers in animals or humans (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof). Other embodiments include treatment following one or more treatments for hematopoietic cancers, myelodysplastic syndromes, myeloproliferative disorders, exposure to chemicals, exposure to ionizing radiation, or treatment of hematopoietic cancers (e.g., by chemotherapy, ionizing radiation, or both). Some embodiments of the present disclosure 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) comprising one or more doses of one or more such compositions, wherein if there are two or more doses, the compositions may be the same or different.

[0232] In some embodiments, the therapeutic method includes administering an effective amount of a composition comprising the compound of the present disclosure (e.g., formula (I)) to a subject. As used herein, the term “effective dose” means a dose or set of doses sufficient to treat (for example, the treatment of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations)) in a subject; or hematopoietic cancers, for example, (but not limited to) acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof. In some embodiments, the effective dose may include a therapeutically effective amount as disclosed herein. In certain embodiments, the effective dose may vary depending on the subject and the specific treatment being treated. The exact amount required may vary, for example, depending on the subject, their age and general condition, the specific adjuvant used (if applicable), the administration protocol, etc. Thus, the effective dose may vary, for example, depending on the specific situation, and an appropriate effective dose can be determined in a particular case. The effective dose may include, for example, any dose or composition amount disclosed herein.In some embodiments, the effective dose of at least one compound of the present disclosure (e.g., formula (I) compounds such as compounds 1 to 137 listed in Tables 1 to 15, but not limited to these) (which can be administered to subjects such as mammals, primates, monkeys, or humans) may be 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. In some embodiments, the dose may be about 0.5 mg / kg body weight or about 6.5 mg / kg body weight. In some cases, the effective dose of at least one compound of the present disclosure (e.g., formula (I) compounds such as compounds 1 to 137 listed in Tables 1 to 15, for example) (which can be administered to subjects such as mammals, rodents, mice, rabbits, cats, pigs, or dogs) may be 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 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 dose of at least one compound of the present disclosure (e.g., formula (I) compounds such as compounds 1 to 1137 listed in Tables 1 to 15, for example) (which can be administered to subjects such as mammals, primates, monkeys, or humans) may be in amounts of about 1 to about 1000 mg / kg body weight, about 5 to about 500 mg / kg body weight, about 10 to about 200 mg / kg body weight, about 25 to about 100 mg / kg body weight, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1000 mg / kg. Under certain conditions, the dose may be about 20 mg / kg human body weight or about 100 mg / kg human body weight. In some cases, the effective dose of at least one compound of this disclosure (e.g., formula (I) such as compounds 1-137 listed in Tables 1-15, but not limited to these) (which can be administered to animals such as mammals, rodents, mice, rabbits, cats, pigs, or dogs) may be about 1-1000 mg / kg body weight, about 5-500 mg / kg body weight, about 10-200 mg / kg body weight, or about 25-100 mg / kg body weight. The amount can be g / kg body weight, approximately 1 mg / kg, approximately 2 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 25 mg / kg, approximately 50 mg / kg, approximately 100 mg / kg, approximately 150 mg / kg, approximately 200 mg / kg, approximately 300 mg / kg, approximately 400 mg / kg, approximately 500 mg / kg, approximately 600 mg / kg, approximately 700 mg / kg, approximately 800 mg / kg, approximately 900 mg / kg, or approximately 1000 mg / kg.

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

[0234] In some embodiments, administration of at least one compound of the Disclosure (e.g., formula (I)) to a subject constitutes adjuvant cancer therapy or part of adjuvant cancer therapy. Adjuvant therapy includes therapy by the mechanisms disclosed herein and, but is not limited to, the treatment of cancers of the Disclosure, including tumors. The corresponding first-line therapy includes, but is not limited to, surgery, chemotherapy, or radiotherapy. In some cases, adjuvant therapy may be a combination of a chemokine receptor antagonist and conventional chemotoxic agents or immunotherapy that can enhance the specificity of the treatment for cancer and limit further systemic side effects. In yet other embodiments, the compound of the Disclosure (e.g., formula (I)) can be used as an adjuvant in conjunction with other chemotherapeutic agents. The use of the compound of the Disclosure (e.g., formula (I)) can, in some cases, reduce side effects and shorten the duration of administration of both the agent and the combination of agents.

[0235] In some embodiments, administration to a subject can reduce the incidence of one or more symptoms associated with a type of MDS / AML / hematopoietic malignancy. In some embodiments, the administration can reduce bone marrow failure, immunodeficiency, progression to overt leukemia, or a combination thereof in a subject compared to a subject not administered the composition.

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

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

[0238] Accordingly, in some embodiments, the compounds and / or compositions described herein may be combined in one or more doses to a subject with one or more BCL2 inhibitors, BTK inhibitors, chemotherapy, targeted therapy, alternative therapy, immunotherapy, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antmetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAb / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, Smound receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof, and if there are multiple doses, the compositions may be the same or different. In some embodiments, if there are multiple doses, at least one composition used in at least one dose is different from the composition of at least one other dose.

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

[0240] When exemplary IRAK inhibitors were combined with venetoclax, the potency of venetoclax unexpectedly increased by approximately 50 times. According to certain aspects of this disclosure, this synergistic combination can enhance the efficacy of venetoclax at low doses, thereby avoiding at least some of the clinically observed toxicity. According to certain aspects, the degree of interaction depends on the combination of dose ratios used, and exemplary IRAK inhibitors result in a greater change in venetoclax IC50 at low concentrations. This unexpected and dramatic change in venetoclax IC50 is substantially beyond an additive response and demonstrates an unexpected synergistic interaction between the two drugs even in cell lines that do not express activated FLT3 variants.

[0241] Accordingly, the present disclosure includes a method for treating a disease or disorder that responds to inhibition of IRAK, comprising administering a composition comprising an IRAK inhibitor compound to a subject, and some embodiments of the method may further include the administration of an apoptosis modulator. The apoptosis modulator may include BTK and / or BCL2 inhibitors. The 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 modulator to the subject. In some embodiments, the apoptosis modulator may include BCL2 inhibitors selected from ABT-263 (navitoclax), ABT-737, ABT-199 (venetoclax), GDC-0199, GX15-070 (ovatoclax) (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 there are many known BCL2 inhibitors that can be used in accordance with this disclosure. In some embodiments, the BCL2 inhibitor includes venetoclax.

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

[0243] In some embodiments, the IRAK inhibitor is selected from compounds 1 to 137, or their salts, isomers, derivatives, or analogs, and the BCL2 inhibitor is venetoclax, or its salts, isomers, derivatives, or analogs.

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

[0245] In some embodiments, the compounds and / or compositions described herein can be used with or in combination with one or more BTK inhibitors, such as ibrutinib or its salts, isomers, derivatives, or analogs, for one or more doses to a subject.

[0246] For example, the compounds and / or compositions described herein include, for example, DNA methyltransferases / hypomethylating agents such as azacitidine, decitabine, cytarabine, and / or guadecitabine; anthracyclines such as, for example, daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a constant molar ratio of 5:1); for example, vorinostat, panobinostat, valproic acid, and / or These include histone deacetylase (HDAC) inhibitors such as prasinostat; purine nucleoside analogs (antmetabolites) such as fludarabine, cladribine, and / or clofarabine; isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors such as ivosidenib and / or enasidenib; anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin), and / or anti-CD45 (e.g., I 131- Antibody drug conjugates such as apamistamab; mAb / immunotherapy such as anti-CD70 (e.g., ARGX-110, xatuzumab), bispecific antibodies (e.g., floteuzumab (CD123×CD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (maglorimab)); Plk inhibitors such as volasertib and / or rigosertib; for example, MEK inhibitors such as lametinib, cobimetinib, selumetinib, pimacertib, and / or refametinib; CDK9 inhibitors such as arbocidib and / or borciclib; CDK8 inhibitors such as SEL120; retinoic acid receptor agonists such as ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); TP53 activators such as APR-246 (eprenetapopt); smoothed receptor antagonists such as glasdezib; for example, urin ERK inhibitors such as ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, such as xerutinib, SCH772984, laboxerutinib, MK-8353, and / or VTX-11e; PI3K inhibitors such as fimepinostat (CUDC-907), alpelisib, reniolisib (CDZ-173), piraralisib (XL147, SAR245408), and / or vimiralisib (PQR-309); for example, vimiralisib (PQR-309), sapanicertib (TAK-228, INK-128), ridaf mTOR inhibitors such as lolimus (MK-8669, AP-23573), everolimus, and / or vistasetib (AZD2014); agonists including, for example, prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or antagonists including mifepristone, myricolinant, and / or onapristone, and / or other binding ligands including vamorolone (VBP15);And / or, for example, it can be used in combination with or in combination with EZH2 inhibitors such as tazemetostat in one or more doses. In some embodiments, the compound and the pharmaceutical composition containing it can be used for the prevention of secondary malignancies when used in combination with an EZH2 inhibitor. Further therapeutic agents are described below, but combination therapy is intended in the context of this disclosure.

[0247] Chemotherapy / targeted therapy / alternative therapy Cancer is generally treated with chemotherapy and / or targeted therapy and / or alternative therapy. Chemotherapy works by indiscriminately targeting rapidly dividing cells, including not only tumor cells but also normal cells, while targeted cancer therapy works by interfering with specific molecules or molecular targets involved in the growth and progression of cancer. Targeted therapy typically targets only cancer cells, minimizing damage to normal cells. Approved and / or clinically-staged chemotherapeutic and targeted therapy agents are known to those skilled in the art. Any such compound can be used in the implementation of this disclosure.

[0248] For example, approved chemotherapy agents include abitrexate (methotrexate injection), Abraxane (paclitaxel injection), Adcetris (brentuximab vedotin injection), Adriamycin (doxorubicin), Adolsil injection (5-FU (fluorouracil)), Afinitor (everolimus), Afinitor Disperse (everolimus), Alimta (pemetrexed), Alkeran injection (melphalan injection), Alkeran tablets (melphalan), Aredia (pamidronate), Arimidex (anastrozole), and Aromasin. N (exemestane), Alanone (nelarabine), Alzera (ofatumumab injection), Avastin (bevacizumab), Beleodac (bellinostat injection), Vexar (tocitumomab), BiCNU (carmustine), Blenoxan (bleomycin), Brincyt (blinatumomab injection), Boslif (bosutinib), Busulfex injection (busulfan injection), Campas (alemtuzumab), Camptosar (irinotecan), Caprelsa (vandetanib), Casodex (bicalutamide), CeeNU (lomustine), CeeNU Dose Pack (Lomustine), Seruvidine (Daunorubicin), Chlor (Clofarabine Injection), Cometrix (Cabozantinib), Cosmegen (Dactinomycin), Cotelic (Cobimetinib), Cyramza (Ramucirumab Injection), Cytosar (Cytarabine), Cytoxan (Cytoxan), Cytoxan Injection (Cyclophosphamide Injection), Dacogen (Decitabine), Daunoxosome (Daunorubicin Lipid Complex Injection), Decadron (Dexamethasone), Depoty (Cytarabine Lipid Complex Injection), Dexamethasone Intensol (Dexamethasone), dexpak Taperpak (dexamethasone), Docefrez (docetaxel), Doxil (doxorubicin lipid complex injection), Droxia (hydroxyurea), DTIC (decarbazine), Eligard (leuprolide), Elence (Erence (epirubicin)), Eloxatin (eloxatin (oxaliplatin)), Elspar (asparaginase), Emcyte (estramustine), Erbitux (cetuximab), Elevedge (bismodegib), Elwinase (asparaginase, erwinia chrysanthemis),Ethiol (amifostin), Etopophos (etoposide injection), Oilexin (flutamide), Fareston (toremifene), Faridac (panobinostat), Fastlodex (fulvestrant), Femara (letrozole), Firmagon (degarelix injection), Fludara (fludarabine), Forex (methotrexate injection), Forotin (pralatrexate injection), FUDR (FUDR (floxuridine)), Gajiba (Obi Nutuzumab injection, Gemzar (gemcitabine), Girotrif (afatinib), Gleevec (imatinib mesylate), Gliadelwafer (carmustine wafer), Halaven (eribulin injection), Herceptin (trastuzumab), Hexalen (altretamine), Hycamtin (topotecan), Hycamtin (topotecan), Hydrea (hydroxyurea), Ibrance (palbociclib), Iclusig (ponatinib), Idamycin PFS (idarubicin), Ifex (ifosfamide), Imbruvica (ibrutinib), Inlyta (axitinib), Intron A Alphab (interferon Alpha-2a), Iressa (gefitinib), Istodax (romidepsin injection), Ixempra (ixabepirone injection), Jakafi (ruxolitinib), Jevtana (cabazitaxel injection), Kadcyla (adtrastuzumab emtansine), Keytruda (pembrolizumab injection), Kyprolis (carfilzomib), Lamvima (lenvatinib), Leukeran (chlorambucil), Leukin (salglamostim), Leustatin (cladribine), Lonsurf (trifluridine and tipiracil), Leupron (leuprolide), Lupron Depot (leuprolide), Lupron Depot PE (leuprolide), Lympherza (olaparib), Risodren (mitotane), Marquivo Kit (vincristine lipid complex injection), Maturan (procarbazine), Megas (megestrol), Mekinist (trametinib), Mesnex (mesna), Mesnex (mesna injection), Metastron (strontium-89 chloride), Mexart (methotrexate injection), Mustagen (mechloretamine), Mutamycin (mitomycin), Myrelan (busulfan),Mylotarg (gemtuzumab ozogamicin), Navelbine (vinorelbine), Neosal injection (cyclophosphamide injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Newpogen (filgrastim), Nexavar (sorafenib), Nilandrone (nilandrone (nilutamide)), Nipent (pentostatin), Nolvadex (tamoxifen), Novantrone (mitoxantrone), Odomzo (sonidegib), Oncaspar (pegaspargus), Oncovin (vincristine), Ontak (denileukin Diftitox, Onxol (paclitaxel injection), Opdivo (nivolumab injection), Panretin (alitretinoin), Paraplatin (carboplatin), Perjeta (pertuzumab injection), Platinol (cisplatin), Platinol (cisplatin injection), Platinol AQ (cisplatin), Platinol AQ (cisplatin injection), Pomalist (pomalidomide), Prednisone Intensol (prednisone), Proleukin (aldesleukin), Prinetol (mercaptopurine), Leclast (zoledronic acid), Revlimid (lenalidomide), Rheumatrex (methotrexate), Rituxan (rituximab), Loferon A Alpha a (interferon) Alpha-2a), Rubex (doxorubicin), Sandostatin (octreotide), Sandostatin LAR Depot (octreotide), Soltamox (tamoxifen), Sprycel (dasatinib), Sterap Red (prednisone), Sterap Red DS (prednisone), Stivarga (regorafenib), Suprelin LA (Histrelin implant), Sutent (Sunitinib), Cilatron (Peginterferon alpha-2b injection (Cilatron)), Silvant (Siltuximab injection), Synribo (Omasetaxin injection), Tabloid (Thiogunine), Tafrinal (Dabrafenib), Tarceva (Erlotinib), Targretin capsules (Bexarotene), Tasigna (Decarbazine), Taxol (Paclitaxel injection), Taxotere (Docetaxel), Temodar (Temozolomide), Temodar (Temozolomide injection), Tepadina (Thiotepa), Salomid (Thalidomide),theraCys BCG (BCG), Tioplex (thiotepa), TICE BCG (BCG), Toposal (etoposide injection), Tricel (temsirolimus), Tranda (bendamustine hydrochloride), Torelstar (triptorelin injection), Trexol (methotrexate), Trisenox (arsenic trioxide), Tykar (lapatinib), Unituxin (dinutuximab injection), Valstar (barrubicin intravesical injection), Vantus (histrelin implant), Vectibix (panitumumab), Vervan (vinblastine), Velcade (bortezomib), Bepecid (etoposide), Bepecid (etoposide injection), Besanoid (tretinoin), Vidaza (azacitidine), Vincasar PFS (vincristine), Vincrex (vincristine) This includes Botrient (pazopanib), Bumon (teniposide), Welcovorin IV (leucovorin injection), Zalkoli (crizotinib), Xeloda (capecitabine), Xtandi (enzalutamide), Yervoy (ipilimumab injection), Yondelis (trabectedin injection), Zaltrap (dibuaflibercept injection), Zanosal (streptozosin), Zelboraf (vemurafenib), Zevalin (ibritumomab tiucetane), Zoladex (goserelin), Zolinza (vorinostat), Zometa (zoledronic acid), Zoltores (everolimus), Zyderig (idelalisib), Zycadia (ceritinib), Zytiga (abiraterone), and others, as well as their analogs and derivatives. For example, approved targeted therapies include adtrastuzumab emtansine (Kadcyla), afatinib (Giotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campas), axitinib (Inrita), belimumab (Benlysta), belinostat (Bereodac), bevacizumab (Avastin), and bortezomib (Velcade). Bosutinib (Voslif), Brentuximab Vedotin (Adcetris), Cabozantinib (Cabometyx [tablets], Cometrix [capsules]), Canakinumab (Ilaris), Carfilzomib (Cyprolis), Ceritinib (Zykadia), Cetuximab (Erbitux), Cobimetinib (Cotelic), Crizotinib (Zalcoli), Dabrafenib (Tafinlar),Daratumumab (Darzalex), Dasatinib (Sprycel), Denosumab (Kusugeba), Dinutuximab (Unituxin), Elotuzumab (Empliciti), Erlotinib (Tarceva), Everolimus (Afinitor), Gefitinib (Iressa), Ibritumomab, Chiuxetan (Zevalin), Ibrutinib (Imbruvica), Idelalisib (Zyderig), Imatinib (Gleebeck), Ipilimumab (Yervoy), Ixazomib (Ninlaro), Lapatinib (Tykerb), Lenvatinib (Lenvima), Necitumumab (Portolaza), Nilotinib (Tasigna), Nivolumab (Opdivo), Obinutuzumab (Gazyva), Ofatumumab (Al Zera, HuMax-CD20), olaparib (Lymparza), osimertinib (Tagrisso), palbociclib (Ibrance), panitumumab (Vectibix), panobinostat (Faridac), pazopanib (Botrian), pembrolizumab (Keytruda), pertuzumab (Perjeta), ponatinib (Iclusig), ramucirumab (Cyramza), rapamycin, le Gorafenib (Stivarga), Rituximab (Rituxan, Mabucera), Romidepsin (Istodax), Ruxolitinib (Jakafi), Siltuximab (Sylvant), Cypreucel-T (Provenzi), Sirolimus, Sonidegib (Odomzo), Sorafenib (Nexavar), Sunitinib, Tamoxifen, Temsirolimus (Tricel), Tocilizumab (Actemra), Tofa This includes citinib (Xeljanz), tositumomab (Vexal), trametinib (Mekinist), trastuzumab (Herceptin), vandetanib (Caprelsa), vemurafenib (Zelboraf), venetoclax (Venclexta), bismodegib (Elivedge), vorinostat (Zolinza), dib-aflibercept (Zaltrap), and their analogs and derivatives.

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

[0250] immunotherapy In some embodiments, immunotherapy involves 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.), e.g., Oncophage, Cipleucel-T), immunomodulators (e.g., interleukins, cytokines, chemokines, etc.), topical immunotherapy (e.g., imiquimod, etc.), injectable immunotherapy, adoptive cell transfer, oncolytic virus therapy (e.g., tarimodine). This includes cell-based immunotherapies, such as rherpalepvec (T-VEC), immunosuppressants, helminth therapy, and other nonspecific 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 (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda). Nonspecific immunotherapy includes cytokines, interleukins, and interferons. In some embodiments, the immunotherapy assigned to or administered to the target is inter The treatment includes administration of one or more suitable antibody-based reagents such as leukin, and / or interferon (IFN), and / or denileuxin difutitox, and / or an antibody-based reagent selected from the group consisting of ad-trastuzumab, emtansine, alemtuzumab, atezolizumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, catumakisomab, gemtuzumab, ibritumomab tiucetan, iripimumab, natalizumab, nimotuzumab, nivolumab, ofatumumab, panitumumab, pembrolizumab, rituximab, tocitumomab, trastuzumab, vivataxin, etc.In some embodiments, the immunotherapy assigned to or administered to the subject may include indoleamine 2,3-dioxygenase (IDO) inhibitors, adoptive T-cell therapy, viral therapy (T-VEC), and / or any other immunotherapy whose efficacy is significantly dependent on antitumor immunity.

[0251] Those skilled in the art can determine appropriate immunotherapy options, including approved therapies and those in clinical trials or development. In implementing this disclosure, any relevant immunotherapy treatment strategy can be used alone or in combination with one or more further cancer therapies.

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

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

[0254] Dosage and route of administration Other embodiments of the Disclosure may include methods of administering or treating animals / humans, and may include treatment using an amount of at least one compound of the Disclosure (e.g., formula (I)) that is effective in treating or inducing a desired physiological effect in an organism having, suspected to be having, or being susceptible to, a disease, condition, or disorder. In some embodiments, a composition or pharmaceutical composition comprises at least one compound of the present disclosure (e.g., formula (I)) that can be administered to an animal (e.g., a mammal, primate, monkey, or human) in an amount of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, or about 15 mg / kg. Under certain conditions, the dose may be approximately 0.5 mg / kg human body weight or approximately 6.5 mg / kg human body weight. In some cases, certain subjects (e.g., mammals, mice, rabbits, cats, pigs, or dogs) may be administered doses of approximately 0.005 to approximately 50 mg / kg body weight, approximately 0.01 to approximately 15 mg / kg body weight, approximately 0.1 to approximately 10 mg / kg body weight, approximately 0.5 to approximately 7 mg / kg body weight, approximately 0.005 mg / kg, approximately 0.01 mg / kg, approximately 0.05 mg / kg, approximately 0.1 mg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 40 mg / kg, approximately 50 mg / kg, approximately 80 mg / kg, approximately 100 mg / kg, or approximately 150 mg / kg. Needless to say, those skilled in the art will understand that various concentrations can be used in the methods of this disclosure to find the concentration that achieves the desired result in a given situation, and that any number of concentrations can be prepared and tested using some of the guidelines provided herein.In some embodiments, the dose or therapeutically effective dose of the compounds disclosed herein is an amount sufficient to achieve a plasma concentration of the compound or its active metabolite within the ranges shown herein, for example, 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM, 0.1 to 1 μM, 1 to 10 μM, 10 to 100 μM, 100 to 200 μM, 200 to 500 μM, or 500 to 1000 μM, preferably about 1 to 10 nM, 10 to 100 nM, or 0.1 to 1 μM. While we do not wish to be bound by any theory, such compounds are considered to be applicable to the treatment or management of hematopoietic cancers such as MDS and / or AML and / or DLBCL, other types of cancer described herein, inflammatory conditions and / or autoimmune diseases.

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

[0256] Compounds and pharmaceutical compositions are preferably prepared and administered in dose units. Solid dose units are tablets, capsules, and suppositories. Different daily doses may be used for the treatment of the target, depending on the activity of the compound, the method of administration, the nature and severity of the disease or disorder, and the age and weight of the target.

[0257] However, in certain circumstances, a higher or lower daily dose may be appropriate. The daily dose can be administered as a single dose in the form of individual dose units or several other smaller dose units, or as multiple doses of divided doses at specific intervals.

[0258] The compounds and pharmaceutical compositions intended herein can be administered topically or systemically in therapeutically effective doses. The effective dose naturally depends on the severity of the disease or disorder, as well as the subject's body weight and overall condition. Doses typically used in vitro can provide useful guidelines for effective doses of pharmaceutical compositions administered in situ, and animal models can be used to determine effective doses for treating specific disorders.

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

[0260] However, it is understood that the specific dose level for a particular patient depends on various factors, including the activity of the particular compound used, age, weight, general health status, sex, diet, administration time, route of administration, excretion rate, concomitant use of other drugs, and the severity of the particular disease being treated.

[0261] In some embodiments, the compound and / or pharmaceutical composition may contain a unit dose of one or more compounds of the Disclosure (e.g., the compound of formula (I) and a pharmaceutical composition comprising it) in combination with a pharmaceutically acceptable carrier, and may further contain other agents, pharmaceuticals, carriers, adjuvants, diluents, and excipients. In certain embodiments, the carrier, vehicle, or excipient may facilitate the administration, delivery, and / or improve the storage of the composition. In other embodiments, the one or more carriers may include, but are not limited to, saline solutions such as physiological saline, Ringer's solution, PBS (phosphate-buffered saline), and mixtures of various salts, including potassium salts and phosphates, with or without sugar additives such as glucose. The carrier may include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, bactericidal antibiotics, and formulations that are isotonic with the body fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. In other embodiments, one or more excipients may include, but are not limited to, water, saline solution, dextrose, glycerol, ethanol, and combinations thereof. Non-toxic auxiliary substances 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.

[0262] The amount of the active ingredient in a unit dose formulation can be changed or adjusted within the range of 0.1 mg to 10,000 mg, more typically 1.0 mg to 1,000 mg, and most typically 10 mg to 500 mg, depending on the specific use and the potency of the active ingredient. The composition may also contain other suitable therapeutic agents as desired.

[0263] The compounds of this disclosure (e.g., compounds relating to formula (I)) can be administered to subjects by any number of suitable routes of administration or formulations. The compounds of this disclosure (e.g., formula (I)) can also be used to treat a variety of diseases of 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, birds (e.g., chickens), mice, rabbits, and rats. As used herein, the term “subject” encompasses both human and non-human subjects unless otherwise specified.

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

[0265] Some embodiments of the present disclosure are methods for giving a subject a composition (e.g., a pharmaceutical composition) comprising one or more compounds of the present disclosure described herein (e.g., formula (I)), comprising one or more doses of one or more such compositions, wherein if there are multiple doses, the compositions may be the same or different.

[0266] toxicity The ratio between the toxicity and therapeutic effect of a particular compound is its therapeutic index, LD50. 50 (The amount of a compound that is lethal to 50% of the population) and ED 50It can be expressed as a ratio between (the amount of the compound effective in 50% of the population). Compounds exhibiting a high therapeutic index are preferred. Therapeutic index data obtained from in vitro assays, cell culture assays, and / or animal studies can be used when formulating dose ranges for use in humans. The dose of such a compound should have little to no toxicity and be ED-free. 50 It is preferable that the plasma concentration be within the range of [specific range]. The dose may vary within this range depending on the dosage form used and the route of administration utilized. See, for example, Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch.1, pl, 1975. The exact formulation, route of administration, and dose can be selected by each practitioner, taking into account the patient's condition and the specific method by which the compound is used. In the case of in vitro formulations, the exact formulation and dose may be selected by each practitioner, taking into account the patient's condition and the specific method by which the compound is used.

[0267] While this disclosure has been described in detail, it is clear that modifications, alterations, and equivalent embodiments are possible without departing from the scope of this disclosure as set forth in the attached claims. Furthermore, it should be understood that all examples in this disclosure are given as non-limiting examples.

[0268] The following sections describe specific embodiments.

[0269] Term 1. Formula (I): [ka] Compounds selected from, or their salts, esters, solvates, optical isomers, geometric isomers, salts of isomers, prodrugs, or derivatives. (In the formula, R 1The elements are H, halogen, hydroxyl, oxo, -CN, amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl are halogen, hydroxyl It may be substituted with one or more of the following: C1-C7 alkyl, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl; R 2The elements are H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, heteroaryl, or condensed ring heteroaryl, and the amino, O-aryl, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl are halogen, hydroxy, oxo, methyloyl(- It may be substituted with one or more of the following: COH), carboxy(-CO2H), nitro(-NO2), -NH2, -NHCH3, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, condensed ring aryl, heteroaryl, condensed ring heteroaryl, or cycloalkyl-substituted C1-C7 alkyl; R 3 , R 4 , and R 5The following are independently selected from H, halogen, hydroxyl, oxo, -CN, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, wherein the methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl are halogen, hydroxyl It may be substituted with one or more of the following: C1-C7 alkyl, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl; R 6 teeth, [ka] And R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14The elements are independently selected from H, halogen, hydroxyl, oxo, -CN, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, wherein the methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 The elements are independently selected from H, halogen, hydroxyl, oxo, -CN, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, wherein the methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and u+v+w+x is at least 1.

[0270] Section 2.R 1 The compound according to item 1, wherein is H, halogen, -CONH2, -CONHCH3, -CON(CH3)2, benzyl, C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl, wherein the C1-C7 alkyl, C1-C7 alkoxy, or cycloalkyl may be substituted with one or more halogens, hydroxyl, C1-C7 alkyl, or C1-C7 haloalkyl.

[0271] Section 3.R 1 The compound according to claim 1 or claim 2, wherein is H, Cl, -CONH2, -CONHCH3, methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl, and the methoxy, ethoxy, cyclopropyl, or C1-C4 alkyl may be substituted with one or more F, -OH, methoxy, or CF3.

[0272] Section 4.R 1 The compound described in item 1 or item 2, which is not H.

[0273] Section 5.R 2 The elements are H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, condensed ring aryl, heteroaryl, or condensed ring heteroaryl, and the aforementioned O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, condensed ring aryl, heteroaryl, or condensed ring heteroaryl. The compound described in any of claims 1 to 3 is a compound that may be substituted with one or more of the following: halogen, hydroxy, -CN, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused ring aryl, fused ring heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or a C1-C7 alkyl substituted with a cycloalkyl.

[0274] Section 6.R2 The compound according to any one of claims 1 to 5, wherein is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, condensed ring aryl, heteroaryl, or condensed ring heteroaryl, and the O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more of halogen, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or a C1-C7 alkyl substituted with a cycloalkyl.

[0275] Section 7.R 2 The compound is one of the compounds described in any of items 1 to 6, wherein is H, Cl, hydroxy, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -OCHF2, -OPh, -CF3, -CHF2, unsubstituted C1-C7 alkyl, substituted amino, substituted C1-C7 alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted condensed ring heteroaryl, or unsubstituted condensed ring heteroaryl.

[0276] Section 8.R 2 is a compound that is not H, as described in any of items 1 to 5.

[0277] Section 9.R 3The C1-C7 alkyl or C2-C6 alkoxy is H, halogen, hydroxyl, -CN, methanolyyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy is halogen, hydroxyl, methanolyyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), hetero A compound according to any one of claims 1 to 8, which may be substituted with one or more of the following: cyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or a C1-C7 alkyl substituted with a cycloalkyl.

[0278] Section 10.R 3 The compound is one of the compounds described in any of items 1 to 9, wherein is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.

[0279] Section 11.R 4 The C1-C7 alkyl or C2-C6 alkoxy is H, halogen, hydroxyl, -CN, methanolyyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy is halogen, hydroxyl, methanolyyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterosyl A compound according to any one of claims 1 to 10, which may be substituted with one or more of the following: krill, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl.

[0280] Section 12.R4 The compound is one of the compounds described in any of items 1 to 11, wherein is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.

[0281] Section 13.R 5 The C1-C7 alkyl or C2-C6 alkoxy is H, halogen, hydroxyl, -CN, methanolyyl (-COH), carboxyl (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy is halogen, hydroxyl, methanolyyl (-COH), carboxyl (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterosyl A compound according to any one of claims 1 to 12, which may be substituted with one or more of the following: krill, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl.

[0282] Section 14.R 5 The compound is one of the compounds described in any of items 1 to 13, wherein is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.

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

[0284] Section 16.R 6 The following: [ka] A compound as described in any of items 1 to 15.

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

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

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

[0288] Section 20.R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 The compound is one of the compounds listed in items 1 to 17, wherein H is present in all cases.

[0289] Section 21.R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14The compound according to any one of claims 1 to 20, wherein is independently selected from H, halogen, hydroxyl, oxo, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl, wherein the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spirocondensed cycloalkyl may be substituted with one or more halogens.

[0290] Section 22.R 7 , R 8 , R 9 , and R 10 is H, and R 11 , R 12 , R 13 , and R 14 The compound according to claim 21, wherein at least one of is a halogen, hydroxyl, oxo, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl, and the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spirocondensed cycloalkyl may be substituted with one or more halogens.

[0291] Section 23.R 11 , R 12 , R 13 , and R 14 is H, and R 7 , R 8 , R 9 , and R 10 The compound according to claim 21, wherein at least one of is a halogen, hydroxyl, oxo, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl, and the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spirocondensed cycloalkyl may be substituted with one or more halogens.

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

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

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

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

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

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

[0298] Section 30.R 6 The following: [ka] A compound as described in any of items 1 to 15.

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

[0300] Compound according to any of items 1 to 15 or 30 to 31, item 32.q is 0 or 1, r is 0 or 1, s is 0 or 1, t is 0 or 1, u is 0 or 1, v is 0 or 1, w is 0 or 1, and x is 0 or 1.

[0301] Section 33.R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30The compound according to any one of claims 1 to 15 or 30 to 32, wherein is independently selected from H, halogen, hydroxyl, oxo, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spirocondensed cycloalkyl, wherein the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spirocondensed cycloalkyl may be substituted with one or more halogens.

[0302] Section 34.R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 If 1 or more of these is H, or 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 The compounds described in any of items 1 to 15 or 30 to 33, wherein H is present in all cases.

[0303] Section 35.R 6 The following: [ka] The compound described in any of items 1 to 15 or 30 to 34.

[0304] Section 36.R 6 The following: [ka] The compound described in any of items 1 to 15 or 30 to 35.

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

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

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

[0308] Item 40. A composition comprising any of the compounds described in items 1 to 39.

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

[0310] Item 42. The composition according to item 40 or 41, further comprising a compounding component, an adjuvant, or a carrier.

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

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

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

[0314] Item 46. The composition according to any one of items 40 to 45, used in combination with one or more chemotherapy drugs, 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, mAb / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, Smound receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof.

[0315] Item 47. The DNA methyltransferase / hypomethylating agent comprises azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a constant molar ratio of 5:1); the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valproic acid , and / or prasinostat; the purine nucleoside analog (antmetabolite) comprises fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor comprises ivosidenib and / or enasidenib; the antibody drug conjugate comprises anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-A pamistamab) is included; the mAb / immunotherapy comprises anti-CD70 (e.g., ARGX-110, xatuzumab), bispecific antibodies (e.g., floteuzumab (CD123×CD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453) and / or anti-CD47 (e.g., 5F9 (maglorimab)); the Plk inhibitor comprises volasertib and / or rigosatib; the MEK inhibitor comprises trametinib, cobimetinib, The CDK9 inhibitor comprises selumetinib, pimacertib, and / or refametinib; the CDK9 inhibitor comprises arbocidib and / or borciclib; the CDK8 inhibitor comprises SEL120; the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activator comprises APR-246 (Eprenetapt); the smoothed receptor antagonist comprises glass-de-gib; the ERK inhibitor comprises urixerutinib, SCH772984, and The PI3K inhibitor comprises voxertinib, MK-8353, and / or VTX-11e, or an ERK2 / MAPK1 inhibitor or an ERK1 / MAPK3 inhibitor; the PI3K inhibitor comprises fimepinostat (CUDC-907), alpelisib, reniolisib (CDZ-173), piraralisib (XL147, SAR245408), and / or vimiralisib (PQR-309); the mTOR inhibitor comprises vimiralisib (PQR-309), sapanicertib (TAK-228, INK-128), ridafololimus (MK-8669, AP-23573), eve The composition according to any one of claims 40 to 46, comprising: lolimus, viscertib (AZD2014); the glucocorticoid receptor modulator being an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol; and / or an antagonist comprising mifepristone, myricolinant, and / or onapristone; and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor comprising tazemetostat.

[0316] Item 48. A method for providing a compound, comprising one or more doses of one or more compositions containing a compound described in any of items 1 to 39, wherein, if there are multiple doses, the compositions may be the same or different.

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

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

[0319] Item 51. The method according to any one of items 48 to 50, wherein at least one of the one or more doses includes parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, local administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.

[0320] Item 52. The method according to any one of items 48 to 51, wherein, if there are multiple doses, at least one composition used in at least one dose is different from the composition of at least one other dose.

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

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

[0323] Item 55. A method for treating a disease or disorder, comprising one or more doses to a subject of one or more compositions comprising a compound described in any of items 1 to 39, wherein the compositions may be the same or different if there are multiple doses.

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

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

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

[0327] Item 59. The method according to any one of items 55 to 58, wherein at least one of the one or more doses includes parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, local administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.

[0328] Item 60. The method according to any one of items 55 to 59, wherein at least one of the one or more doses is administered orally.

[0329] Item 61. The method according to any one of items 55 to 60, wherein, if there are multiple doses, at least one composition used in at least one dose is different from the composition of at least one other dose.

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

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

[0332] Item 64. The method described in any of items 55 to 63, wherein the subject is in need of the treatment described above.

[0333] Item 65. The method described herein, which is for the treatment of hematopoietic cancer, as described in any of items 55 to 64.

[0334] Item 66. The method according to any one of items 55 to 65, wherein the method is for the treatment of myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML).

[0335] Item 67. The method according to any one of items 55 to 65, wherein the method is for the treatment of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.

[0336] Item 68. The method according to any one of items 55 to 64, for the treatment of at least one cancer selected from glioblastoma polymorphoni, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by hyperactive IRAK1 and / or IRAK4, or a combination thereof.

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

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

[0339] Item 71. The method described above is for treating DLBCL, wherein the DLBCL comprises the L265P MYD88 variant (ABC) subtype of DLBCL, as described in any of items 55 to 67.

[0340] Item 72. The method according to item 71, further comprising administering a composition comprising a BTK inhibitor.

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

[0342] Section 74. The subject is susceptible to AML and / or MDS, and / or the method is used to prevent or improve future AML and / or MDS, according to any method in Sections 55 to 73.

[0343] Item 75. The method according to any one of items 55 to 74, performed after one or more of the following: contraction of myelodysplastic syndrome, contraction of myeloproliferative disorder, occurrence of exposure to chemicals, exposure to ionizing radiation, or treatment of cancer.

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

[0345] Item 77. The method according to any one of items 55 to 76, wherein the compound described in any one of items 1 to 39 and the BCL2 inhibitor may be administered together or separately in one or more doses of one or more compositions.

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

[0347] Item 79. The method according to any one of items 55 to 78, further comprising the administration of one or more chemotherapy agents, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antmetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAb / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, Smound receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof.

[0348] Item 80. The DNA methyltransferase / hypomethylating agent comprises azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a constant molar ratio of 5:1); the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valproic acid , and / or prasinostat; the purine nucleoside analog (antmetabolite) comprises fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor comprises ivosidenib and / or enasidenib; the antibody drug conjugate comprises anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-A pamistamab) is included; the mAb / immunotherapy comprises anti-CD70 (e.g., ARGX-110, xatuzumab), bispecific antibodies (e.g., floteuzumab (CD123×CD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453) and / or anti-CD47 (e.g., 5F9 (maglorimab)); the Plk inhibitor comprises volasertib and / or rigosatib; the MEK inhibitor comprises trametinib, cobimetinib, The CDK9 inhibitor comprises selumetinib, pimacertib, and / or refametinib; the CDK9 inhibitor comprises arbocidib and / or borciclib; the CDK8 inhibitor comprises SEL120; the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activator comprises APR-246 (Eprenetapt); the smoothed receptor antagonist comprises glass-de-gib; the ERK inhibitor comprises urixerutinib, SCH772984, The PI3K inhibitor comprises laboxerutinib, MK-8353, and / or VTX-11e, or an ERK2 / MAPK1 inhibitor or an ERK1 / MAPK3 inhibitor; the PI3K inhibitor comprises fimepinostat (CUDC-907), alpelisib, reniolisib (CDZ-173), piraralisib (XL147, SAR245408), and / or vimiralisib (PQR-309); the mTOR inhibitor comprises vimiralisib (PQR-309), sapanicertib (TAK-228, INK-128), ridafololimus (MK-8669, AP-23573), and The method according to any one of claims 55 to 79, comprising verolimus, viscertib (AZD2014); the glucocorticoid receptor modulator comprising an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricolinant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor comprising tazemetostat.

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

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

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

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

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

[0354] Item 86. The compound according to any one of items 81 to 85, wherein at least one of the one or more doses includes oral administration.

[0355] Item 87. If there are multiple doses, at least one composition used in at least one dose is different from the composition of at least one other dose, according to any of the compounds in items 81 to 86.

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

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

[0358] Item 90. The subject is a compound according to any one of items 81 to 89, which is in need of treatment.

[0359] Item 91. The compound described in any of items 81 to 90, wherein the method is for the treatment of hematopoietic cancer.

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

[0361] Article 93. The method described above is for the treatment of at least one of the following: lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, according to any one of the compounds described in Articles 81 to 91.

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

[0363] Article 95. The compound described in Article 94, for the treatment of one or more inflammatory or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or combinations thereof.

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

[0365] Item 97. The method described above is for the treatment of DLBCL, wherein the DLBCL comprises a compound according to any one of items 81 to 93, comprising the L265P MYD88 variant (ABC) subtype of DLBCL.

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

[0367] Item 99. The BTK inhibitor is a compound according to item 98, comprising ibrutinib.

[0368] Item 100. The subject is susceptible to AML and / or MDS, and / or the method prevents or improves future AML and / or MDS, the compound according to any one of items 81 to 99.

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

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

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

[0372] Item 104. The BCL2 inhibitor is a compound according to any one of items 81 to 103, including venetoclax, or a salt, isomer, derivative, or analog thereof.

[0373] Item 105. The compound according to any one of items 81 to 104, further comprising the administration of one or more therapeutic agents selected from one or more chemotherapy regimens, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antametabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAb / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, Smound receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof.

[0374] Item 106. The DNA methyltransferase / hypomethylating agent comprises azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a constant molar ratio of 5:1); the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valpro The present invention comprises an acid and / or prasinostat; the purine nucleoside analog (antimetabolite) comprises fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor comprises ivosidenib and / or enasidenib; the antibody drug conjugate comprises anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-A pamistamab) is included; the mAb / immunotherapy comprises anti-CD70 (e.g., ARGX-110, xatuzumab), bispecific antibodies (e.g., floteuzumab (CD123×CD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453) and / or anti-CD47 (e.g., 5F9 (maglorimab)); the Plk inhibitor comprises volasertib and / or rigosatib; the MEK inhibitor comprises trametinib, cobimetinib, The CDK9 inhibitor comprises selumetinib, pimacertib, and / or refametinib; the CDK9 inhibitor comprises arbocidib and / or borciclib; the CDK8 inhibitor comprises SEL120; the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activator comprises APR-246 (Eprenetapt); the smoothed receptor antagonist comprises glass-de-gib; the ERK inhibitor comprises urixerutinib, SCH772984, and The PI3K inhibitor comprises voxertinib, MK-8353, and / or VTX-11e, or an ERK2 / MAPK1 inhibitor or an ERK1 / MAPK3 inhibitor; the PI3K inhibitor comprises fimepinostat (CUDC-907), alpelisib, reniolisib (CDZ-173), piraralisib (XL147, SAR245408), and / or vimiralisib (PQR-309); the mTOR inhibitor comprises vimiralisib (PQR-309), sapanicertib (TAK-228, INK-128), ridafololimus (MK-8669, AP-23573), evero The compound comprises limus, viscertib (AZD2014); the glucocorticoid receptor modulator is an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricolinant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor is a compound according to any one of claims 81 to 105, comprising tazemetostat.

[0375] Section 201. Formula (I): [ka] Compounds thereof, or their salts, esters, solvates, optical isomers, geometric isomers, salts of isomers, prodrugs, or derivatives. (In the formula, R 1 The ion is selected from H, halogen, hydroxyl, oxo, -CN, amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the amide, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl is halogen, hydroxyl It may be substituted with one or more of the following C1-C7 alkyl groups: roxy, oxo, methanoyl(-COH), carboxy(-CO2H), nitro(-NO2), -NH2, -NHCH3, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-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 cycloalkyl; R 2The elements are selected from H, halogen, hydroxyl, oxo, -CN, amino, O-aryl, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, heteroaryl, or condensed ring heteroaryl, and the amino, O-aryl, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl are halogen, hydroxyl, oxo, methyloyl (-COH), carboxy(-CO2H), nitro(-NO2), -NH2, -NHCH3, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, condensed ring aryl, heteroaryl, condensed ring heteroaryl, or C1-C7 alkyl substituted with cycloalkyl; R 3 , R 4 , and R 5Each of these is independently selected from H, halogen, hydroxyl, oxo, -CN, methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the methanolyyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl are halogens, hydrogens It may be substituted with one or more of the following: roxy, oxo, methanoyl(-COH), carboxy(-CO2H), nitro(-NO2), -NH2, -NHCH3, -N(CH3)2, cyano(-CN), ethynyl(-CCH), propynyl, sulfo(-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholine-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or cycloalkyl-substituted C1-C7 alkyl; R 6 teeth, [ka] And R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14Each of these is independently selected from H, halogen, hydroxyl, oxo, -CN, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 Each of these is independently selected from H, halogen, hydroxyl, oxo, -CN, methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the methyloyl(-COH), carboxy(-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and u+v+w+x is at least 1.

[0376] Section 202. The compound of formula (I) is formula (IIf): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; During the ceremony, R 20f The substituent is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O-(C3-C6 cycloalkyl), wherein the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogen, and the C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) may each be substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 21f , R 22f , and R 23f Each is independently selected from H and halogen; R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb The compound according to item 201, wherein each is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, and the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more halogen atoms.

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

[0378] Section 204.R 20fThe compound described in item 202 or 203, wherein H is present.

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

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

[0381] Item 207. The compound of formula (I) is formula (IIg): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; During the ceremony, R 20g It is selected from H and C1-C6 alkoxy; R 21g These include halogens, C1-C6 alkyls, C1-C6 alkoxys, C3-C6 cycloalkyls, and -O-(C6-C12 aryl), C3-C9 heterocyclyl, and -NR 28ga R 28gb Selected from the above, the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogens, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogens, and the C3-C9 heterocyclyl may be substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, and halogens; R 22g , R 23g , and R 24g Each is independently selected from H and halogen; R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of these is independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, and the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more halogen atoms; R 28ga and R 28gb The compounds described in item 201, each independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl.

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

[0383] Section 209.R 20g The compound described in item 207 or 208, wherein H is present.

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

[0385] Item 211. The compound is one of the compounds described in any of items 207 to 210, selected from the following: [ka] TIFF0007877318000212.tif158124TIFF0007877318000213.tif152124TIFF0007877318000214.tif154125JPEG0007877318000215.jpg125125

[0386] Item 212. The compound of formula (I) is formula (IIh): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, During the ceremony, R 20hIt is selected from H and C1-C6 alkoxy; R 21h The C1-C6 alkyl group is selected from C1-C6 alkyl groups, C3-C6 cycloalkyl groups, and C3-C9 heterocyclil groups, wherein the C1-C6 alkyl group may be substituted with one or more substituents selected from -OH groups and halogens, and the C3-C6 cycloalkyl group and C3-C9 heterocyclil group may each be substituted with one or more substituents selected from C1-C6 alkyl groups, -OH groups, and halogens; R 22ha , R 22hb , R 23ha , and R 23hb Each of these is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl may be substituted with one or more halogen atoms; R 24h , R 25h , and R 26h The compounds described in item 212, each independently selected from H and halogens.

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

[0388] Item 214. The compound is one of the compounds described in item 212 or 213, which is one of the compounds described below. [ka]

[0389] Section 215. The compound of formula (I) is formula (IIi): [ka] A compound of, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, During the ceremony, the below described: [ka] The following: [ka] Selected from; R 20i It is selected from H and C1-C6 alkoxy; R 21i The C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclil are selected from C1-C6 alkyl and C1-C6 alkoxy, respectively, and the C1-C6 alkyl and C1-C6 alkoxy may each be substituted with one or more substituents selected from -OH and halogens, the C3-C6 cycloalkyl may be substituted with one or more substituents selected from C1-C6 alkyl and halogens, and the C3-C9 heterocyclil may be substituted with one or more substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclil, -OH, -C=O, and halogens; R 22i , R 23i , and R 24i Each is independently selected from H and halogen; R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ibEach of these is independently selected from H, halogen, -OH, or C1-C6 alkyl, and is a compound as described in item 201.

[0390] Section 216.R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib One or more of the compounds are independently selected from halogens, -OH groups, and C1-C6 alkyl groups, as described in item 215.

[0391] Section 217.R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib Each of the compounds is H, as described in item 215.

[0392] Item 218. A compound described in any of items 215 to 217, wherein at least one of (i) to (xi) below is met. (i)R 20i This is selected from H and -OCH3; (ii)R 21i The following: [ka] , unsubstituted C3 cycloalkyl, see below: [ka] (wherein J is N or CH), and below: [ka] Selected from; (iii)R 21i The following: [ka] And in the formula, R 220i H, -CH3, below: [ka] and selected from unsubstituted C3 cycloalkyl groups; (iv)R 22i , R 23i , and R 24i These are H, respectively; (v)R 22i and R 24i These are F and R respectively. 23i H is; (vi)R 22i and R 24i These are H and R respectively. 23i is F; (vii) See below: [ka] The following: [ka] And R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib Each of them is H, and R 25ib is F; (viii) See below: [ka] The following: [ka] And R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ibEach of them is H; (ix) Se...

Claims

1. A compound, or a salt, ester, solvate, optical isomer, geometric isomer thereof, or a salt of the optical isomer or geometric isomer thereof, characterized by being represented by the following formula (I). 【Chemistry 1】 (In the formula: R ７ , ３ is selected from H, halogen, hydroxy, oxo, -CN, amide, methanoyl (-COH), carboxy (-CO ２ H), C １ -C ７ alkyl, C ２ -C ７ alkenyl, C ２ -C ７ alkynyl, C １ -C ７ heteroalkyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and the amide, methanoyl (-COH), carboxy (-CO ２ H), C<000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ １ -C ７ Perfluoroalkyl, C １ -C ７ Alkoxy, C １ -C ７ C substituted with haloalkoxy or cycloalkyl １ -C ７ It may be substituted with one or more alkyl groups; R ２ H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methyl(-COH), carboxy(-CO) ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Selected from alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, aryl, heteroaryl, or condensed ring heteroaryl, and the amino, O-aryl, methyl(-CO), carboxy(-CO) ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Heteroalkyl, C １ -C ７ Alkoxy, cycloalkyl, heterocyclyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl are halogens, hydroxy, oxo, methanol (-COH), carboxy (-COH). ２ H), Nitro (-NO ２ ), -NH ２ , - NHCH ３ , -N(CH ３ ) ２ cyano(-CN), ethinyl(-CCH), propynyl, sulfo(-SO) ３ H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , C １ -C ７ Alkyl, C １ -C ７ Heteroalkyl, C １ -C ７ Haloalkyl, C １ -C ７ perfluoroalkyl, C １ -C ７ alkoxy, C １ -C ７ haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused-ring aryl, heteroaryl, fused-ring heteroaryl, or C substituted with cycloalkyl １ -C ７ may be substituted with one or more of alkyl; R ３ 、R ４ 、and R ５ are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO ２ OH), C １ -C ７ alkyl, C ２ -C ７ alkenyl, C ２ -C ７ alkynyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein the methanoyl (-COH), carboxy (-CO ２ OH), C １ -C ７ alkyl, C ２ -C ７ alkenyl, C ２ -C ７ alkynyl, C １ -C ７ alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl are halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO ２ OH), nitro (-NO ２ ), -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO ３ OH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , C １ -C ７ alkyl, C １ -C ７ haloalkyl, C １ [[ID=七十二]]-C ７ perfluoroalkyl, C １ -C ７ Alkoxy, C １ -C ７ C substituted with haloalkoxy or cycloalkyl １ -C ７ It may be substituted with one or more alkyl groups; R ６ teeth, 【Chemistry 2】 And R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ These are, independently, H, halogen, hydroxyl, oxo, -CN, methanolyyl (-COH), and carboxyl (-CO). ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Selected from alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, or R7 and R8, R9 and R10, R11 and R12, or R13 and R14 are bonded to form a spirocondensed cycloalkyl, and the methanoly(-CO) and carboxy(-CO) compounds are used. ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens; R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２９ , R ２９ , and R ３０ These are, independently, H, halogen, hydroxyl, oxo, -CN, methanolyyl (-COH), and carboxyl (-CO). ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Selected from alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl, and the methanoly(-CO) and carboxy(-CO) compounds. ２ H), C １ -C ７ Alkyl, C ２ -C ７ Alkenil, C ２ -C ７ Alkinyl, C １ -C ７ Alkoxy, cycloalkyl, spirocondensed cycloalkyl, heterocyclyl, aryl, heteroaryl, or condensed ring heteroaryl may be substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q + r + s + t is at least 1, and u + v + w + x is at least 1.

2. The compound of the following formula (IIf), or its salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer; 【Transformation 3】 (In the formula: R ２０ｆ H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl and -O-(C ３ -C ６ Selected from cycloalkyl, the C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from -OH and halogens, and the C ３ -C ６ Cycloalkyl and -O-(C ３ -C ６ Cycloalkyls are, respectively, C １ -C ６ They may be substituted with one or more substituents selected from alkyl and halogen; R ２１ｆ , R ２２ｆ , and R ２３ｆ Each is independently selected from H and halogen; R ２４ｆａ , R ２４ｆｂ , R ２５ｆａ , R ２５ｆｂ , R ２６ｆａ , and R ２６ｆｂ These are H, halogen, -OH, and C, respectively, independently. １ -C ６ Alkyl and C １ -C ６ Selected from alkoxy, the C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more halogen atoms), or The compound of the following formula (IIg), or its salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer; 【Chemistry 4】 (In the formula: R ２０ｇ H and C １ -C ６ Selected from alkoxy; R ２１ｇ is halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, -O-(C ６ -C １２ Aryl), C ３ -C ９ Heterocyclyl, heteroaryl and -NR ２８ｇａ R ２８ｇｂ Selected from, the C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from -OH and halogens, and the C ３ -C ６ Cycloalkyl is C １ -C ６ The C may be substituted with one or more substituents selected from alkyl and halogens. ３ -C ９ Heterocyclyls and heteroaryls are C １ -C ６ Alkyl, C ３ -C ６ - Cycloalkyl, C ３ -C ９ - It may be substituted with one or more substituents selected from heterocyclyl, -OH, and halogens; R ２２ｇ , R ２３ｇ , and R ２４ｇ Each is independently selected from H and halogen; R ２５ｇａ , R ２５ｇｂ , R ２６ｇａ , R ２６ｇｂ , R ２７ｇａ , and R ２７ｇｂ These are H, halogen, -OH, and C, respectively, independently. １ -C ６ Alkyl and C １ -C ６ Selected from alkoxy, the C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more halogen atoms; R ２８ｇａ and R ２８ｇｂ These are H and C, respectively, independently. １ -C ６ Alkyl and C ３ -C ６ Selected from cycloalkyl groups), A compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer described in claim 1.

3. R ２４ｆａ , R ２４ｆｂ , R ２５ｆａ , R ２５ｆｂ , R ２６ｆａ , and R ２６ｆｂ One or more of these may independently be a halogen, -OH, or a substituted C １ -C ６ Alkyl and optionally substituted C １ -C ６ Selected from alkoxy, or R ２５ｇａ , R ２５ｇｂ , R ２６ｇａ , R ２６ｇｂ , R ２７ｇａ , and R ２７ｇｂ One or more of these may independently be a halogen, -OH, or a substituted C １ -C ６ Alkyl and optionally substituted C １ -C ６ Selected from alkoxy, The compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer described in claim 2.

4. R ２０ｆ is H, or R ２０ｇ H is A compound or a salt thereof, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to claim 2 or 3.

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

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

7. A compound of the following formula (IIh), or a salt, ester, solvate, optical isomer, geometric isomer thereof, or a salt of said optical isomer or geometric isomer; 【Chemistry 19】 (In the formula: R ２０ｈ H and C １ -C ６ Selected from alkoxy; R ２１ｈ C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C3-C ９ Selected from heterocyclyls and heteroaryls, the C １ -C ６ The alkyl group may be substituted with one or more substituents selected from -OH and halogens, and the C ３ -C ６ Cycloalkyl, C ３ -C ９ Heterocyclyls and heteroaryls are, respectively, C １ -C ６ It may be substituted with one or more substituents selected from alkyl, -OH, and halogen; R ２２ｈａ , R ２２ｈｂ , R ２３ｈａ , and R ２３ｈｂ These are H and C, respectively, independently. １ -C ６ Selected from alkyl, the C １ -C ６ Alkyl may be substituted with one or more halogen atoms; R ２４ｈ , R ２５ｈ , and R ２６ｈ (Each is independently selected from H and halogen), or The compound of the following formula (IIIi), or its salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer; 【Chemistry 20】 (In the formula: the below described: 【Chemistry 21】 The following: 【Chemistry 22】 Selected from; R ２０ｉ H and C １ -C ６ Selected from alkoxy; R ２１ｉ C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, C3-C ９ Selected from heterocyclyls and heteroaryls, the C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from -OH and halogens, and the C ３ -C ６ Cycloalkyl is C １ -C ６ The C may be substituted with one or more substituents selected from alkyl and halogens. ３ -C ９ Heterocyclyls and heteroaryls are, respectively, C １ -C ６ Alkyl, C ３ -C ６ - Cycloalkyl, C ３ -C ９ - It may be substituted with one or more substituents selected from heterocyclyl, -OH, oxo, and halogens; R ２２ｉ , R ２３ｉ , and R ２４ｉ Each is independently selected from H and halogen; R ２５ｉａ , R ２５ｉｂ , R ２６ｉａ , R ２６ｉｂ , R ２７ｉａ , R ２７ｉｂ , R ２８ｉａ , R ２８ｉｂ , R ２９ｉａ , and R ２９ｉｂ These are, independently, H, halogen, -OH, or C. １ -C ６ Selected from alkyl groups), A compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer described in claim 1.

8. R ２５ｉａ , R ２５ｉｂ , R ２６ｉａ , R ２６ｉｂ , R ２７ｉａ , R ２７ｉｂ , R ２８ｉａ , R ２８ｉｂ , R ２９ｉａ , and R ２９ｉｂ One or more of these are, independently, halogen, -OH, and C １ -C ６ A compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to claim 7, selected from alkyl groups.

9. R ２５ｉａ , R ２５ｉｂ , R ２６ｉａ , R ２６ｉｂ , R ２７ｉａ , R ２７ｉｂ , R ２８ｉａ , R ２８ｉｂ , R ２９ｉａ , and R ２９ｉｂ Each of the isomers is H, the compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to claim 7.

10. The compound is a compound of formula (IIh) and at least one of the following (i) to (iv): (i) R ２０ｈ H is; (ii) R ２１ｈ The following: 【Chemistry 23】 It is; (iii) R ２２ｈａ , R ２２ｈｂ , R ２３ｈａ , and R ２３ｈｂ These are H, respectively; (iv)R ２４ｈ , R ２５ｈ , and R ２６ｈ These are H, or The compound is a compound of formula (IIIi) and at least one of the following (i) to (xi) is met: (i) R ２０ｉ H and -OCH ３ Selected from; (ii) R ２１ｉ The following: 【Chemistry 24】 , unsubstituted C ３ Cycloalkyl, see below: 【Chemistry 25】 (wherein J is N or CH), and below: 【Chemistry 26】 Selected from; (iii) R ２１ｉ The following: 【Chemistry 27】 And in the formula, R ２２０ｉ H, -CH ３ ,the below described: 【Chemistry 28】 and non-substituted C ３ Selected from cycloalkyl groups; (iv)R ２２ｉ , R ２３ｉ , and R ２４ｉ These are H, respectively; (v) R ２２ｉ and R ２４ｉ These are F and R respectively. ２３ｉ H is; (vi)R ２２ｉ and R ２４ｉ These are H and R respectively. ２３ｉ F is; (vii) See below: 【Chemistry 29】 The following: 【Transformation 30】 And R ２５ｉａ , R ２６ｉａ , R ２６ｉｂ , R ２７ｉａ , R ２７ｉｂ , R ２８ｉａ , and R ２８ｉｂ Each of them is H, and R ２５ｉｂ F is; (viiii) Below: 【Chemistry 31】 The following: 【Chemistry 32】 And R ２５ｉａ , R ２５ｉｂ , R ２６ｉａ , R ２６ｉｂ , R ２７ｉａ , R ２７ｉｂ , R ２８ｉａ , and R ２８ｉｂ Each of them is H; (ix) See below: 【Transformation 33】 The following: 【Transformation 34】 And R ２５ｉａ , R ２５ｉｂ , R ２７ｉａ , R ２７ｉｂ , R ２８ｉａ , R ２８ｉｂ、 R ２９ｉａ , and R ２９ｉｂ Each of them is H; (x) See below: 【Chemistry 35】 The following: 【Transformation 36】 And R ２５ｉａ , R ２５ｉｂ , R ２７ｉａ , R ２７ｉｂ , R ２８ｉａ , R ２９ｉａ , and R ２９ｉｂ Each of them is H, and R ２８ｉｂ F is; (xi) Below: 【Chemistry 37】 The following: 【Transformation 38】 And R ２５ｉａ , R ２５ｉｂ , R ２７ｉａ , R ２８ｉａ , R ２８ｉｂ , R ２９ｉａ , and R ２９ｉｂ Each of them is H, and R ２７ｉｂ F is A compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to any one of claims 7 to 9.

11. The compound is selected from the following: a compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to any one of claims 7 to 10. 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】

12. The compound of the following formula (IIj), or its salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer: 【Chemistry 43】 (In the formula: the below described: 【Chemistry 44】 The following: 【Chemistry 45】 Selected from; R ２０ｊ H and C １ -C ６ Selected from alkoxy; R ２１ｊ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy and C ３ -C ６ Selected from cycloalkyl, the C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from halogens and -OH groups, and the C ３ -C ６ Cycloalkyl is C １ -C ６ They may be substituted with one or more substituents selected from alkyl and halogen; R ２２ｊ , R ２３ｊ , and R ２４ｊ (Each is independently selected from H and halogen), or The compound of the following formula (IIIq) or its salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer; 【Chemistry 46】 (In the formula: R ３０ｑ H and C １ -C ６ Selected from alkoxy; R ３１ｑ C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, C3-C ９ Selected from heterocyclyls and heteroaryls, the C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from -OH and halogens, and the C ３ -C ６ Cycloalkyl is C １ -C ６ The C may be substituted with one or more substituents selected from alkyl and halogens. ３ -C ９ Heterocyclyls and heteroaryls are, respectively, C １ -C ６ Alkyl, C ３ -C ６ - Cycloalkyl, C ３ -C ９ - Heterocyclyl, C ６ -C １２ It may be substituted with one or more substituents selected from aryl, -OH, oxo, and halogen; R ３２ｑ , R ３３ｑ , and R ３４ｑ Each of these is independently selected from H and halogen. A compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer described in claim 1.

13. The compound is of formula (IIj) and satisfies at least one of the following conditions (i) to (iv): (i) R ２０ｊ H and -OCH ３ Selected from; (ii) R ２１ｊ is unsubstituted C ３ It is cycloalkyl; (iii) R ２２ｊ , R ２３ｊ , and R ２４ｊ These are H, respectively; (iv) See below: 【Chemistry 47】 The following: 【Chemistry 48】 is, or The compound is of formula (IIIq) and satisfies at least one of the following (i) to (iv): (i) R ３０ｑ H is; (ii) R ３１ｑ The following: 【Chemistry 49】 (wherein d is 1 or 2), and below: [Transformation 50] (wherein K is selected from N or CH); (iii) R ３１ｑ The following: 【Chemistry 51】 And in the formula, R ３５ｑ H, -CH ３ Selected from isopropyl, phenyl, azetidinyl, and tetrahydropyranil; (iv)R ３２ｑ , R ３３ｑ , and R ３４ｑ These are H, A compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to claim 12.

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

15. A compound of the following formula (IIIr), or a salt, ester, solvate, optical isomer, geometric isomer thereof, or a salt of said optical isomer or geometric isomer; 【Chemistry 54】 (In the formula: R ３０ｒ C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, C3-C ９ Selected from heterocyclyls and heteroaryls, the C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from -OH and halogens, and the C ３ -C ６ Cycloalkyl is C １ -C ６ The C may be substituted with one or more substituents selected from alkyl and halogens. ３ -C ９ Heterocyclyls and heteroaryls are, respectively, C １ -C ６ Alkyl, C ３ -C ６ - Cycloalkyl, C ３ -C ９ - Heterocyclyl, C ６ -C １２ It may be substituted with one or more substituents selected from aryl, -OH, oxo, and halogen; R ３１ｒ H and C １ -C ６ Selected from alkoxy; R ３２ｒ , R ３３ｒ , and R ３４ｒ (Each is independently selected from H and halogen), or A compound of the following formula (IIIs) or its salt, ester, solvate, optical isomer, geometric isomer, or salt of said optical isomer or geometric isomer; 【Transformation 55】 (In the formula: R ３０ｓ H and C １ -C ６ Selected from alkoxy; R ３１ｓ C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, C3-C ９ Selected from heterocyclyls and heteroaryls, the C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from -OH and halogens, and the C ３ -C ６ Cycloalkyl is C １ -C ６ The C may be substituted with one or more substituents selected from alkyl and halogens. ３ -C ９ Heterocyclyls and heteroaryls are, respectively, C １ -C ６ Alkyl, C ３ -C ６ - Cycloalkyl, C ３ -C ９ - Heterocyclyl, C ６ -C １２ It may be substituted with one or more substituents selected from aryl, -OH, oxo, and halogen; R ３２ｓ , R ３３ｓ , and R ３４ｓ Each of these is independently selected from H and halogen. A compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer described in claim 1.

16. The compound is of formula (IIIr) and at least one of the following (i) to (iv) is true: (i) R ３０ｒ The following: 【Transformation 56】 (wherein L is N or CH) and below: 【Chemistry 57】 Selected from; (ii) R ３０ｒ The following: 【Chemistry 58】 And in the formula, R ３５ｒ H, -CH ３ Selected from isopropyl, phenyl, azetidinyl, and tetrahydropyranil; (iii) R ３１ｒ H is; (iv)R ３２ｒ , R ３３ｒ , and R ３４ｒ These are H, or The compound is of formula (IIIs) and at least one of the following (i) to (iv) is true: (i) R ３０ｓ H is; (ii) R ３１ｓ The following: 【Chemistry 59】 (wherein M is N or CH) and below: 【Transformation 60】 Selected from; (iii) R ３１ｓ The following: 【Chemistry 61】 And in the formula, R ３５ｓ H, -CH ３ Selected from isopropyl, phenyl, azetidinyl, and tetrahydropyranil; (iv)R ３２ｓ , R ３３ｓ , and R ３４ｓ These are H, A compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to claim 15.

17. The compound is selected from the following: the compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to claim 15 or 16. 【Transformation 62】 【Transformation 63】

18. The compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3, and is a compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to any one of claims 1 to 17.

19. FLT3 is selected from WT FLT3, activated FLT3, and mutant FLT3, and is a compound or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer according to claim 18.

20. The compound, or a salt, ester, solvate, optical isomer, geometric isomer, or salt of the optical isomer or geometric isomer, according to claim 19, wherein the mutant FLT3 is D835Y mutant FLT3 or F691L mutant FLT3.

21. A composition comprising a compound or a salt thereof, an ester, a solvate, an optical isomer, a geometric isomer, or a salt of the optical isomer or geometric isomer according to any one of claims 1 to 20, and further comprising a compounding component, an adjuvant, or a carrier.

22. A pharmaceutical composition for the treatment of a disease or disorder in a subject, characterized by comprising a therapeutically effective amount of a compound or a salt thereof, ester, solvate, optical isomer, geometric isomer, or a salt of the optical isomer or geometric isomer described in any one of claims 1 to 20, or the composition described in claim 21.

23. The pharmaceutical composition according to claim 22, for the treatment of a disease or disorder that responds to at least one of interleukin-1 receptor-related kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition.

24. The pharmaceutical composition according to any one of claims 22 to 23, wherein the disease or disorder includes hematopoietic carcinoma.

25. The disease or disorder is, (i) Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, marginal zone lymphoma, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer At least one cancer selected from cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or (ii) At least one inflammatory or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, and type 1 diabetes. A pharmaceutical composition according to any one of claims 22 to 24, comprising:

26. The disease or disorder includes any of (i) to (iii) below: (i) MDS having a splicing factor mutation, MDS having a mutation in isocitrate dehydrogenase 1, or MDS having a mutation in isocitrate dehydrogenase 2; (ii) AML having a splicing factor mutation, AML in which the expression and / or activity of IRAK4-Long is enhanced in relation to IRAK4-Short, and / or AML that expresses IRAK4-Long but is not promoted by an FLT3 mutation; (iii) DLBCL L265P MYD88 mutant (ABC) subtype or DLBCL S219C MYD88 mutant (GCB) subtype, A pharmaceutical composition according to any one of claims 22 to 25.

27. ​​The MDS having the splicing factor mutation includes an MDS having a splicing factor mutation in U2AF1 or SF3B1, or The pharmaceutical composition according to claim 26, wherein the AML having the splicing factor mutation includes AML having a splicing factor mutation in U2AF1 or SF3B1.

28. The pharmaceutical composition may include chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antmetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAb / immunotherapy, Plk inhibitors, MEK inhibitors, CDK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, Smoothund receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoid receptor modulators, EZH2 inhibitors, Hedgehog (Hh) inhibitors, topoisomerase I inhibitors, and topoisomerase II inhibitors. Agents, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura A inhibitors, Aurora kinase inhibitors, EGFR inhibitors, Aurora B / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PD A pharmaceutical composition according to any one of claims 22 to 27, used in combination with one or more further therapeutic agents selected from GFRA / B inhibitors, AKT1, 2, and / or 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, and multikinase inhibitors.

29. The pharmaceutical composition according to claim 28, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical composition according to any one of claims 22 to 29, wherein the disease or disorder is a disease or disorder of resistance to BCL2 inhibitors and / or FLT3 inhibitors.

31. The pharmaceutical composition according to any one of claims 22 to 30, wherein the disease or disorder is BCL2 inhibitor-resistant acute myeloid leukemia (AML), BCL2 inhibitor-resistant refractory acute myeloid leukemia (AML), BCL2 inhibitor-resistant relapsed acute myeloid leukemia (AML), venetoclax-resistant acute myeloid leukemia (AML), venetoclax-resistant refractory acute myeloid leukemia (AML), venetoclax-resistant relapsed acute myeloid leukemia (AML), FLT3 inhibitor-resistant acute myeloid leukemia (AML), FLT3 inhibitor-resistant refractory acute myeloid leukemia (AML), and / or FLT3 inhibitor-resistant relapsed acute myeloid leukemia (AML).

32. A compound according to any one of claims 1 to 20, or a salt, ester, solvate, optical isomer, geometric isomer, or a salt of the optical isomer or geometric isomer, or a composition according to claim 21, and The pharmaceutical composition according to claim 28, wherein one or more further therapeutic agents are administered together in a single dose or as a single composition.

33. A compound according to any one of claims 1 to 20, or a salt, ester, solvate, optical isomer, geometric isomer, or a salt of the optical isomer or geometric isomer, or a composition according to claim 21, and The pharmaceutical composition according to claim 28, wherein the one or more further therapeutic agents are administered separately in multiple doses or as multiple compositions.

34. The pharmaceutical composition according to any one of claims 22 to 33, wherein the disease or disorder is a disease or disorder that is mitigated by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject.

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