Polycyclic IRAK and FLT3 inhibitor compounds and uses thereof

Abstract

Some embodiments of the disclosure include compounds of the 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 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 treatment using a combination of an IRAK and / or FLT3 inhibitor compound of the invention and another therapeutic agent, such as a cancer therapeutic agent.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to U.S. Provisional Application No. 63 / 129,895, filed December 23, 2020, which is incorporated herein by reference in its entirety.

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

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

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

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

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

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

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

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

[0010] In one embodiment, the compound of formula (I) has the formula (IIf): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; 20f is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(CH2) a -(C3-C6 cycloalkyl), and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, and =O, and any two adjacent substituents can be bonded or fused to form a ring; R 21f , R 22f , and R 23f are each independently selected from H and halogen; R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; and a is selected from 0, 1, 2, 3, 4, 5, and 6. In one embodiment, R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R26fb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 20f is H. In one embodiment, at least one of the following (i) to (viii) is true: (i) R 20f is t-butyl, unsubstituted C3 cycloalkyl, pyrrolidinyl, -OCH3, -OCH2CH3, [ka] (wherein b is 1 or 2); (ii) R 20f is as follows: [ka] where R 27f is as follows: [ka] (iii) R 20f is as follows: [ka] where R 28f is =O and R 220fa and R 220fb are each -CH3, or R 220fa and R 220fb is bonded or condensed to form oxetanyl; (iv) R 21f , R 22f , and R 23f are H, respectively; (v) R 21f and R 23f are F and R, respectively. 22f is H; (vi) R 21f and R 23f are H and R, respectively. 22f is F; (vii) R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fbare each H; (viii) R 25fa , R 25fb , R 26fa , and R 26fb are H and R, respectively. 24fa and / or R 24fb is selected from F, —CH 3 , and —CF 3 . In one embodiment, the compound is selected from: [ka] TIFF2024501658000009.tif152125TIFF2024501658000010.tif178125JPEG2024501658000011.jpg123124

[0011] In another embodiment, the compound of formula (I) has the formula (IIg): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; [ka] is as follows: [ka] Selected from;R 20g is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -OH, and =O; R 21g , R 22g , and R 23gare each independently selected from H and halogen; R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb are each independently selected from H, halogen, —OH, and C1-C6 alkyl. 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb is independently selected from halogen, —OH, and C1-C6 alkyl. 20g is H. In one embodiment, at least one of the following (i) to (xi) applies: (i) R 20g is t-butyl, unsubstituted C3 cycloalkyl, [ka] (wherein c is 1 or 2); (ii) R 20g is as follows: [ka] and R 29g is an unsubstituted C3 cycloalkyl, -CH3, [ka] (iii) R 21g , R 22g , and R 23g are each H; (iv) R 21g and R 23g are F and R, respectively. 22g is H; (v) R 21g and R 23g are H and R, respectively.22g is F; (vi) the following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb each of which is H; (vii) the following: [ka] is as follows: [ka] and R 24ga , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 24gb is F; (viii) the following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 25ga , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25gb is -CH3; (ix) the following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb each of which is H; (x) the following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb Each of is H and R 27ga and / or R 27gb is F or -CH3; (xi) the following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 27ga , R 27gb , R 26ga , R 28ga , and R 28gb Each of is H and R 26gb is F or -CH3. In one embodiment, the compound is selected from: [ka] TIFF2024501658000031.tif187125TIFF2024501658000032.tif152124TIFF2024501658000033.tif151124JPEG2024501658000034.jpg65124

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

[0013] In one embodiment, the compound of Formula (I) is an inhibitor of at least one of IRAK1, IRAK4, and FLT3. In one embodiment, the compound of Formula (I) is an inhibitor of at least two of IRAK1, IRAK4, and FLT3. In one embodiment, the compound of Formula (I) is an inhibitor of IRAK1 and IRAK4. In one embodiment, the compound of Formula (I) is an inhibitor of IRAK1, IRAK4, and FLT3. In one embodiment, the FLT3 is selected from WT FLT3, activated FLT3, and mutant FLT3. In one embodiment, the mutant FLT3 is D835Y mutant FLT3 or F691L mutant FLT3.

[0014] In another aspect, the disclosure provides a composition comprising a compound of formula (I), said composition further comprising a formulation component, adjuvant, or carrier. In one embodiment, the composition is selected from the group consisting of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2 / MAPK1 or ERK1 / MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a topoisomerase inhibitor, a ribozyme ... In one embodiment, the composition is used in combination with one or more of a BCL2 inhibitor, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an aminopeptidase / leukotriene A4 hydrolase inhibitor, a FLT3 / Axl / ALK inhibitor, a FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, a NEDD8 activator, an MDM2 inhibitor, a PLK1 inhibitor, an AuraA inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a Menin-KMT2A / MLL inhibitor, and a multikinase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

[0015] In yet another aspect, the disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a composition comprising a compound of Formula (I). In one embodiment, the method comprises administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (I) and a formulation ingredient, adjuvant, or carrier. In one embodiment, the disease or disorder responds to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition. In one embodiment, the administration comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. In one embodiment, the compound of Formula (I) is administered to the subject in an amount of about 0.005 mg / kg to about 1,000 mg / kg of the subject's body weight. In one embodiment, the disease or disorder comprises a hematopoietic cancer. In one embodiment, the disease or disorder comprises myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML). In one embodiment, the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid carcinoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MYD88-mutated DLBCL, follicular lymphoma, or marginal zone lymphoma. In one embodiment, the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof.In one embodiment, the disease or disorder comprises one or more inflammatory or autoimmune diseases selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof. In one embodiment, the disease or disorder comprises (i) MDS, MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2; or (ii) AML with splicing factor mutations, AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or AML that is not driven by FLT3 mutations but expresses IRAK4-Long. In one embodiment, the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1, and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1. In one embodiment, the disease or disorder comprises DLBCL, and the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL or the S219C MYD88 mutant (GCB) subtype of DLBCL.In one embodiment, the method further comprises administering to a subject a therapeutic agent selected from the group consisting of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2 / MAPK1 or ERK1 / MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a topoisomerase I inhibitor , a topoisomerase II inhibitor, an aminopeptidase / leukotriene A4 hydrolase inhibitor, a FLT3 / Axl / ALK inhibitor, a FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, a NEDD8 activator, an MDM2 inhibitor, a PLK1 inhibitor, an AuraA inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a Menin-KMT2A / MLL inhibitor, and a multikinase inhibitor. In one embodiment, the additional therapeutic agent is a BCL2 inhibitor. 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, the compound of Formula (I) or a composition comprising a compound of Formula (I) and the one or more additional therapeutic agents are administered together in a single dose or composition. In one embodiment, the compound of Formula (I) or a composition comprising a compound of Formula (I) and the one or more additional therapeutic agents are administered separately in multiple doses or multiple compositions. In one embodiment, the disease or disorder is alleviated in a subject by inhibiting at least one of IRAK1, IRAK4, and FLT3. In one embodiment, the disease or disorder is alleviated in a subject by inhibiting at least two of IRAK1, IRAK4, and FLT3. In one embodiment, the disease or disorder is alleviated in a subject by inhibiting IRAK1 and IRAK4. In one embodiment, the disease or disorder is alleviated in a subject by inhibiting IRAK1, IRAK4, and FLT3. In one embodiment, the FLT3 is selected from WT FLT3, activated FLT3, and mutant FLT3. In one embodiment, the mutant FLT3 is a D835Y mutant FLT3 or an F691L mutant FLT3.

[0016] Detailed Description of the Disclosure The following related applications are incorporated by reference in their entirety for all purposes: U.S. Patent Application No. 62 / 414,058, "Overexpression of U2AF1 as a Genetic Predictor of Activated IRAK," filed October 28, 2016; U.S. Patent Application No. 62 / 429,289, "Overexpression of U2AF1 as a Genetic Predictor of Activated IRAK," filed December 2, 2016; PCT Patent Publication No. WO2018081738, "Treatment of Diseases Associated with Activated IRAK," filed October 30, 2017; U.S. Patent Application No. 16 / 339,692, "Treatment of Diseases Associated with Activated IRAK." IRAK, filed April 4, 2019; U.S. Patent Application No. 61 / 826,211, Combination Therapy for MDS, filed May 22, 2013; PCT Patent Publication No. WO2014190163, Combination Therapy for MDS, filed May 22, 2014; U.S. Patent No. 9,168,257, Combination Therapy for MDS, issued October 27, 2015; U.S. Patent No. 9,504,706, Combination Therapy for MDS, issued November 29, 2016; U.S. Patent No. 9,855,273, Combination Therapy for MDS, issued January 2, 2018; U.S. Patent No. 10,487,329, Methods and Compositions for the Treatment of Head and Neck Cancer, issued November 26, 2019; U.S. Patent Application No. 62 / 375,965, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 17, 2016;PCT Patent Publication No. WO2018038988, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 16, 2017; U.S. Patent Application No. 16 / 326,571, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed February 19, 2019; U.S. Patent Application No. 16 / 804,518, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed February 28, 2020; U.S. Patent Application No. 62 / 812,948, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing COMPOUNDS, filed March 1, 2019; U.S. Patent Application No. 63 / 059,815, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 31, 2020; International Patent Application No. PCT / US2021 / 044089, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 31, 2021; U.S. Patent Application No. 63 / 125,654, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed December 15, 2020; and U.S. Patent Application No. 63 / 285,663, IRAK Inhibitors Combination Therapies, filed December 3, 2021.

[0017] While embodiments embodying the general inventive concept may take a variety of forms, various embodiments are described herein with the understanding that the disclosure should be considered merely as exemplary and that the general inventive concept is not intended to be limited to the disclosed embodiments.

[0018] Some embodiments of the disclosure include compounds of the invention (e.g., compounds of Formula (I)). Other embodiments include compositions (e.g., pharmaceutical compositions) including compounds of the invention. Still other embodiments of the disclosure include compositions using compounds of the invention to, for example, treat specific diseases. Some embodiments include methods of using compounds of the invention (e.g., in compositions or pharmaceutical compositions) for administration and treatment. Further embodiments include methods of making compounds of the invention. Still other embodiments include methods for determining whether a particular patient is likely to respond to treatment with compounds and compositions of the invention.

[0019] Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.

[0020] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are drawn up according to the standard rules of chemical valency known in the chemical arts.

[0021] Where substituents are designated by a conventional chemical formula written from left to right, they also encompass the chemically identical substituents obtained by writing the structure from right to left. For example, -CHO- is equivalent to -OCH-.

[0022] As used herein, with respect to compounds of Formula (I), (II), (III), etc., the term "attached" means a stable covalent bond, with particular preferred points of attachment being apparent to those skilled in the art.

[0023] As used herein (unless otherwise specified), the term "alkyl" refers to a monovalent, straight- or branched-chain hydrocarbon chain having the specified number of carbon atoms (i.e., C-C means 1 to 10 carbons), which can be fully saturated, monovalent, or polyunsaturated, and which can include divalent and polyvalent radicals. For example, the terms "C-C alkyl" or "C-C alkyl" refer to a straight- or branched-chain saturated hydrocarbon group having 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7) or 1 to 4 (e.g., 1, 2, 3, or 4) carbon atoms, respectively. Examples of C-C alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, and n-heptyl. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl.

[0024] As used herein (unless otherwise specified), the term "alkenyl" refers to a monovalent straight or branched hydrocarbon chain containing one or more (e.g., 1, 2, 3, or 4) double bonds. The double bond may occur at any stable point along the chain, and the carbon-carbon double bond may have a cis or trans configuration. For example, this definition includes, but is not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, 1-pentenyl-3-cyclohexenyl, and the like. Similarly, "heteroalkenyl" refers to a heteroalkyl having one or more double bonds. Further examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0025] As used herein (unless otherwise specified), the term "alkynyl" refers to a monovalent straight or branched hydrocarbon chain that contains one or more (e.g., 1, 2, 3, or 4) triple bonds and optionally contains one or more (e.g., 1, 2, 3, or 4) double bonds within the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0026] As used herein (unless otherwise specified), the term "alkoxy" means any of the above alkyl, alkenyl, or alkynyl groups attached to the remainder of the molecule by an oxygen atom (alkyl-O-). Examples of alkoxy groups include, but are not limited to, methoxy (sometimes written as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy.

[0027] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, exemplified but not limited by -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms.

[0028] As used herein (unless otherwise specified), the term "cycloalkyl" refers to a monovalent, monocyclic or bicyclic, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon group. The ring may be saturated or partially unsaturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyl (e.g., bicyclooctanes, such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane; bicyclononanes, such as [4.3.0]bicyclononane; and bicyclodecanes, such as [4.4.0]bicyclodecane (decalin), or spiro compounds). In the case of a monocyclic cycloalkyl, the ring is not aromatic. In the case of a bicyclic cycloalkyl, if one ring is aromatic, the other ring is not aromatic. In the case of bicyclic cycloalkyls, one or both rings may be substituted.

[0029] The term "heteroalkyl," by itself or in combination with other terms, means, unless otherwise stated, stable, linear or branched chains, or combinations thereof, which consist of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms can be oxidized, and the nitrogen heteroatom can be quaternized. The heteroatom(s) O, N, P, S, and Si can be placed at any position within the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two heteroatoms may be consecutive, e.g., -CH2-NH-OCH3.

[0030] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, as used herein, heteroalkyl groups include groups that are attached to the remainder of the molecule through a heteroatom, e.g., —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and / or —SOR′. When “heteroalkyl” is recited followed by a specific heteroalkyl group, such as —NR′R″, it is understood that the terms heteroalkyl and —NR′R″ are not overlapping or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term “heteroalkyl,” as used herein, should not be construed as excluding specific heteroalkyl groups, such as —NR′R″.

[0031] As used herein (unless otherwise specified), the term "halogen" or "halo" refers to monovalent Cl, F, Br, or I. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0032] As used herein (unless otherwise specified), the term "aryl" refers to a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic hydrocarbon group, which may be monocyclic or polycyclic (preferably 1 to 3 rings) that are fused together (i.e., fused-ring aryl) or covalently linked to each other. Fused-ring aryl refers to multiple rings fused together, where at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. In the case of bicyclic aryls, one or both rings may be substituted.

[0033] As used herein (unless otherwise specified), the term "heteroaryl" refers to a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon group in which 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic ring system is aromatic. A heteroaryl group (or ring) can contain 1 to 4 heteroatoms selected from N, O, and S, and the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen atom can be quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together in which at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, one of which has 5 members and the other has 6 members, and at least one ring is a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one of which has 6 members and the other has 6 members, and at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, one of which has 6 members and the other has 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group can be attached to the rest of the molecule through a carbon or heteroatom. Examples of heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisoxazolyl, 1H-pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl. In the case of bicyclic heteroaryls, if one ring is aryl, the other ring is heteroaryl. In the case of bicyclic heteroaryls, one or both rings can have one or more heteroatoms. In the case of bicyclic heteroaryls, one or both rings can be substituted.

[0034] "Arylene" and "heteroarylene," alone or as part of another substituent, refer to divalent radicals derived from aryl and heteroaryl, respectively. Thus, the term "aryl" can refer to unsubstituted, monosubstituted, disubstituted, or trisubstituted monocyclic, polycyclic, biaryl, and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, with particular preferred points of attachment being apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl). Aryl substituents can independently be halo, nitro, cyano, trihalomethyl, C 1-16 Alkyl, aryl C 1-16 Alkyl, C0- 16 Alkyloxy C0- 16 Alkyl, aryl C0- 16 Alkyloxy C0- 16 Alkyl, C0- 16 AlkylthioC0- 16 Alkyl, aryl C0- 16 AlkylthioC0- 16 Alkyl, C0- 16 Alkylamino C0- 16 Alkyl, aryl C0- 16 Alkylamino C0- 16 Alkyl, di(aryl C1- 16 Alkyl)aminoC0- 16 Alkyl, C1- 16 Alkylcarbonyl C0- 16 Alkyl, aryl C 1-16 Alkylcarbonyl C0- 16 Alkyl, C1- 16 Alkyl carboxy C0- 16 Alkyl, aryl C1- 16 Alkyl carboxy C0- 16 Alkyl, C 1-16 AlkylcarbonylaminoC0- 16 Alkyl, aryl C1- 16 AlkylcarbonylaminoC0- 16 Alkyl, -C0- 16 Alkyl COOR4, -C0- 16alkylCONR5R6, where R4, R5, and R6 are independently hydrogen, C1-C 11 Alkyl, aryl C0-C 11 alkyl, or R5 and R6, when joined, form one C 1-16 Alkyl, aryl C0-C 16 Alkyl, or C0-Cl 16 and (together with the nitrogen to form a ring system containing 3 to 8 carbon atoms, with or without alkylaryl substituents). Aryl includes, but is not limited to, pyrazolyl and triazolyl.

[0035] Briefly, the term "aryl," when used in conjunction with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the terms "arylalkyl," "aralkyl," and the like are intended to include radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like), wherein the alkyl group includes alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like) or a sulfur atom. Thus, terms such as "arylalkyl" (e.g., (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represent an aryl group, as defined above, attached via an alkyl group, as defined above, having the indicated number of carbon atoms.

[0036] The terms "cycloalkyl" and "heterocycloalkyl," also referred to as "heterocyclyl," by themselves or in combination with other terms, refer to cyclic versions of "alkyl" and "heteroalkyl," respectively, unless otherwise stated. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. As used herein (unless otherwise stated), the term "heterocycloalkyl" or "heterocyclyl" means a monovalent, monocyclic or bicyclic, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered hydrocarbon ring in which 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur atoms, and the monocyclic or bicyclic ring system is not aromatic. Furthermore, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, Examples of heterocyclic rings include pyrrolidin-3-yl, pyrrolidin-4-yl, piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, or piperazin-4-yl), piperidinyl (e.g., piperadin-1-yl, piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl), and morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl). In the case of a bicyclic heterocyclyl, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), the other ring is not aromatic. In the case of a bicyclic heterocyclyl, one or both rings can have one or more heteroatoms.For bicyclic heterocyclyls, one or both rings can be substituted, etc. "Cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0037] As used herein (unless otherwise specified), the term "heteroatom" means an atom selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0038] As used herein (unless otherwise specified), the term "hydroxy" or "hydroxyl" refers to the monovalent --OH group.

[0039] The term "acyl," unless otherwise indicated, means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0040] As used herein, the term "oxo" means an oxygen that is double bonded to a carbon atom.

[0041] As used herein, the term "alkylsulfonyl" means a moiety having the formula -S(O2)-R', where R' is an alkyl group as defined above. R' can have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0042] The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge.

[0043] In the above definitions, the terms "alkyl" and "alkenyl" can be used interchangeably as long as a stable chemical entity is formed, as will be apparent to those skilled in the art.

[0044] The term "linker" refers to a linking group that is interposed between substituents. In some embodiments, the linker is an amide (-CONH-R n or -NHCO-R n ), thioamide (-CSNH-R n or -NHCS-R n ), carboxyl (-CO2-R n or -OCOR n ), carbonyl (-CO-R n ), urea (-NHCONH-R n ), thiourea (-NHCSNH-R n ), sulfonamide (-NHSO2-R n or -SO2NH-R n ), ether (-OR n ), sulfonyl (-SO2-R n ), sulfoxyl (-SO-R n ), carbamoyl (-NHCO2-R n or -OCONH-R n ), or amino (-NHR n ) including the connecting portion.

[0045] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl," and "heteroaryl," etc.) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein.

[0046] As used herein (unless otherwise specified), the term "substituted" (e.g., in substituted alkyl) means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from a specified set of options. The substitution can occur at one or more positions. The term "optionally substituted" means that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) can be replaced, but is not required to be replaced.

[0047] As used herein, "substituent group" means a non-hydrogen substituent that may be, and preferably is, a group selected from the following moieties: (A) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), -CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties substituted with at least one substituent selected from: (i) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), -CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties substituted with at least one substituent selected from: (a) -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-SO3H), -CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties substituted with at least one substituent selected from the following: -NH2, -SH, -CN, -CF3, -NO2, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -N(CH3)2, ethynyl (-CCH), propynyl, sulfo (-S03H), -CONH2, -CONHCH3, -CON(CH3)2, unsubstituted C1-C7 alkyl, unsubstituted C1-C7 heteroalkyl, unsubstituted C1-C7 perfluoroalkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0048] As used herein, a "size-limited substituent" or "size-limited substituent group" means, for example, a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4- to 8-membered heterocycloalkyl.

[0049] As used herein, a "lower substituent" or "lower substituent group" means, for example, a group selected from all of the substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C5-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5- to 7-membered heterocycloalkyl.

[0050] The term "about" when used in the context of a numerical value indicates a range of + / - 10% of the numerical value, unless otherwise specified.

[0051] Some compounds of the present disclosure may have one or more chiral centers, and may exist and be isolated in optically active racemic forms with respect to any one or more chiral centers. Some compounds may exhibit polymorphism. The compounds of the present disclosure (e.g., Formula I) encompass any optically active form, racemate, stereoisomeric form, polymorph, or mixture thereof. When a chiral center does not provide an indication of its configuration (i.e., R or S) in the chemical structure, it is considered to represent R, S, or racemate.

[0052] As used herein, the term "sample" encompasses samples obtained from a subject or patient. The sample can be any biological tissue or fluid. Such samples include, but are not limited to, sputum, saliva, buccal samples, oral cavity samples, blood, serum, mucus, plasma, urine, blood cells (e.g., white blood cells), circulating cells (e.g., stem cells or endothelial cells in blood), tissue, core or fine needle biopsy samples, cell-containing body fluids, free-floating nucleic acids, urine, stool, peritoneal fluid, and pleural fluid, tears, or cells derived therefrom. Samples can also include tissue sections, such as frozen or fixed sections taken for histological purposes, or microdissected cells or their extracellular portions. The sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch, excision, or other surgical methods resulting in biopsy or excised cellular material. Such samples can include cells obtained from a subject or patient. In some embodiments, the sample is a bodily fluid, including, but not limited to, blood fluid, serum, mucus, plasma, lymph, peritoneal fluid, gynecological fluids, or urine, hi some embodiments, the sample can be a non-invasive sample, such as, for example, a saline swish, buccal scrape, or buccal swab.

[0053] As used herein, "blood" can include, for example, plasma, serum, whole blood, blood lysate, and the like.

[0054] As used herein, the term "assessing" includes any form of measurement and includes determining whether an element is present or not. The terms "determining," "measuring," "evaluating," "assessing," "analyzing," and "assaying" can be used interchangeably and can include quantitative and / or qualitative determinations.

[0055] As used herein, the term "monitoring" with respect to a cancer type refers to a method or process of determining the severity or extent of the cancer type or stratifying the cancer type based on the risk and / or probability of death. In some embodiments, monitoring relates to a method or process of determining the therapeutic effectiveness of a treatment being administered to a patient.

[0056] As used herein, "outcome" can refer to the outcome studied. In some embodiments, "outcome" can refer to survival / mortality over a given period of time. For example, "outcome" can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or more. In some embodiments, an increased risk of poor prognosis indicates poor efficacy of the treatment, and a decreased risk of poor prognosis indicates good efficacy of the treatment.

[0057] As used herein, the term "high-risk clinical trial" refers to a clinical trial in which the investigational agent poses "more than minimal risk" (as defined by the terminology used by Institutional Review Boards, or IRBs). In some embodiments, a high-risk clinical trial is a clinical trial.

[0058] As used herein, the term "low-risk clinical trial" refers to a clinical trial in which the risk of the investigational agent is "minimal" (as defined by the terminology used by the IRB). In some embodiments, a low-risk clinical trial is a clinical trial that is not a clinical trial. In some embodiments, a low-risk clinical trial involves the use of monitoring or clinical practice processes. In some embodiments, a low-risk clinical trial is an observational clinical trial.

[0059] As used herein, unless otherwise specified or clear from the context of a particular usage, the terms "modulated" or "modulation," or "regulated" or "regulation" and "differentially regulated" can mean both upregulation (i.e., activation or stimulation, e.g., by stimulating or enhancing) and downregulation (i.e., inhibition or suppression, e.g., by antagonizing, decreasing, or inhibiting).

[0060] As used herein, the term "subject" refers to any suitable (e.g., treatable) member of the animal kingdom. In the methods, the subject is preferably a mammal. In the methods, the subject is preferably a human patient. In the methods, the subject may be a pediatric mammalian patient. In the methods, a pediatric patient is a mammalian (e.g., preferably human) patient under the age of 18, while an adult patient is 18 or older.

[0061] As used herein, the term "treat" (and variations thereof, such as "treatment," "treat," "treating," etc.) is intended in its broadest context, unless otherwise indicated, to mean obtaining a desired pharmacological and / or physiological effect. In particular, for example, the term "treat" does not necessarily imply or require that an animal be treated until complete recovery. Thus, "treating" includes amelioration of symptoms, alleviation of symptoms or effects associated with a condition, reduction in the severity of a condition, or prevention of symptoms, prophylactic amelioration of symptoms, or reduction in the risk of developing a particular condition. In some aspects, "treatment" does not require or include prevention. As used herein, reference to "treating" an animal includes, but is not limited to, prophylactic and therapeutic treatment. The effect may be prophylactic, in that a disease or its symptoms are completely or partially prevented, and / or therapeutic, in that a disease and / or side effects that may result from the disease are partially or completely cured. As used herein, "treatment" encompasses any treatment of a disease in a subject, preferably a mammal (e.g., a human), and may include one or more of the following: (a) preventing the onset of the disease in a subject who may be predisposed to the disease but has not yet been diagnosed as having the disease; (b) inhibiting the disease, i.e., preventing its onset; and (c) alleviating the disease, i.e., causing regression or elimination of the disease and / or alleviating one or more disease symptoms. In certain aspects of the method, such as for conditions or disorders characterized by dysregulated IRAK expression or a dysregulated (e.g., overactive) IRAK-mediated signaling pathway, treatment can be or include reducing such expression or signaling. "Treatment" can also encompass the delivery of an agent or administration of a therapeutic agent to provide a pharmacological effect, even in the absence of a disease or condition. Any of the compositions (e.g., pharmaceutical compositions) described herein can be used to treat a suitable subject.

[0062] A "therapeutically effective amount" refers to an amount effective to achieve a desired and / or beneficial effect. An effective amount can be administered in one or more administrations. In the methods, a therapeutically effective amount is an amount adequate to treat an indication. Treating an indication means achieving any desired effect, such as one or more of palliating, ameliorating, stabilizing, reversing, slowing, or delaying the progression of a disease, improving quality of life, or extending lifespan. Such achievement can be measured by any suitable method, such as measuring tumor size or blood counts, or any other suitable measurement.

[0063] As used herein, the term "marker" or "biomarker" refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, etc., whose presence or concentration can be detected and correlated with a known condition, such as a diseased state. It can also be used to refer to a differentially expressed gene whose expression pattern can be used as part of a predictive, prognostic, or diagnostic process in healthy or diseased states, or can be used in methods to identify useful therapeutic or preventative measures.

[0064] As used herein, an mRNA "isoform" is an alternative transcript of a particular mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, truncated, shortened, or aberrant mRNA, modified mRNA (including, for example, any residue modification, capping variants, polyadenylation variants, etc.), and the like.

[0065] "Antibody" or "antibody peptide" refers to an intact antibody or a binding fragment thereof that competes with the intact antibody for specific binding; this definition encompasses monoclonal and polyclonal antibodies. Binding fragments are produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies. An antibody other than a "bispecific" or "bifunctional" antibody is understood to have each of its binding sites identical. For example, an antibody substantially inhibits the adhesion of a receptor to its counter-receptor when an excess of the antibody reduces the amount of receptor bound to the counter-receptor by at least about 20%, 40%, 60%, or 80%, more typically by greater than about 85%, as measured in an in vitro competitive binding assay.

[0066]

[0013] Embodiments of the disclosure described herein include compounds of the invention (e.g., compounds of Formula (I), such as compounds of Formula (II) and Formula (III)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising compounds of the invention. Still other embodiments of the disclosure include compositions (e.g., pharmaceutical compositions) using compounds of the invention, for example, to treat a particular disease. Some embodiments include methods of administering and using compounds of the invention (e.g., in compositions or pharmaceutical compositions) for treatment (e.g., of a disease such as cancer or a blood disorder). Some embodiments include methods of determining whether a patient is suitable for or may respond favorably to a particular treatment. Further embodiments include methods of making compounds of the invention. Additional embodiments of the disclosure are also described herein.

[0067] Compounds and compositions containing pharmaceutical compositions Some embodiments of the present disclosure provide compounds of formula (I): [ka] 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). In some embodiments, the compound is not an ester, is not a solvate, or is not a prodrug.

[0068] In an exemplary embodiment, R 2 , R 3 , R 4 , and R 5 are independently selected from H, halogen, hydroxy, oxo, -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein said amino, amido, -O-aryl, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl are independently selected from halogen, hydroxy, (=O), -O - , oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl, and any two adjacent substituents can be joined or fused to form a ring.

[0069] In some embodiments, R 2 can be H, halogen, hydroxy, oxo, -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amino, amido, -O-aryl, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl can be H, halogen, hydroxy, oxo (=O), -O - , methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, fused-ring aryl, heteroaryl, fused-ring heteroaryl, or C-C alkyl substituted with cycloalkyl; R 3 , R 4 , and R 5can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl can be H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; and optionally substituted with one or more of carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; any two adjacent substituents can be joined or fused to form a ring.

[0070] R 6 can be: [ka]

[0071] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogen and / or C-C alkyl; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, as defined above, , C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl may be substituted with one or more halogen and / or C1-C6 alkyl); m, n, o, p, q, r, s, t, u, v, w, and x can be 0, 1, 2, 3, 4, or 5, and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0072] In some embodiments, R 2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, and said O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl is halogen, hydroxy, (═O), —O - , -CN, amino, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, fused ring aryl, fused ring heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. 2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, wherein said O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 2is H, Cl, hydroxy, -NHCH, -N(CH), -OCH, -OCF, -OCHF, -OPh, -CF, -CHF, unsubstituted C-C alkyl, substituted amino, substituted C-C alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl. In some embodiments, R 2 is not H.

[0073] In some embodiments, R 3 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, wherein said C1-C7 alkyl or C2-C6 alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 3 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0074] In some embodiments, R 4is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, wherein said C1-C7 alkyl or C2-C6 alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 4 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0075] In some embodiments, R 5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, wherein said C1-C7 alkyl or C2-C6 alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl. In some embodiments, R 5 is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0076] In some embodiments, R4 is methyl or -CF3, and R 3 and R 5 At least one of is H or halogen.

[0077] In some embodiments, R 6 A chiral center exists at the bond carbon. In some embodiments, the chiral center is an R chiral center, an S chiral center, or racemic. In certain embodiments, the chiral center can be represented by the following bond: [ka] As will be appreciated by those skilled in the art, where chiral centers can exist at other positions in compounds according to formula (I), the depicted straight bond can also be: [ka]

[0078] In some embodiments, R 6 is as follows: [ka]

[0079] In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and each of said methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; The alkyl group may be optionally substituted with one or more halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl.

[0080] In one embodiment, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 At least one of R is not H. In another embodiment, 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 Each of, if present, is H.

[0081] 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 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, and each of said methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; The alkyl group may be optionally substituted with one or more halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl.

[0082] In one embodiment, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27, R 29 , R 29 , and R 30 At least one of R is not H. In another embodiment, 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 Each of, if present, is H.

[0083] In some embodiments, m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5; and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0084] Some embodiments of the present disclosure include compounds having a structure according to formula (I): [ka] In the formula, Y to R 6 Wave coupling to: [ka] In some cases, R 6 indicates the presence of a chiral center at the bonding carbon. In some embodiments, R 6 When a chiral center is present at the bonded carbon, the wavy bond can represent an R chiral center, an S chiral center, or a racemate. [ka] is as follows: [ka] As will be appreciated by those skilled in the art, where chiral centers can exist at other positions in compounds according to formula (I), the depicted direct bond can also be: [ka]

[0085] In some embodiments, R 6 is (Ia) and gives the structure of formula (II) below: [ka]

[0086] In some embodiments according to Formula (II), m is 0 or 1; n is 0 or 1; o is 0 or 1; and p is 0 or 1.

[0087] In some embodiments, R 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14 At least one of is not H, and / or R 11 , R 12 , R 13 , and R 14 is H and R 7 , R 8 , R 9 , and R 10 At least one of R is not H. In specific embodiments, 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkoxy, cycloalkyl, or spirofused cycloalkyl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, or spirofused cycloalkyl is optionally substituted with one or more halogens. 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14 At least one of is halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spirofused cycloalkyl, wherein said methanoyl (—COH), carboxy (—COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spirofused cycloalkyl is optionally substituted with one or more halogens. 11 , R 12 , R 13 , and R 14 is H and R 7 , R 8 , R 9 , and R 10 At least one of is halogen, hydroxy, oxo, methanoyl (—COH), carboxy (—COH), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spirofused cycloalkyl, wherein said methanoyl (—COH), carboxy (—COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spirofused cycloalkyl is optionally substituted with one or more halogens. 7 , R 8 , R 9 , and R 10At least one of R is halogen, hydroxyl, C-C alkyl, C-C haloalkyl, C-C alkoxy, cycloalkyl, or spiro-fused cycloalkyl. 7 , R 8 , R 9 , and R 10 At least one of R is F, hydroxyl, methyl, methoxy, —CHF, —CF, cyclopropyl, spirofused cyclopropyl, spirofused cyclobutyl, or spirofused cyclopentyl. 7 and R 8 Both or R 9 and R 10 are both F or R 7 and R 8 Both or R 9 and R 10 In some embodiments, both R 11 , R 12 , R 13 , and R 14 At least one of R is halogen, hydroxyl, C-C alkyl, C-C haloalkyl, C-C alkoxy, cycloalkyl, or spiro-fused cycloalkyl. 11 , R 12 , R 13 , and R 14 At least one of R is F, hydroxyl, methyl, methoxy, —CHF, —CF, cyclopropyl, spirofused cyclopropyl, spirofused cyclobutyl, or spirofused cyclopentyl. 11 and R 12 Both or R 13 and R 14 are both F or R 11 and R 12 Both or R 13 and R 14 Both of the are methyl.

[0088] In addition to the embodiment in which the compound has the structure of formula (II), the compound can have a structure according to any of (IIa)-(IIe), where V, W, X, Y, and Z are independently selected from R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , or R 14 and at least one of V, W, X, Y, and Z is not H. [ka] TIFF2024501658000054.tif138125

[0089] In one embodiment, the compound of formula (II) has the formula (IIf): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony: R 20f is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(CH2) a -(C3-C6 cycloalkyl), and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, and =O; R 21f , R 22f , and R 23f are each independently selected from H and halogen; R 24fa , R 24fb , R25fa , R 25fb , R 26fa , and R 26fb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; a is selected from 0, 1, 2, 3, 4, 5, and 6.

[0090] In one embodiment, R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is independently selected from halogen, —OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb Each of is H.

[0091] In one embodiment, R 20f is H. In another embodiment, R 20f is not H. In one embodiment, R 20f is unsubstituted C1-C6 alkyl. In one embodiment, R 20f is t-butyl. In another embodiment, R 20f is C1-C6 alkyl substituted with one or more -OH and / or halogen. In one embodiment, R 20f is C1-C6 alkyl substituted with one or more -OH and / or F. In one embodiment, R 20f is as follows: [ka] In another embodiment, R 20f is unsubstituted C1-C6 alkoxy. In one embodiment, R 20f are -OCH3, -OCH2CH3, and the following: [ka] In another embodiment, R 20f is C1-C6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20f is as follows: [ka] In another embodiment, R 20f is C-C cycloalkyl. In one embodiment, R 20f is an unsubstituted C cycloalkyl. In one embodiment, R 20f is a C cycloalkyl substituted with C-C alkyl. 20f is as follows: [ka] In one embodiment, R 20f is a C cycloalkyl substituted with one or more fluorine atoms. 20f is as follows: [ka] In another embodiment, R 20f is -O-(CH2) a -(Ccycloalkyl). In one embodiment, R 20f is as follows: [ka] In another embodiment, R 20f is an unsubstituted C-C heterocyclyl. In one embodiment, R 20f is pyrrolidinyl and the following: [ka] In another embodiment, R 20f is halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, =O, and -O- and adjacent substituents can be joined or fused to form a ring. 20f is as follows: [ka] where R 20f is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens and / or —OH. 20f is as follows: [ka] where R 27f is unsubstituted C1-C6 alkyl. In one embodiment, R 20f is as follows: [ka] where R 27f is —CH3. In one embodiment, R 20f is as follows: [ka] where R 27f is C1-C6 alkyl substituted with one or more -OH and / or F. In one embodiment, R 20f is as follows: [ka] where R 27f is as follows: [ka] In another embodiment, R 20f is halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, =O, and -O -and adjacent substituents can be joined or fused to form a ring. 20f is as follows: [ka] where R 28f is selected from H and ═O, and R 29fa and R 29fb are each independently selected from H, C1-C6 alkyl, —OH, and halogen, wherein the C1-C6 alkyl is optionally substituted with one or more halogens, and b is 1 or 2. In one embodiment, R 29fa and R 29fb are each independently H, -CH3, [ka] , —CF3, —OH, and F. In one embodiment, R 20f is as follows: [ka] In one embodiment, R 20f is as follows: [ka] where R 28f is =O and R 220fa and R 220fb are each independently selected from H, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy can be joined or fused to form a ring. 20f is as follows: [ka] where R 28f is =O and R 220fa and R 220fb are each -CH3. In one embodiment, R 20f is as follows: [ka] where R 28f is =O and R 220fa and R 220fb In another embodiment, R 20f is as follows: [ka] wherein b is 1 or 2. In another embodiment, R 20f is as follows: [ka] is selected from.

[0092] In one embodiment, R 21f , R 22f , and R 23f is H. In one embodiment, R 21f and R 23f are each independently a halogen, and R 22f is H. In one embodiment, R 21f and R 23f are F and R, respectively. 22f is H. In one embodiment, R 21f and R 23f are H and R, respectively. 22f is halogen. In one embodiment, R 21f and R 23f are H and R, respectively. 22f is F.

[0093] In one embodiment, R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R24fa and / or R 24fb is halogen. In one embodiment, R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R 24fa is F. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R 24fa and R 24fb Each of R is F. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb are H and R, respectively. 24fa and / or R 24fb is C1-C6 alkyl. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R 24fa and R 24fb Each of R is -CH3. 24fb , R 25fa , R 25fb , R 26fa , and R 26fb Each of is H and R 24fa is —CH3. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb are H and R, respectively. 24fa and / or R 24fb is C1-C6 alkyl substituted with one or more halogens. In one embodiment, R 25fa , R 25fb , R 26fa , and R 26fb are H and R, respectively. 24fa and / or R 24fb is C alkyl substituted with one or more F. In one embodiment, R 24fa , R 25fa , R 25fb , R 26fa, and R 26fb are H and R, respectively. 24fb is -CF3.

[0094] In one embodiment, the compound of formula (IIf) has one or more stereocenters. In one embodiment, the compound of formula (IIf) has the following moiety: [ka] contains a stereocenter at the point of attachment to the remainder of formula (IIf). In one embodiment, the compound of formula (IIf) is 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and / or R 26fb In one embodiment, the compound of formula (IIf) contains a stereocenter at one or more of R 20f contains a stereocenter.

[0095] In one embodiment, the compound of formula (IIf) is selected from: [ka] TIFF2024501658000079.tif146124TIFF2024501658000080.tif176125JPEG2024501658000081.jpg149124

[0096] In one embodiment, the compound of formula (II) has the formula (IIg): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, wherein: [ka] is as follows: [ka] Selected from; R 20g is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and said C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -OH, and =O; R 21g , R 22g , and R 23g are each independently selected from H and halogen; R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb are each independently selected from H, halogen, —OH, or C1-C6 alkyl.

[0097] In one embodiment, R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb is independently selected from halogen and C1-C6 alkyl. 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb Each of is H.

[0098] In one embodiment, R 20g is H. In another embodiment, R 20g is unsubstituted C1-C6 alkyl. In one embodiment, R 20g is t-butyl. In another embodiment, R 20g is C1-C6 alkyl substituted with one or more F and / or —OH. In one embodiment, R 21i is as follows: [ka] In another embodiment, R 20g is unsubstituted C1-C6 alkoxy. In one embodiment, R 20g is as follows: [ka] In another embodiment, R 20g is C1-C6 alkoxy substituted with one or more F and / or —OH. In one embodiment, R 20g is as follows: [ka] In another embodiment, R 20g is unsubstituted C-C cycloalkyl. In one embodiment, R 20g is an unsubstituted C cycloalkyl. In one embodiment, R 20g is a C cycloalkyl substituted with C-C alkyl. 20g is as follows: [ka] In one embodiment, R 20g is a Ccycloalkyl substituted with one or more C-C alkyl and one or more fluorine atoms. 20g is as follows: [ka] In another embodiment, R20g is C-C alkyl, C-C cycloalkyl, C-C heterocyclyl, C-C heterocyclyl substituted with one or more substituents selected from -OH, -C=O, and halogen. 20g is as follows: [ka] where R 29g is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogens and / or —OH. 20g is as follows: [ka] where R 29g is unsubstituted C1-C6 alkyl. In one embodiment, R 20g is as follows: [ka] where R 29g is —CH3. In one embodiment, R 20g teeth, the below described: [ka] where R 29g is C1-C6 alkyl substituted with one or more -OH and / or F. In one embodiment, R 20g is as follows: [ka] where R 29g is as follows: [ka] In one embodiment, R 20g is as follows: [ka] where R 29g is unsubstituted C-C cycloalkyl. In one embodiment, R 20g is as follows: [ka] where R 29g is an unsubstituted C cycloalkyl. In one embodiment, R 20g is pyrrolidinyl monosubstituted with -C=O. In one embodiment, R 20g is as follows: [ka] In another embodiment, R 20g is piperidinyl monosubstituted with -C=O. In one embodiment, R 20g is as follows: [ka] In another embodiment, R 20g is as follows: [ka] wherein c is 1 or 2. In another embodiment, R 20g is as follows: [ka] is selected from.

[0099] In one embodiment, R 21g , R 22g , and R 23g is H. In one embodiment, R 21g and R 23g are each independently a halogen, and R 22g is H. In one embodiment, R 21g and R 23g are F and R, respectively. 22g is H. In one embodiment, R 21g and R23g are H and R, respectively. 22g is halogen. In one embodiment, R 21g and R 23g are H and R, respectively. 22g is F.

[0100] In one embodiment, the following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H. In one embodiment, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 24ga and / or R 24gb is halogen. In one embodiment, R 24ga , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 24gb is F. In one embodiment, R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25ga and / or R 25gb is unsubstituted C1-C6 alkyl. In one embodiment, R 24ga , R 24gb , R 25ga , R 26ga , R 26gb , R27ga , and R 27gb Each of is H and R 25gb is -CH3.

[0101] In one embodiment, the following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb is H. In one embodiment, R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb Each of is H and R 27ga and / or R 27gb is halogen. In one embodiment, R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb Each of is H and R 27ga and R 27gb Each of R is F. In one embodiment, R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , R 28ga , and R 28gb Each of is H and R 27gb is F. In one embodiment, R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb Each of is H and R 27ga and / or R 27gbis unsubstituted C1-C6 alkyl. In one embodiment, R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb Each of is H and R 27ga and R 27gb Each of is -CH3. In another embodiment, R 24ga , R 24gb , R 27ga , R 27gb , R 28ga , and R 28gb Each of is H and R 26ga and / or R 26gb is halogen. In one embodiment, R 24ga , R 24gb , R 26ga、 R 27ga , R 27gb , R 28ga , and R 28gb Each of is H and R 26gb is F. In one embodiment, R 24ga , R 24gb , R 27ga , R 27gb , R 28ga , and R 28gb Each of is H and R 26ga and / or R 26gb is unsubstituted C1-C6 alkyl. In one embodiment, R 24ga , R 24gb , R 26ga、 R 27ga , R 27gb , R 28ga , and R 28gb Each of is H and R 26gb is -CH3.

[0102] In one embodiment, the compound of formula (IIg) contains one or more stereocenters. In one embodiment, the compound of formula (IIg) contains R 20g In one embodiment, the compound of formula (IIg) contains a stereocenter at: [ka] contains a stereocenter at the point of attachment to the remainder of formula (IIg). 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and / or R 28gb At least one of the groups contains a stereocenter.

[0103] In one embodiment, the compound of formula (IIg) is selected from: [ka] TIFF2024501658000108.tif155124TIFF2024501658000109.tif160124TIFF2024501658 000110.tif155125TIFF2024501658000111.tif124124JPEG2024501658000112.jpg61124

[0104] In one embodiment, the compound of formula (II) has the formula (IIh): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; [ka] is as follows: [ka] Selected from; R 20his selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and —OH, and said C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 21h , R 22h , and R 23h are each independently selected from H and halogen.

[0105] In one embodiment, R 20h is H. In another embodiment, R 20h is C1-C6 alkyl substituted with one or more halogens. In one embodiment, R 20h is as follows: [ka] In another embodiment, R 20h is C1-C6 alkoxy substituted with one or more halogens. In one embodiment, R 20h is as follows: [ka] In another embodiment, R 20h is unsubstituted C-C cycloalkyl. In one embodiment, R 20h is an unsubstituted C cycloalkyl. In another embodiment, R 20h is a C-C cycloalkyl substituted with one or more C-C alkyls. 20h is as follows: [ka] In another embodiment, R 20h is a C-C cycloalkyl substituted with one or more C-C alkyl and one or more fluorine atoms. 20h is as follows: [ka] is.

[0106] In one embodiment, R 21h , R 22h , and R 23h are each H. In one embodiment, R 21h and R 23h are each independently a halogen, and R 22h is H. In one embodiment, R 21h and R 23h are F and R, respectively. 22h is H. In one embodiment, R 21h and R 23h are H and R, respectively. 22h is halogen. In one embodiment, R 21h and R 23h are H and R, respectively. 22h is F.

[0107] In one embodiment, the following: [ka] is as follows: [ka] is.

[0108] In one embodiment, the compound of formula (IIh) has one or more stereocenters. In one embodiment, the compound of formula (IIh) has R 20h In one embodiment, the compound of formula (IIh) contains a stereocenter at: [ka] contains a stereogenic center at the point of attachment to the remainder of formula (IIh).

[0109] In one embodiment, the compound of formula (IIh) is selected from: [ka]

[0110] In some embodiments, R 6 is (Ib), giving the structure of formula (III) below: [ka]

[0111] In some embodiments according to Formula (III), q, r, s, t, u, v, w, and x are independently 0, 1, or 2. In some embodiments, q is 0 or 1, r is 0 or 1, s is 0 or 1, t is 0 or 1, u is 0 or 1, v is 0 or 1, w is 0 or 1, and x is 0 or 1.

[0112] In some embodiments, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkoxy, or spirofused cycloalkyl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkenyl, C-C alkoxy, or spirofused cycloalkyl is optionally substituted with one or more halogens. 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23, R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 One or more of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are both H.

[0113] In addition to the embodiment in which the compound has the structure of formula (III), the compound can have a structure according to any of (IIIa)-(IIIp) below. [ka] TIFF2024501658000126.tif188125JPEG2024501658000127.jpg202123TIFF2024501658 000128.tif183125JPEG2024501658000129.jpg195125TIFF2024501658000130.tif67125

[0114] In some embodiments, the compound of Formula (I), such as a compound of Formula (II) or Formula (III), can be any of those identified as compounds 1-132 in Tables 1-21. In some embodiments, the compound can be Compound 1, Compound 5, Compound 6, Compound 8, Compound 12, Compound 14, Compound 16, Compound 35, Compound 40, Compound 44, Compound 45, Compound 46, Compound 47, Compound 51, or Compound 55.

[0115] In some embodiments, compounds of Formula (I), such as compounds of Formula (II) or Formula (III), can be in the form of salts, optical and geometric isomers, and salts of isomers. In other embodiments, the compounds can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including, but not limited to, hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates. In some cases, in the case of salts of acidic compounds, the salts can include metals, amines, or organic cations (e.g., quaternary ammonium). In still other embodiments, simple derivatives of compounds (e.g., ethers, esters, or amides) can be used that have desirable retention and release characteristics but are easily hydrolyzed by body pH, enzymes, or other suitable means.

[0116] In some embodiments, compounds of the present disclosure have chiral centers and can exist and be isolated in optically active, racemic form. In other embodiments, the compounds may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomer of the compounds described herein, including isotopically and radiolabeled compounds, or mixtures thereof. See, e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be isolated by standard resolution techniques, including, for example, fractional crystallization, chiral chromatography, and the like. See, e.g., Eliel, EL & Wilen SH, 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. Preparation of optically active forms can be accomplished by any suitable method, including, but not limited to, resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0117] In some embodiments, the compounds disclosed herein have asymmetric centers and can exist as racemates, racemic mixtures, and individual enantiomers or diastereomers, and all isomeric forms and mixtures thereof are contemplated for use in the compounds and methods described herein. Compounds contemplated for use in the compounds and methods described herein do not include compounds known in the art to be unstable and unable to be synthesized and / or isolated.

[0118] The compounds disclosed herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 The compounds may be radiolabeled with a radioactive isotope such as C. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the intended scope.

[0119] In some embodiments, metabolites of the compounds disclosed herein are useful in the methods disclosed herein.

[0120] In some embodiments, compounds contemplated herein may be provided in the form of a prodrug. The term "prodrug" refers to a compound that can be converted in vivo to a compound described herein (e.g., a biologically active compound). Prodrugs may be useful for a variety of reasons known in the art, including ease of administration, e.g., by improving oral bioavailability. Prodrugs may also have improved solubility in pharmaceutical compositions relative to the biologically active compound. Non-limiting examples of prodrugs include compounds that are administered as esters (i.e., "prodrugs") to facilitate penetration across cell membranes, where water solubility is a disadvantage, but that are metabolically hydrolyzed to the active carboxylic acid once inside the cell, where water solubility is advantageous. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in *Design of Prodrugs* (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference for the limited purpose of describing the procedures and preparation of suitable prodrug derivatives.

[0121] Certain compounds disclosed herein can exist in solvated forms, including hydrated forms, as well as unsolvated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the intended compounds. Certain compounds disclosed herein can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods intended herein and are intended to be within the scope of the disclosed compounds.

[0122] In certain embodiments, one or more compounds of the present disclosure (e.g., Formula (I)) can be part of the composition and can be at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, It can be an amount (by weight of the total composition) of at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, or about 99.99% or less, about 0.0001% to about 99%, about 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%.

[0123] In some embodiments, one or more compounds of the present disclosure (e.g., Formula (I)) are present in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 15%, at least about 20%, at least about 25 ... Both can be purified or isolated in an amount of about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, about 99.99% or less, about 0.0001% to about 99%, about 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%.

[0124] Process for preparing compounds of formula (I) Some embodiments of the present disclosure include methods for preparing compounds of Formula (I). In certain embodiments, compounds of Formula (I) can be prepared including one or more steps described in Examples 1-24 herein. The synthetic routes shown and described in Examples 1-24 can be used to prepare, for example, compounds 1-132 shown in Tables 1-21, and structurally related compounds.

[0125] Pharmaceutical Compositions and Formulations Some embodiments of the present disclosure include compositions comprising one or more compounds of the present disclosure (e.g., Formula (I)). In certain embodiments, the composition is a pharmaceutical composition, such as a composition suitable for administration to an animal (e.g., a mammal, a primate, a monkey, a human, a dog, a cat, a pig, a mouse, a rabbit, a rat, etc.). In some embodiments, a pharmaceutical composition is provided comprising a compound disclosed herein and a pharmaceutically acceptable excipient. The compound can be a compound of any of Formulas (I)-(III) disclosed herein, a compound shown in Tables 1-21, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof. In some embodiments, the compound is shown in any of Tables 1-21 herein.

[0126] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds disclosed herein contain a relatively acidic functional group, base addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salts, or similar salts. When compounds disclosed herein contain a relatively basic functional group, acid addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, bicarbonate, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphoric acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0127] The compounds disclosed herein can exist as salts with pharmaceutically acceptable acids, etc. Accordingly, the compounds contemplated herein include such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, salts with amino acids such as glutamic acid, etc. These salts can be prepared by methods known to those skilled in the art.

[0128] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0129] Pharmaceutically acceptable salts of the compounds described above, in which basic or acidic groups are present in the structure, are also included within the scope of the compounds contemplated herein. When acidic substituents such as -NHSOH, -COOH, and -P(O)(OH) are present, ammonium, sodium, potassium, calcium salts, and the like, may be formed for use as dosage forms. Basic groups such as amino or basic heteroaryl radicals, or acid salts such as pyridyl, and hydrochloride, hydrobromide, acetate, maleate, pamoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as dosage forms.

[0130] Additionally, in embodiments where R—COOH is present, pharmaceutically acceptable esters can be used (e.g., methyl, ethyl, tert-butyl, pivaloyloxymethyl, etc.) and esters known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations can be used.

[0131] In some cases, the pharmaceutical compositions are non-toxic, do not cause side effects, or both, while in some embodiments, they may exhibit inherent side effects (e.g., may be harmful to the patient or may exhibit some degree of toxicity or harm in some patients).

[0132] In some embodiments, one or more compounds of the present disclosure (e.g., Formula (I)) can be part of a pharmaceutical composition, and may be present in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, The amount can be at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, about 75% or less, about 90% or less, about 95% or less, about 99% or less, or about 99.99% or less, about 0.001% to about 99%, about 0.001% to about 50%, about 0.1% to about 99%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%. In some embodiments, the pharmaceutical composition can be in a dosage form suitable for topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, dermal, nasal, vaginal, or ocular administration. In other embodiments, the pharmaceutical composition can be in a dosage form suitable for parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. The pharmaceutical composition can be in the form of, for example, a tablet, capsule, pill, powder, suspension, emulsion, solution, gel (including hydrogel), paste, ointment, cream, poultice, lotion, delivery device, suppository, enema, injectable, implant, spray, aerosol, or other suitable form.

[0133] In some embodiments, the compounds disclosed herein can be orally administered as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups, or elixirs. Oral compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to produce pharmaceutically elegant and palatable formulations. Thus, pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein are also provided.

[0134] In some embodiments, tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate; (2) granulating and disintegrating agents such as cornstarch or alginic acid; (3) binders such as starch, gelatin, or acacia; and (4) lubricants such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used.

[0135] When preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid.Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.A solid carrier can be one or more substances that also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0136] The compounds disclosed herein can be administered parenterally for in vivo applications, either as free compounds or in the form of pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts, by injection or by gradual perfusion over time. Administration can be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavity, or transdermal. For in vitro studies, the compounds can be added or dissolved in an appropriate biologically acceptable buffer and added to cells or tissues.

[0137] In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0138] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "formulation" is intended to include formulations of the active compound with encapsulating materials as carriers to provide a capsule in which the active ingredient is surrounded by a carrier in which it is associated, with or without other carriers. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0139] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously by stirring, The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.

[0140] Liquid preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0141] When parenteral application is necessary or desired, particularly suitable mixtures for the compounds disclosed herein are injectables, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants (including suppositories). These suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectables can also be prepared as sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles, carriers, and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables. In particular, carriers for parenteral administration include aqueous solutions such as dextrose, saline, purified water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, and polyoxyethylene block polymers. Ampoules are convenient unit doses. The compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical mixtures suitable for use in the pharmaceutical compositions and methods disclosed herein include, for example, those described in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of both of which are incorporated herein by reference.

[0142] In some embodiments, formulations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions (including saline and buffered media). Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol, and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents (e.g., sterile water, alcohol, glycerol, and polyols). Intravenous vehicles include fluid and nutrient replenishers. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose, and sodium chloride. Lactated Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (e.g., those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, growth factors, and inert gases and the like.

[0143] Preservatives include antimicrobial agents, antioxidants, chelating agents, and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients including salts, preservatives, buffers, and the like, as described in, for example, Remington's Pharmaceutical Sciences, 15th ed., Easton: Mack Publishing Co., pp. 1405-1412, 1461-1487 (1975) and The National Formulary XIV., 14th ed., Washington: American Pharmaceutical Association (1975), the contents of which are incorporated herein by reference. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to ordinary skill in the art. See, for example, Goodman and Gilman (eds.), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).

[0144] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the micronized active ingredient in water together with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Aqueous suspensions usually contain the active ingredient mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and the like; (2) dispersing or wetting agents which can be (a) a naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, e.g., polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long-chain aliphatic alcohol, e.g., heptadecaethyleneoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).

[0145] Also included are solid preparations intended to be converted, shortly before use, to liquid preparations for oral administration. Such liquid preparations include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0146] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form is a packaged preparation, the package containing individual doses of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0147] In some embodiments, the pharmaceutical composition can include one or more formulary ingredients. A "formulary ingredient" refers to any suitable ingredient (e.g., suitable for the drug, suitable for the drug dosage, suitable for the timing of drug release, suitable for the disease, suitable for the pathology, or suitable for the delivery route), including, but not limited to, water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water containing chloroform), sugar (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made therefrom), ethanol, glycerol, glycol (e.g., propylene glycol), acetone, ether, DMSO, surfactants (e.g., The composition may include any suitable ingredients, including, for example, anionic surfactants, cationic surfactants, zwitterionic surfactants, or nonionic surfactants (e.g., polysorbates), oils (e.g., animal oils, vegetable oils (e.g., coconut oil or peanut oil), mineral oil), oil derivatives (e.g., ethyl oleate, glyceryl monostearate, or hydrogenated glycerides), excipients, preservatives (e.g., vitamins (e.g., A, E, or C), selenium, retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens (e.g., methylparaben or propylparaben)), or combinations thereof.

[0148] In certain embodiments, pharmaceutical compositions can be formulated to release the active ingredient (e.g., one or more disclosed compounds, such as Formula (I)) immediately upon administration or at a substantially predetermined time or time after administration. Such formulations include controlled release formulations, such as various controlled release compositions and coatings.

[0149] Other formulations (eg, formulations of pharmaceutical compositions) can, in certain embodiments, include inclusion of the drug (or controlled release formulation) in a food, foodstuff, feed, or beverage.

[0150] 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.

[0151] A viscosity higher than that of a simple aqueous solution may be desirable to reduce variability during dispensing of the formulation, to reduce physical separation of components of a suspension or emulsion formulation, and / or to improve formulation. Such viscosity-building agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations thereof. Such agents are typically used in amounts of about 0.01% to about 2% by weight.

[0152] The compositions disclosed herein can further include ingredients to provide sustained release and / or comfort. Such ingredients include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and micronized drug carrier matrices. These ingredients are described in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760, the entire contents of which are incorporated herein by reference for all purposes.

[0153] Various pharmaceutical compositions useful for ameliorating specific diseases and disorders are provided. In one embodiment, pharmaceutical compositions are prepared by formulating a compound disclosed herein, alone or with other pharmaceutical agents, in the form of a free compound or a pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt, using carriers, excipients, and additives or adjuvants suitable for administration to a subject. Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents (e.g., sterile water, alcohol, glycerol, and polyols). Intravenous vehicles include fluid and nutrient replenishers.

[0154] Various pharmaceutical compositions useful for ameliorating specific diseases and disorders are provided. In one embodiment, pharmaceutical compositions are prepared by formulating a compound disclosed herein, alone or with other pharmaceutical agents, in the form of a free compound or a pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt, using carriers, excipients, and additives or adjuvants suitable for administration to a subject. Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents (e.g., sterile water, alcohol, glycerol, and polyols). Intravenous vehicles include fluid and nutrient replenishers.

[0155] In addition to their ability to inhibit IRAK, IRAK inhibitors have been shown to have selectivity toward multiple kinases. In some embodiments, compounds described herein according to Formula (I), such as compounds 1-132 listed in Tables 1-21, exhibit inhibitory activity against one or more kinases, such as interleukin-1 receptor-associated kinase (IRAK) and FMS-like tyrosine kinase 3 (FLT3). The inhibitory effect on one or more kinases, such as IRAK and FLT3, enables the treatment and / or prevention of diseases in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cows, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using compounds of the present disclosure (e.g., Formula (I)) including, but not limited to, hematopoietic cancers (e.g., disorders of hematopoietic stem cells in the bone marrow or disorders associated with the myeloid lineage), MDS, AML, myeloproliferative disorders, and diseases (e.g., hematopoietic cancers) associated with mutations in IRAK1, IRAK4, and / or FLT3 (e.g., a mutation in the juxtamembrane region of FLT3, a mutation in the kinase domain of FLT3, a FLT3 point mutation, a FLT3 internal tandem duplication mutation, a FLT3-ITD mutation, a D835Y FLT3 mutation, a D835V FLT3 mutation, a F691L FLT3 mutation, or a R834Q FLT3 mutation).

[0156] In some embodiments, compounds of the present disclosure can inhibit one or more activities of FLT3, a FLT3 mutation (e.g., a FLT3 juxtamembrane region mutation, a FLT3 kinase domain mutation, a FLT3 point mutation, a FLT3 internal tandem duplication mutation, a FLT3-ITD mutation, a D835Y FLT3 mutation, a D835V FLT3 mutation, a F691L FLT3 mutation, or a R834Q FLT3 mutation), IRAK4 (interleukin-1 receptor-associated kinase 4), an isoform of IRAK4, a mutation of IRAK4, IRAK1 (interleukin-1 receptor-associated kinase 1), an isoform of IRAK1, and / or a mutation of IRAK1. In some embodiments, compounds of the present disclosure can inhibit the activity of one or both of FLT3 and FLT3 mutations (e.g., FLT3 juxtamembrane region mutations, FLT3 kinase domain mutations, FLT3 point mutations, FLT3 internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and may inhibit one or more of IRAK4, isoforms of IRAK4, mutations of IRAK4, IRAK1, isoforms of IRAK1, or mutations of IRAK1. In some embodiments, compounds of the present disclosure can inhibit the activity of one or both of FLT3 and FLT3 mutations (e.g., FLT3 juxtamembrane region mutations, FLT3 kinase domain mutations, FLT3 point mutations, FLT3 internal tandem duplication mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and may inhibit one or both of IRAK4 and IRAK1, or isoforms or mutations thereof. In some embodiments, compounds of the present disclosure can inhibit FLT3 in combination with IRAK4, in combination with IRAK1, or in combination with IRAK4 and IRAK1.

[0157] In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3 that is 1 μM or greater, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 nM or greater. In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3 at a level between 0.1 nM and 1 nM, e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 nM. In some embodiments, the compounds described herein exhibit inhibitory activity against IRAK and / or FLT-3 at a level of 0.1 μM or less, e.g., about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of values ​​using any combination of the values ​​recited herein as upper and / or lower limits are also contemplated, for example, but not limited to, 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM. In some embodiments, the inhibitory activity is in the range of about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or even 500-1000 μM.For purposes of quantification, it is understood that terms such as "activity," "inhibitory activity," "biological activity," "IRAK activity," "IRAK1 activity," "IRAK4 activity," "FLT-3 activity," and the like, in the context of the inhibitory compounds disclosed herein, can be quantified by various methods known in the art. Unless otherwise specified, as used herein, such terms refer to IC in their conventional sense. 50 (i.e., the concentration to achieve half-maximal inhibition).

[0158] In some embodiments, hematopoietic cancers that can be treated in animals (e.g., mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, humans) using compounds of the present disclosure (e.g., Formula (I)) include, but are not limited to, hematopoietic cancers and cancers of myeloid blood cells, cancers at increased risk due to other blood disorders, cancers at increased risk due to chemical exposure (e.g., anti-cancer treatments or occupational chemical exposure), cancers at increased risk due to ionizing radiation (e.g., anti-cancer therapy), cancers arising from myelodysplastic syndromes, cancers arising from myeloproliferative disorders, and cancers of B cells.

[0159] In some embodiments, hematopoietic cancers that can be treated include, but are not limited to, MDS, AML, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., ABC DLBCL with MYD88 mutations (e.g., L265P)), follicular lymphoma, or marginal zone lymphoma, or a combination thereof.

[0160] In some embodiments, cancers characterized by dysregulated IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling that can be treated include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof.

[0161] In some embodiments, compounds of the present disclosure can be used to inhibit targets in the context of additional conditions characterized by overactive IRAK1 and / or IRAK4. According to specific aspects of the present disclosure, compounds of the present disclosure can be used to inhibit overactive IRAK1 and / or IRAK4 in conditions such as inflammatory and autoimmune diseases, where the inflammatory and autoimmune diseases are characterized by overactive IRAK1 and / or IRAK4. In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., overactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling can be treated, including, but not limited to, chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, and the like, and combinations thereof.

[0162] In certain embodiments, MDS that can be treated in subjects (e.g., mammals, pigs, dogs, birds (e.g., chickens), cows, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using compounds of the present disclosure (e.g., Formula (I)) include, but are not limited to, MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, MDS with mutations in isocitrate dehydrogenase 2, refractory hematopoietic stem cell transplants with single blood cell lineage dysplasia, and MDS with mutations in isocitrate dehydrogenase 2. Cytopenias (e.g., refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ringed sideroblasts, animals / humans with pathological changes not limited to erythroid cells such as prominent leukocyte progenitor and / or platelet progenitor (megakaryocyte) dysplasia), refractory anemia with excess blasts I and II, 5q syndrome, megakaryocytic dysplasia with fibrosis, and refractory cytopenia of childhood. In some embodiments, MDS that can be treated includes, but is not limited to, hereditary MDS, MDS with an increased risk due to a genetic predisposition, MDS with an increased risk due to other blood disorders, MDS with an increased risk due to exposure to chemicals, MDS with an increased risk due to ionizing radiation, MDS with an increased risk due to cancer treatment (e.g., radiation in combination with a radiomimetic alkylating agent such as busulfan, nitrosoureas, or procarbazine (latency period 5-7 years) or a DNA topoisomerase inhibitor), MDS that evolves from acquired aplastic anemia and Fanconi anemia after immunosuppressive therapy, MDS with an increased risk due to mutations in splicing factors, MDS with an increased risk due to mutations in isocitrate dehydrogenase 1, and MDS with an increased risk due to mutations in isocitrate dehydrogenase 2. Animals that can be treated include, but are not limited to, mammals, rodents, primates, monkeys (e.g., macaques, rhesus monkeys, pig-tailed monkeys), humans, dogs, cats, pigs, birds (e.g., chickens), cows, mice, rabbits, and rats. In the methods, the term "subject" can refer to both human and non-human subjects.In some settings, the subject is in need of treatment (eg, exhibits symptoms of a disease such as MDS, AML, cancer, an autoimmune disease, an inflammatory condition, or has a low blood count).

[0163] In some embodiments, MDS that can be treated in a subject (e.g., a mammal, pig, dog, bird (e.g., chicken), cow, cat, primate, rodent, monkey, rabbit, mouse, rat, and human) using a compound of the present disclosure (e.g., Formula (I)) include, but are not limited to, MDS that can be treated by inhibiting one or more of FLT3 (e.g., with a FLT3 inhibitor), a FLT3 mutation (e.g., with an inhibitor of a FLT3 mutation), IRAK4 (e.g., with an IRAK4 inhibitor), a IRAK4 mutation (e.g., with an inhibitor of a IRAK4 mutation), IRAK1 (e.g., with an IRAK1 inhibitor), and / or a IRAK1 mutation (e.g., with an inhibitor of a IRAK1 mutation). In some embodiments, MDS that can be treated include, but are not limited to, MDS that can be treated by inhibiting IRAK4 (or mutations thereof), MDS that can be treated by inhibiting IRAK1 (or mutations thereof), or MDS that can be treated by inhibiting IRAK4 (or mutations thereof) and IRAK1 (or mutations thereof). In some embodiments, MDS that can be treated include, but are not limited to, MDS that can be treated by inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 makes it possible to treat tumors with FLT3 mutations that may be resistant or become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms caused by IRAK.In some embodiments, the MDS that can be treated is characterized as an MDS with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or an MDS that is not caused by a FLT3 mutation but expresses IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (see, e.g., U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies."). Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties.

[0164] In some embodiments, AML that can be treated in a subject (e.g., mammal, pig, dog, bird (e.g., chicken), cow, cat, primate, rodent, monkey, rabbit, mouse, rat, and human) using a compound of the present disclosure (e.g., Formula (I)) includes, but is not limited to, hereditary AML, AML with an increased risk of developing due to a genetic predisposition, AML with one or more recurrent genetic abnormalities (e.g., those involving the following inversions or translocations, e.g., MLLT3 / MLL ("MLL"), a translocation between chromosomes 9 and 11, AML with a translocation between chromosomes 8 and 21, and AML with a translocation between chromosomes 16). or inversion, AML with translocation between chromosomes 9 and 11, APL with translocation between chromosomes 15 and 17 (M3), AML with translocation between chromosomes 6 and 9, AML with translocation or inversion on chromosome 3, AML with translocation between chromosomes 1 and 22, AML with myelodysplasia-related changes, AML related to previous chemotherapy or radiotherapy (e.g., alkylating agent-related AML, topoisomerase II inhibitor-related AML, etc.), AML not elsewhere classified (those not falling into the above categories (similar to the FAB classification); for example, AML minimally differentiated (M0), AML with minimal maturation (M1), AML with mature AML (M2), etc.) Maturation (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroblastic leukemia (M6), acute megakaryoblastic leukemia (M7), acute basophilic leukemia, acute panmyelosis with fibrosis, etc.), myeloid sarcoma (also known as granulocytic sarcoma, chloroma, or extramedullary myeloblastoma), undifferentiated and biphenotypic acute leukemia (also known as mixed phenotype acute leukemia), AML at increased risk due to other blood disorders, AML at increased risk due to exposure to chemicals, AML at increased risk due to ionizing radiation, AML evolving from myelodysplastic syndrome, AML evolving from myeloproliferative disorder, AML at increased risk due to FLT3 mutations, AML at increased risk due to FLT3 mutations in the juxtamembrane region of FLT3, AML at increased risk due to FLT3 mutations in the juxtamembrane region of FLT3,These include AML with increased risk due to a FLT3 mutation in the kinase domain of FLT3, AML with increased risk due to a FLT3 mutation D835Y, AML with increased risk due to a FLT3 mutation D835V, AML with increased risk due to a FLT3 mutation F691L, AML with increased risk due to a FLT3 mutation R834Q, etc. In some embodiments, AML that can be treated includes AML that can be treated by inhibiting one or more of FLT3 (e.g., with a FLT3 inhibitor), a FLT3 mutation (e.g., with an inhibitor of a FLT3 mutation), IRAK4 (e.g., with an IRAK4 inhibitor), a IRAK4 mutation (e.g., with an inhibitor of an IRAK4 mutation), IRAK1 (e.g., with an IRAK1 inhibitor), and / or a IRAK1 mutation (e.g., with an inhibitor of an IRAK1 mutation). In certain embodiments, AML that can be treated includes, but is not limited to, AML that can be treated by inhibiting IRAK4 (or mutations thereof), MDS that can be treated by inhibiting IRAK1 (or mutations thereof), or AML that can be treated by inhibiting IRAK4 (or mutations thereof) and IRAK1 (or mutations thereof). In some embodiments, AML that can be treated includes, but is not limited to, AML that can be treated by inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 allows for the treatment of tumors with FLT3 mutations that may be resistant or become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms caused by IRAK. In some embodiments, the AML that can be treated is characterized as AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or the AML is characterized as AML that is not caused by a FLT3 mutation but expresses IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (e.g.,U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies." Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties.

[0165] In some embodiments, hematopoietic cancers that can be treated in a subject (e.g., a mammal, pig, dog, bird (e.g., chicken), cow, cat, primate, rodent, monkey, rabbit, mouse, rat, and human) using a compound of the present disclosure (e.g., Formula (I)) include, but are not limited to, hematopoietic cancers (e.g., MDS, AML, DLBCL, etc.) that can be treated by inhibiting (e.g., reducing the activity or expression of) one or more of FLT3 (e.g., with an FLT3 inhibitor), a FLT3 mutation (e.g., with an inhibitor of an FLT3 mutation), IRAK4 (e.g., with an IRAK4 inhibitor), an IRAK4 isoform, an IRAK4 mutation (e.g., with an inhibitor of an IRAK4 mutation), IRAK1 (e.g., with an IRAK1 inhibitor), an IRAK1 isoform, or an IRAK1 mutation (e.g., with an inhibitor of an IRAK1 mutation). In certain embodiments, hematopoietic cancers that can be treated include, but are not limited to, cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof) and IRAK4 (or mutations thereof), hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof) and IRAK1 (or mutations thereof), or hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or mutations thereof), IRAK4 (or isoforms or mutations thereof), and IRAK1 (or isoforms, mutations thereof). In some embodiments, hematopoietic cancers that can be treated include, but are not limited to, hematopoietic cancers that can be treated by inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 along with IRAK4, IRAK1, or both IRAK4 and IRAK1 allows for the treatment of tumors with FLT3 mutations that may be resistant or may become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms caused by IRAK.In some embodiments, the hematopoietic cancer that can be treated is characterized as a hematopoietic cancer with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or the hematopoietic cancer is characterized as a hematopoietic cancer that is not caused by a FLT3 mutation but expresses IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (see, e.g., U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies."). Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties.

[0166] In some embodiments, cancers that can be treated include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, and combinations thereof, which can be treated by inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, inhibiting FLT3 together with IRAK4, IRAK1, or both IRAK4 and IRAK1 allows for the treatment of tumors with FLT3 mutations that may be resistant or become resistant to FLT3 inhibitors, for example, due to adaptive resistance mechanisms caused by IRAK. In some embodiments, the cancer that can be treated is characterized as a cancer with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or the cancer is characterized as a cancer that is not caused by a FLT3 mutation but expresses IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (see, e.g., U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies."). Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties.

[0167] In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., overactive) IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling that can be treated include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, and the like, and combinations thereof. In some embodiments, inhibiting FLT3 in conjunction with IRAK4, IRAK1, or both IRAK4 and IRAK1 allows for the treatment of inflammatory and autoimmune diseases with FLT3 mutations that may be, or may become, resistant to FLT3 inhibitors, e.g., due to adaptive resistance mechanisms driven by IRAK. In some embodiments, the cancers that can be treated are characterized by inflammatory and autoimmune diseases with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or the inflammatory and autoimmune diseases are not caused by FLT3 mutations but express IRAK4-Long, based on IRAK4L usage and the ratio of IRAK4L to IRAK4S (e.g., as described in U.S. Patent Application No. 16 / 339,692; and Smith, MA, et al. (2019). "U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies." Nat Cell Biol 21(5): 640-650. DOI:10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entireties).

[0168] In relation to the treatment of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2), treatment can include, but is not limited to, prophylactic treatment and therapeutic treatment. As such, treatment includes, but is not limited to, preventing MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS); reducing the risk of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS); alleviating or reducing the symptoms of MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS); inducing a body response to MDS (e.g., splicing factor mutated MDS, isocitrate dehydrogenase 1 mutated MDS, or isocitrate dehydrogenase 2 mutated MDS); inhibiting the onset or progression of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); inhibiting or preventing the onset of symptoms associated with ...) reduction in the severity of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); amelioration of one or more symptoms associated with MDS (e.g., an increase in blood counts); remission of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2);Remission of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations); prevention of relapse of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); or prevention of relapse of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) in animals / humans with intrinsic or acquired resistance to other MDS treatments. In some embodiments, treatment does not include prophylactic treatment of MDS (e.g., prevention or amelioration of future MDS).

[0169] In relation to the treatment of hematopoietic cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation (e.g., ABC DLBCL with MYD88 mutation L265P), follicular lymphoma, or marginal zone lymphoma, and combinations thereof), treatment can include, but is not limited to, prophylactic treatment and therapeutic treatment. As such, treatments include, but are not limited to, cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, prevention of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, reducing the risk of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); alleviating or reducing the symptoms of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof);eliciting a body response to cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); eliciting a body response to cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); inhibiting the onset or progression of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, inhibiting or preventing the onset of symptoms associated with cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, reduction in the severity of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); amelioration of one or more symptoms associated with cancer (e.g., reduction in tumor size);Cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL remission of cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations); remission of acute myeloid leukemia by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or D835Y mutations); remission of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, prevention of recurrence of cancers (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof) in animals / humans with intrinsic or acquired resistance to other cancer therapies (such as with some FLT3 inhibitors or MLL); prevention of recurrence of cancers (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutant, follicular lymphoma, or marginal zone lymphoma, and combinations thereof);or prevention of recurrence of acute myeloid leukemia in animals / humans with intrinsic or acquired resistance to other cancer treatments (e.g., with some FLT3 inhibitors or MLL). In some embodiments, treatment does not include prophylactic treatment of cancer (e.g., prevention or amelioration of future cancers);

[0170] Treatment of a subject can be carried out using any suitable administration method (e.g., a method disclosed herein) and any suitable amount of a compound of the present disclosure (e.g., Formula (I)). In some embodiments, the method of treatment includes treating an animal or human for MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2). In some embodiments, methods of treatment include treating a hematopoietic cancer in an animal or human (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88-mutated, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, etc.). Other embodiments include treatment following one or more of suffering from a blood disorder, suffering from a myelodysplastic syndrome, suffering from a myeloproliferative disorder, exposure to a chemical, exposure to ionizing radiation, or treatment for a hematopoietic cancer (e.g., with chemotherapy, ionizing radiation, or both). Some embodiments of the present disclosure include methods of treating a subject (e.g., a human or an animal such as a primate) with a composition (e.g., a pharmaceutical composition) comprising a compound of the present disclosure (e.g., Formula (I)), comprising one or more administrations of one or more such compositions; if there are two or more administrations, the compositions may be the same or different.

[0171] In some embodiments, the method of treatment comprises administering to a subject an effective amount of a composition comprising a compound of the present disclosure (eg, Formula (I)). The term "effective amount," as used herein, refers to a dose or series of doses sufficient to affect treatment (e.g., but not limited to, treatment of MDS (e.g., MDS with splicing factor mutations, MDS with mutations in isocitrate dehydrogenase 1, or MDS with mutations in isocitrate dehydrogenase 2)); or to treat a hematopoietic cancer, such as, but not limited to, acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid carcinoma, non-Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, in a subject. In some embodiments, an effective amount can include a therapeutically effective amount, as disclosed herein. In certain embodiments, the effective amount may vary depending on the subject and the particular treatment being affected. The exact amount required may vary, for example, from subject to subject, and may vary depending on the subject's age and general condition, the particular adjuvant used (if any), the administration protocol, etc. Thus, the effective amount may vary, for example, depending on the particular circumstances, and an appropriate effective amount can be determined in a particular case. The effective amount may include, for example, any of the doses or amounts of compositions disclosed herein.In some embodiments, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, compounds 1-132 listed in Tables 1-21), which can be administered to a subject, such as a mammal, primate, monkey, or human, can be about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, or about 15 mg / kg. For some embodiments, the dose can be about 0.5 mg / kg body weight or about 6.5 mg / kg body weight. In some cases, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, Compounds 1-132 listed in Tables 1-21), which can be administered to a subject such as a mammal, rodent, mouse, rabbit, cat, pig, or dog, can be about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 80 mg / kg, about 100 mg / kg, or about 150 mg / kg.In some embodiments, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, compounds 1-132 listed in Tables 1-21), which can be administered to a subject, such as a mammal, primate, monkey, or human, can be about 1 to about 1000 mg / kg body weight, about 5 to about 500 mg / kg body weight, about 10 to about 200 mg / kg body weight, about 25 to about 100 mg / kg body weight, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1000 mg / kg. For some conditions, the dose can be about 20 mg / kg human body weight or about 100 mg / kg human body weight. In some cases, an effective amount of at least one compound of the present disclosure (e.g., Formula (I), such as, but not limited to, Compounds 1-132 listed in Tables 1-21), which can be administered to an animal such as a mammal, rodent, mouse, rabbit, cat, pig, or dog, can be about 1 to about 1000 mg / kg body weight, about 5 to about 500 mg / kg body weight, about 10 to about 200 mg / kg body weight, about 25 to about 100 mg / kg body weight, or about 100 mg / kg body weight. The amount can be about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1000 mg / kg.

[0172] In some embodiments, the treatment may include one or more of surgical intervention, chemotherapy, radiation therapy, hormone therapy, immunotherapy, and adjuvant systemic therapy. Adjuvant therapy may include, but is not limited to, chemotherapy (e.g., temozolomide), radiation therapy, antiangiogenic therapy (e.g., bevacizumab), and hormone therapy such as administration of LHRH agonists; antiestrogens such as tamoxifen; high-dose progestogens; aromatase inhibitors; and / or adrenalectomy. Chemotherapeutic agents may be used alone or in combination with known or new therapeutic agents.

[0173] In some embodiments, administration of at least one compound of the present disclosure (e.g., Formula (I)) to a subject is an adjuvant or part of an adjuvant cancer therapy. Adjuvant therapy includes treatments by the mechanisms disclosed herein and cancer treatments of the present disclosure, including, but not limited to, tumors. Corresponding primary therapy includes, but is not limited to, surgery, chemotherapy, or radiation therapy. In some cases, adjuvant therapy may be a combination of a chemokine receptor antagonist with a conventional chemotoxic agent or immunotherapy, which may enhance the specificity of treatment for cancer and limit additional systemic side effects. In yet other embodiments, a compound of the present disclosure (e.g., Formula (I)) can be used as an adjuvant with other chemotherapeutic agents. The use of a compound of the present disclosure (e.g., Formula (I)) can, in some cases, shorten the administration period of both the drug and the drug combination, reducing side effects.

[0174] In some embodiments, administration to a subject can reduce the occurrence of one or more symptoms associated with MDS / AML / hematopoietic malignancies, ie, bone marrow failure, immune dysfunction, transformation to overt leukemia, or a combination thereof, in the subject compared to a subject not administered the composition.

[0175] In some embodiments, the method can reduce a viability marker of MDS cells, AML cells, or cancer cells in a subject. In one aspect, the method can reduce a viability marker of MDS, AML, and / or cancer cells. The marker is selected from survival over time, proliferation, growth, migration, colony formation, chromosome assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or a combination thereof.

[0176] Combination therapy In some embodiments, the treatments disclosed herein can include other drugs (e.g., antibiotics) or therapeutic agents for treating diseases (e.g., MDS / AML / hematopoietic cancers). For example, antibiotics can be used to treat infections and can be combined with compounds of the present disclosure for treating diseases (e.g., infections). In other embodiments, intravenous immunoglobulin (IVIG) therapy can be used as part of a treatment regimen (i.e., in addition to administration of a compound of the present disclosure). For example, treatment regimens for various types of cancer can include one or more elements selected from chemotherapy, targeted therapy, alternative therapy, immunotherapy, etc.

[0177] Thus, in some embodiments, a compound and / or composition described herein can be combined with one or more BCL2 inhibitors, BTK inhibitors, chemotherapy, targeted therapy, replacement therapy, immunotherapy, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or the like, or one or more combinations thereof, in one or more administrations to a subject; where multiple administrations are present, the compositions can be the same or different. In some embodiments, when there are multiple administrations, at least one composition used in at least one administration is different from the composition in at least one other administration.

[0178] In particular, IRAK inhibitors have been shown to have synergistic effects when administered in combination with apoptosis modulators / inhibitors, such as BCL2 inhibitors.As described in U.S. Patent Application No. 16 / 804,518 (incorporated herein by reference in its entirety), exemplary apoptosis / BCL2 inhibitors have been shown to have synergistic effects when combined with exemplary IRAK inhibitors in multiple AML cell lines.Venetoclax was used as a representative apoptosis / BCL2 inhibitor.

[0179] When the concentration of an exemplary IRAK inhibitor was combined with venetoclax, the efficacy of venetoclax unexpectedly increased by ~50-fold. According to certain embodiments of the present disclosure, this synergistic combination can enhance the efficacy of venetoclax at low doses, avoiding at least some of the toxicities observed in the clinic. According to certain embodiments, the extent of the interaction depends on the dose ratio combination used, with the exemplary IRAK inhibitor resulting in a greater change in venetoclax IC50 at lower concentrations. This unexpected and dramatic change in venetoclax IC50 is substantially more than an additive response, demonstrating an unexpected synergistic interaction of the two agents, even in cell lines that do not express activating FLT3 mutants.

[0180] Accordingly, the present disclosure includes methods for treating a disease or disorder responsive to inhibition of IRAK, comprising administering to a subject a composition comprising an IRAK inhibitor compound; some embodiments of the methods can further comprise administering an apoptosis modulator. The apoptosis modulator can comprise a BTK and / or a BCL2 inhibitor. BTK and BCL2 inhibitors can be, for example, those known in the art. In some embodiments, the methods can comprise administering to the subject an apoptosis modulator. In some embodiments, the apoptosis modulator can include a BCL2 inhibitor selected from ABT-263 (navitoclax), ABT-737, ABT-199 (venetoclax), GDC-0199, GX15-070 (obatoclax) (all available from Abbott Laboratories), HA14-1, S1, 2-methoxyantimycin A3, gossypol, AT-101, apogossypol, WEHI-539, A-1155463, BXI-61, BXI-72, TW37, MIM1, UMI-77, and the like, and combinations thereof. One of skill in the art will appreciate that there are many known BCL2 inhibitors that can be used in accordance with the present disclosure. In some embodiments, the BCL2 inhibitor includes venetoclax.

[0181] In some embodiments, the administering step comprises administering to the subject a composition comprising an IRAK inhibitor compound and a BCL2 inhibitor, hi some embodiments, the administering step comprises administering a composition comprising an IRAK inhibitor compound in combination with a composition comprising a BCL2 inhibitor.

[0182] In some embodiments, the IRAK inhibitor compound is selected from compounds 1-132, or a salt, isomer, derivative, or analog thereof, and the BCL2 inhibitor is venetoclax, or a salt, isomer, derivative, or analog thereof.

[0183] In some embodiments, the method can further include administering to the subject an immune modulator. The immune modulator can include, for example, lenalidomide (Revlimid; Celgene Corporation). In some embodiments, the method can include administering an epigenetic modulator. The epigenetic modulator can include, for example, a hypomethylating agent, such as azacitidine, decitabine, or a combination thereof.

[0184] In some embodiments, the compounds and / or compositions described herein can be used in conjunction with or in combination with one or more BTK inhibitors, such as ibrutinib, or a salt, isomer, derivative, or analog thereof, for one or more administrations to a subject.

[0185] For example, the compounds and / or compositions described herein may be used in combination with other compounds, such as DNA methyltransferase / hypomethylating agents, such as, for example, azacitidine, decitabine, cytarabine, and / or guadecitabine; anthracyclines, such as, for example, daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a fixed molar ratio combination of cytarabine and daunorubicin at 5:1); or other compounds, such as, for example, vorinostat, panobinostat, valproic acid, and / or histone deacetylase (HDAC) inhibitors, such as pracinostat; purine nucleoside analogs (antimetabolites), such as fludarabine, cladribine, and / or clofarabine; isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, such as ivosidenib and / or enasidenib; anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin), and / or anti-CD45 (e.g., I 131- antibody drug conjugates such as rapamycin; mAbs / immunotherapies such as anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); Plk inhibitors such as volasertib and / or rigosertib; MEK inhibitors such as lametinib, cobimetinib, selumetinib, pimasertib, and / or refametinib; CDK9 inhibitors such as alvocidib and / or voruciclib; CDK8 inhibitors such as SEL120; retinoic acid receptor agonists such as ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); TP53 activators such as APR-246 (eprenetapopt); smoothened receptor antagonists such as glasdegib; ERK inhibitors, such as, for example, ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, such as xertinib, SCH772984, lavoxertinib, MK-8353, and / or VTX-11e; PI3K inhibitors, such as, for example, fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); for example, bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridafone mTOR inhibitors such as rolimus (MK-8669, AP-23573), everolimus, and / or vistasertib (AZD2014); glucocorticoid receptor modulators such as agonists including, for example, prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or antagonists including mifepristone, myricholant, and / or onapristone, and / or other binding ligands including, for example, vamorolone (VBP15);and / or can be used in one or more administrations with or in combination with an EZH2 inhibitor, such as, for example, tazemetostat. In some embodiments, the compounds and pharmaceutical compositions containing same can be used to prevent secondary malignancies when used in combination with an EZH2 inhibitor. Additional therapeutic agents are described below, and combination therapy within the context of this disclosure is contemplated.

[0186] Chemotherapy / targeted therapy / alternative therapy Cancers are commonly treated with chemotherapy, and / or targeted therapy, and / or alternative therapies. While chemotherapy works by indiscriminately targeting rapidly dividing cells, including tumor cells as well as normal cells, targeted cancer therapies work by interfering with specific molecules or molecular targets involved in the growth and progression of cancer. Targeted therapies typically target only cancer cells, minimizing damage to normal cells. Chemotherapeutic and targeted therapy agents that are approved and / or in clinical trials are known to those skilled in the art. Any such compounds can be utilized in the practice of the present disclosure.

[0187] For example, approved chemotherapy drugs include Abitrexate (methotrexate injection), Abraxane (paclitaxel injection), Adcetris (brentuximab vedotin injection), Adriamycin (doxorubicin), Adrsil injection (5-FU (fluorouracil)), Afinitor (everolimus), Afinitor Disperse (everolimus), Alimta (pemetrexed), Alkeran injection (melphalan injection), Alkeran tablets (melphalan), Aredia (pamidronate), Arimidex (anastrozole), and Aromasin. (exemestane), Alanon (nelarabine), Alzera (ofatumumab injection), Avastin (bevacizumab), Beleodac (belinostat injection), Beksar (tositumomab), BiCNU (carmustine), Blenoxane (bleomycin), Blincyto (blinatumomab injection), Bosulif (bosutinib), Busulfex injection (busulfan injection), Campath (alemtuzumab), Camptosar (irinotecan), Caprelsa (vandetanib), Casodex (bicalutamide), CeeNU (lomustine), CeeNU Dose Pack (lomustine), Cervizin (daunorubicin), Chlorar (clofarabine injection), Cometrik (cabozantinib), Cosmegen (dactinomycin), Cotellic (cobimetinib), Cyramza (ramucirumab injection), Cytosar (cytarabine), Cytoxan (cytoxan), Cytoxan injection (cyclophosphamide injection), Dacogen (decitabine), Daunoxome (daunorubicin lipid complex injection), Decadron (dexamethasone), Depocyt (cytarabine lipid complex injection), Dexamethasone Intensor (dexamethasone), Dexpak Taperpak (dexamethasone), Docefrez (docetaxel), Doxil (doxorubicin lipid complex injection), Droxia (hydroxyurea), DTIC (decarbazine), Eligard (leuprolide), Elence (Elance (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Erspar (asparaginase), Emcyte (estramustine), Erbitux (cetuximab), Erivage (vismodegib), Erwinase (asparaginase Erwinia chrysanthemi),Ethyol (amifostine), Etopofos (etoposide injection), Eurexin (flutamide), Fareston (toremifene), Faridak (panobinostat), Faslodex (fulvestrant), Femara (letrozole), Filmagon (degarelix injection), Fludara (fludarabine), Folex (methotrexate injection), Folotin (pralatrexate injection), FUDR (FUDR (floxuridine)), Gadiva (obiotic) Nutuzumab injection), Gemzar (gemcitabine), Gilotrif (afatinib), Gleevec (imatinib mesylate), Gliadel wafer (carmustine wafer), Halaven (eribulin injection), Herceptin (trastuzumab), Hexalen (altretamine), Hycamtin (topotecan), Hydrea (hydroxyurea), Ibrance (palbociclib), Iclusig (ponatinib), Idamycin PFS (idarubicin), Ifex (ifosfamide), Imbruvica (ibrutinib), Inlyta (axitinib), Intron A Alphab (interferon alfa-2a), Iressa (gefitinib), Istodax (romidepsin injection), Ixempra (ixabepilone injection), Jakafi (ruxolitinib), Jevtana (cabazitaxel injection), Kadcyla (ado-trastuzumab emtansine), Keytruda (pembrolizumab injection), Kyprolis (carfilzomib), Ranvima (lenvatinib), Leukeran (chlorambucil), Leukin (sargramostim), Leustatin (cladribine), Lonsurf (trifluridine and tipiracil), Lupron (leuprolide), Lupron Depot (leuprolide), Lupron Depot PE (leuprolide), Lynparza (olaparib), Risodren (mitotane), Marquibo Kit (vincristine lipid complex injection), Maturan (procarbazine), Megas (megestrol), Mekinist (trametinib), Mesnex (mesna), Mesnex (mesna injection), Metastron (strontium-89 chloride), Mexate (methotrexate injection), Mustagen (mechlorethamine), Mutamycin (mitomycin), Myleran (busulfan),Mylotarg (gemtuzumab ozogamicin), Navelbine (vinorelbine), Neosar injection (cyclophosphamide injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (sorafenib), Nilandrone (nilandrone (nilutamide)), Nipent (pentostatin), Nolvadex (tamoxifen), Novantrone (mitoxantrone), Odomzo (sonidegib), Oncaspar (pegaspargas), Oncovin (vincristine), Ontak (denileukin-10) Diftitox), Onxol (paclitaxel injection), Opdivo (nivolumab injection), Panretin (alitretinoin), Paraplatin (carboplatin), Perjeta (pertuzumab injection), Platinol (cisplatin), Platinol (cisplatin injection), Platinol AQ (cisplatin), Platinol AQ (cisplatin injection), Pomalyst (pomalidomide), Prednisone Intensor (prednisone), Proleukin (aldesleukin), Purinetol (mercaptopurine), Reclust (zoledronic acid), Revlimid (lenalidomide), Rheumatrex (methotrexate), Rituxan (rituximab), Roferon A alpha a (interferon) alpha-2a), Rubex (doxorubicin), Sandostatin (octreotide), Sandostatin LAR Depot (octreotide), Soltamox (tamoxifen), Sprycel (dasatinib), Sterup Red (prednisone), Sterup Red DS (prednisone), Stivarga (regorafenib), Suprenin LA (histrelin implant), Sutent (sunitinib), Silatron (peginterferon alpha-2b injection (Silatron)), Silvant (siltuximab injection), Synribo (omacetaxine injection), Tabloid (thioguanine), Taflinal (dabrafenib), Tarceva (erlotinib), Targretin capsules (bexarotene), Tasigna (decarbazine), Taxol (paclitaxel injection), Taxotere (docetaxel), Temodar (temozolomide), Temodar (temozolomide injection), Tepadina (thiotepa), Thalomid (thalidomide),theraCys BCG (BCG), Thioplex (thiotepa), TICE BCG (BCG), Toposar (etoposide injection), Torisel (temsirolimus), Tranda (bendamustine hydrochloride), Trelstar (triptorelin injection), Trexol (methotrexate), Trisenox (arsenic trioxide), Tycarb (lapatinib), Unituxin (dinutuximab injection), Valstar (valrubicin intravesical injection), Vantas (histrelin implant), Vectibix (panitumumab), Velban (vinblastine), Velcade (bortezomib), Bepesid (etoposide), Bepesid (etoposide injection), Vesanoid (tretinoin), Vidaza (azacitidine), Vincasar PFS (vincristine), Vincrex (vincristine) , Votrient (pazopanib), Bumon (teniposide), Wellcovorin IV (leucovorin injection), Xalkori (crizotinib), Xeloda (capecitabine), Xtandi (enzalutamide), Yervoy (ipilimumab injection), Yondelis (trabectedin injection), Zaltrap (dibuaflibercept injection), Zanosar (streptozocin), Zelboraf (vemurafenib), Zevalin (ibritumomab tiusetan), Zoladex (goserelin), Zolinza (vorinostat), Zometa (zoledronic acid), Zoltrex (everolimus), Zydelig (idelalisib), Zykadia (ceritinib), Zytiga (abiraterone), and others, as well as their analogs and derivatives. For example, approved targeted therapies include ado-trastuzumab emtansine (Kadcyla), afatinib (Giotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campus), axitinib (Inrita), belimumab (Benlysta), belinstat (Veleodac), bevacizumab (Avastin), bortezomib (Velcade), and bostib (Bonti). Nib (Boslif), brentuximab vedotin (Adcetris), cabozantinib (Cabometyx, Cometrix), canakinumab (Ilaris), carfilzomib (Cyprolis), ceritinib (Zykadia), cetuximab (Erbitux), cobimetinib (Cotellic), crizotinib (Xalkori), dabrafenib (Tafinlar), daratumumab (Darzalex),Dasatinib (Sprycel), denosumab (Kusugeba), dinutuximab (Unituxin), elotuzumab (Empliciti), erlotinib (Tarceva), everolimus (Afinitor), gefitinib (Iressa), ibritumomab tiuxetan (Zevalin), ibrutinib (Imbruvica), idelalisib (Zydelig), imatinib (Gleevec), ipilimumab (Yervoy), ixazomib (Ninlaro), lapatinib (Tykerb), lenvatinib (Lenvima), necitumumab (Portolaza), nilotinib (Tasigna), nivolumab (Opdivo), obinutuzumab (Gazyva), ofatumumab (Alphabet) Zela, HuMax-CD20), olaparib (Lympaz), osimertinib (Tagrisso), palbociclib (Ibrance), panitumumab (Vectibix), panobinostat (Faridak), pazopanib (Votrient), pembrolizumab (Keytruda), pertuzumab (Perjeta), ponatinib (Iclusig), ramucirumab (Cyramza), rapamycin, Gorafenib (Stivarga), rituximab (Rituxan, MabThera), romidepsin (Istodax), ruxolitinib (Jakafi), siltuximab (Sylvanto), sipuleucel-T (Provenge), sirolimus, sonidegib (Odomzo), sorafenib (Nexavar), sunitinib, tamoxifen, temsirolimus (Toricel), tocilizumab (Actemra), and Tofa These include citinib (Xeljanz), tositumomab (Bexar), trametinib (Mekinist), trastuzumab (Herceptin), vandetanib (Caprelsa), vemurafenib (Zelboraf), venetoclax (Venclexta), vismodegib (Elivege), vorinostat (Zolinza), dib-aflibercept (Zaltrap), and analogs and derivatives thereof.

[0188] Those skilled in the art can determine appropriate chemotherapy and / or targeted therapy and / or alternative therapy options, including approved therapies and therapies in clinical trials or development. Some targeted therapies are also immunotherapies. In practicing the present disclosure, any relevant chemotherapy, targeted therapy, and alternative therapy treatment strategies can be used alone or in combination with one or more additional cancer therapies.

[0189] immunotherapy In some embodiments, immunotherapy involves the treatment of cells that affect the immune response (e.g., lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTLs), antibodies and antibody derivatives (e.g., monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemically labeled antibodies, etc.), immune checkpoint inhibitors, vaccines (e.g., cancer vaccines (e.g., tumor cell vaccines, antigen vaccines, dendritic cell vaccines, vector-based vaccines, etc.), e.g., oncophage, sipuleucel-T), immunomodulatory agents (e.g., interleukins, cytokines, chemokines, etc.), topical immunotherapy (e.g., imiquimod, etc.), injectable immunotherapy, adoptive cell transfer, oncolytic virotherapy (e.g., talimozyme, etc.), and the like. Immunotherapy includes cell-based immunotherapies, including leukemia, leukemia-associated lymphomas (e.g., laherparepvec (T-VEC)), immunosuppressants, helminth therapy, other non-specific immunotherapies, and the like. Immune checkpoint inhibitor immunotherapies target one or more specific proteins or receptors, such as PD-1, PD-L1, CTLA-4, and the like. Immune checkpoint inhibitor immunotherapies include ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), and the like. Non-specific immunotherapies include cytokines, interleukins, interferons, and the like. In some embodiments, the immunotherapy assigned or administered to the subject is an interleukin. and / or administration of one or more suitable antibody-based reagents such as leukin, and / or interferon (IFN), and / or denileuxin diftitox, and / or an antibody-based reagent selected from the group consisting of ado-trastuzumab, emtansine, alemtuzumab, atezolizumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, catumaxomab, gemtuzumab, ibritumomab tiusetan, iripimumab, natalizumab, nimotuzumab, nivolumab, ofatumumab, panitumumab, pembrolizumab, rituximab, tositumomab, trastuzumab, bivataxin, and the like.In some embodiments, the immunotherapy assigned or administered to the subject can include indoleamine 2,3-dioxygenase (IDO) inhibitors, adoptive T cell therapy, viral therapy (T-VEC), and / or any other immunotherapy whose efficacy is significantly dependent on anti-tumor immunity.

[0190] Those skilled in the art can determine appropriate immunotherapeutic options, including approved therapies and therapies in clinical trials or development. Any relevant immunotherapeutic treatment strategy can be used in the practice of the present disclosure, alone or in combination with one or more additional cancer therapies.

[0191] Other cancer treatments In addition to chemotherapy, targeted therapy, alternative therapy, and immunotherapy, cancer can also be treated by other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplantation, precision medicine, etc., and such treatments and the compounds and compositions utilized therein are known to those skilled in the art. Any such treatment strategy can be utilized in the practice of the present disclosure.

[0192] Alternative treatment strategies are also used for various types of cancer. Such treatments can be used alone or in combination with other treatment modalities. These include exercise, massage, relaxation techniques, yoga, acupuncture, aromatherapy, hypnosis, music therapy, dietary changes, and nutritional dietary supplements, and such treatments are known to those skilled in the art. Any such treatment strategy can be used in the practice of the present disclosure, alone or in combination with one or more additional cancer therapies.

[0193] Dosage and Route of Administration Other embodiments of the present disclosure may include methods of administration or treatment to animals / humans, and may include treatment with an amount of at least one compound of the present disclosure (e.g., Formula (I)) effective to treat a disease, condition, or disorder from which the organism is afflicted or suspected of being afflicted or to which it is susceptible, or effective to produce a desired physiological effect. In some embodiments, a composition or pharmaceutical composition comprises at least one compound of the present disclosure (e.g., Formula (I)) that can be administered to an animal (e.g., a mammal, primate, monkey, or human) in an amount of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, or about 15 mg / kg. For some conditions, the dose can be about 0.5 mg / kg human body weight or about 6.5 mg / kg human body weight. In some cases, a subject (e.g., a mammal, mouse, rabbit, cat, pig, or dog) can be administered a dose of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 80 mg / kg, about 100 mg / kg, or about 150 mg / kg. Of course, one of ordinary skill in the art will understand that a variety of concentrations can be used in the methods of the present disclosure, and that any number of concentrations can be adjusted and tested, in part using the guidance provided herein, to find a concentration that achieves the desired result in a given situation.In some embodiments, the dose or therapeutically effective dose of a compound disclosed herein is an amount sufficient to achieve a plasma concentration of the compound or its active metabolite within the ranges set forth herein, e.g., 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or 500-1000 μM, preferably about 1-10 nM, 10-100 nM, or 0.1-1 μM. Without wishing to be bound by any theory, it is believed that such compounds are indicated for the treatment or management of, for example, hematopoietic cancers such as MDS and / or AML and / or DLBCL, other types of cancers described herein, inflammatory conditions, and / or autoimmune diseases.

[0194] In other embodiments, the compounds and / or pharmaceutical compounds of the present disclosure (e.g., compounds of Formula (I) and pharmaceutical compositions comprising same) can be administered in combination with one or more other therapeutic agents for a given disease, condition, or disorder.

[0195] The compounds and pharmaceutical compositions are preferably prepared and administered in dosage units.Solid dosage units are tablets, capsules, and suppositories.Different daily doses can be used to treat a subject, depending on the activity of the compound, the method of administration, the nature and severity of the disease or disorder, and the age and weight of the subject.

[0196] However, in certain circumstances, higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out by a single administration in the form of an individual dosage unit or several other smaller dosage units, or by multiple administration of divided doses at specific intervals.

[0197] The compounds and pharmaceutical compositions contemplated herein can be administered locally or systemically at a therapeutically effective dose. The amount effective for this use will, of course, depend on the severity of the disease or disorder, as well as the weight and general condition of the subject. Typically, the dosage used in vitro can provide a useful guide for the amount useful for in situ administration of the pharmaceutical composition, and animal models can be used to determine the effective dosage for treating a particular disorder.

[0198] Various considerations are described, for example, in Langer, 1990, Science, 249:1527; Goodman and Gilman's (eds.), 1990, Id., each of which is incorporated herein by reference for all purposes. A parenteral dose of an active agent can be converted to a corresponding oral dose by multiplying the parenteral dose by the appropriate conversion factor. For general applications, the parenteral dose in mg / mL is 1.8 times the corresponding oral dose in milligrams ("mg"). For oncology applications, the parenteral dose (mg / mL) is 1.6 times the corresponding oral dose (mg). The average adult weighs approximately 70 kg. See, e.g., Miller-Keane, 1992, Encyclopedia & Dictionary of Medicine, Nursing & Allied Health, 5th Ed., (WB Saunders Co.), pp. 1708 and 1651.

[0199] However, it will be understood that the specific dose level for a particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, concomitant drugs, and the severity of the particular disease being treated.

[0200] In some embodiments, compounds and / or pharmaceutical compositions can include a unit dose of one or more compounds of the present disclosure (e.g., compounds of Formula (I) and pharmaceutical compositions comprising same) in combination with a pharmaceutically acceptable carrier, and can further include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients. In certain embodiments, the carrier, vehicle, or excipient can facilitate administration, delivery, and / or improve the storage of the composition. In other embodiments, the one or more carriers include, but are not limited to, saline solutions such as saline, Ringer's solution, PBS (phosphate buffered saline), and mixtures of various salts, generally including potassium and phosphate salts, with or without sugar additives such as glucose. Carriers can include aqueous and non-aqueous sterile injectable solutions, which can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the body fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents. In other embodiments, the one or more excipients can include, but are not limited to, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. Non-toxic auxiliary substances, such as wetting agents, buffers, or emulsifying agents, can also be added to the compositions. Oral formulations can include commonly used excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.

[0201] The amount of active ingredient in a unit dosage preparation may be varied or adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1,000 mg, and most typically from 10 mg to 500 mg, depending on the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0202] The compounds of the present disclosure (e.g., compounds according to Formula (I)) can be administered to a subject by any number of suitable routes of administration or formulations. The compounds of the present disclosure (e.g., Formula (I)) can also be used to treat various diseases in a subject. Subjects include, but are not limited to, mammals, primates, monkeys (e.g., macaques, rhesus monkeys, or pig-tailed macaques), humans, dogs, cats, cows, pigs, birds (e.g., chickens), mice, rabbits, and rats. As used herein, the term "subject" encompasses both human and non-human subjects, unless otherwise specified.

[0203] The route of administration of the compounds of the present disclosure (e.g., Formula (I)) can be any suitable route. The route of administration can be, but is not limited to, oral, parenteral, cutaneous, nasal, rectal, vaginal, and ocular. In other embodiments, the route of administration can be parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular. The choice of administration route can vary depending on the identity of the compound (e.g., the physical and chemical properties of the compound), the age and weight of the animal / human, the specific disease (e.g., cancer or MDS), and the severity of the disease (e.g., the stage or severity of cancer or MDS). Of course, if desired, a combination of administration routes can be used.

[0204] Some embodiments of the present disclosure include methods for providing a subject with a composition (e.g., a pharmaceutical composition) comprising one or more compounds of the present disclosure (e.g., Formula (I)) described herein, comprising one or more administrations of one or more such compositions, where multiple administrations are present, the compositions may be the same or different.

[0205] toxicity The ratio between the toxicity and therapeutic effect of a particular compound is its therapeutic index, and the LD 50 (the amount of compound that is lethal to 50% of the population) and ED 50Therapeutic indices can be expressed as a ratio between the ED (the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from in vitro assays, cell culture assays, and / or animal studies can be used in formulating a dosage range for human use. Doses of such compounds can be administered with little or no toxicity and at an ED 50 Preferably, the plasma concentration range is within a range having a concentration of 0.05 to 0.05%. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. See, for example, Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 1, pl, 1975. The exact formulation, route of administration, and dosage can be selected by the individual practitioner, taking into account the patient's condition and the particular method in which the compound is used. For in vitro formulations, the exact formulation and dosage can be selected by the individual practitioner, taking into account the patient's condition and the particular method in which the compound is used.

[0206] Although the present disclosure has been described in detail, it will be apparent that modifications, variations, and equivalents are possible without departing from the scope of the present disclosure as defined in the appended claims. Furthermore, it will be understood that any examples in this disclosure are given by way of non-limiting examples.

[0207] The following sections describe specific embodiments.

[0208] Term 1. Formula (I): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof. (In the formula: R 2is H, halogen, hydroxy, oxo, -CN, amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, heteroaryl, or fused-ring heteroaryl, and said amino, O-aryl, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is halogen, hydroxy, oxo (=O), -O - , methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C heteroalkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, cycloalkyl, heterocyclyl, spirofused cycloalkyl, aryl, fused-ring aryl, heteroaryl, fused-ring heteroaryl, or C-C alkyl substituted with cycloalkyl, and any two adjacent substituents can be bonded or fused to form a ring; R 3 , R 4 , and R 5are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl; optionally substituted with one or more of hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C haloalkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl; R 6 teeth, [ka] and R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogens; m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5, and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0209] Section 2.R 2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, and the O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl is The compound according to item 1, wherein the heteroaryl or fused-ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, -CN, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused-ring aryl, fused-ring heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0210] Section 3.R 2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused-ring aryl, heteroaryl, or fused-ring heteroaryl, and the O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, amino, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0211] Section 4.R 2is H, Cl, hydroxy, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -OCHF2, -OPh, -CF3, -CHF2, unsubstituted C1-C7 alkyl, substituted amino, substituted C1-C7 alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused-ring heteroaryl, or unsubstituted fused-ring heteroaryl.

[0212] Section 5.R 2 The compound according to any one of items 1 to 4, wherein is not H.

[0213] Section 6.R 3 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy is halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), hetero The compound according to any one of items 1 to 5, optionally substituted with one or more of cyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0214] Section 7.R 3 7. The compound according to any one of items 1 to 6, wherein is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0215] Section 8.R 4is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy is halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), hetero The compound according to any one of items 1 to 5, optionally substituted with one or more of cyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0216] Section 9.R 4

[0023] The compound according to any one of items 1 to 8, wherein is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.

[0217] Section 10.R 5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, or C1-C7 alkoxy, and the C1-C7 alkyl or C2-C6 alkoxy is halogen, hydroxy, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), hetero The compound according to any one of items 1 to 9, optionally substituted with one or more of cyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluoroalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl substituted with cycloalkyl.

[0218] Section 11.R5 11. The compound according to any one of items 1 to 10, wherein is H, halogen, hydroxy, —CN, methyl, —CF 3 , or methoxy.

[0219] Section 12.R 4 is methyl or -CF3, and R 3 and R 5 Item 12. The compound according to any one of items 1 to 11, wherein at least one of is H or halogen.

[0220] Section 13.R 6 is as follows: [ka] Item 13. The compound according to any one of items 1 to 12, wherein

[0221] Item 14. The compound according to any one of items 1 to 13, wherein m is 0 or 1, n is 0 or 1, o is 0 or 1, and p is 0 or 1.

[0222] Section 15.R 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14 15. The compound according to any one of items 1 to 14, wherein at least one of is not H.

[0223] Section 16.R 11 , R 12 , R 13 , and R 14 is H and R 7 , R 8 , R 9 , and R 10 16. The compound according to any one of items 1 to 15, wherein at least one of is not H.

[0224] Section 17.R 7 , R 8 , R 9 , R 10 , R11 , R 12 , R 13 , and R 14 and (b) are each H.

[0225] Section 18.R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, wherein the methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogens.

[0226] Section 19.R 7 , R 8 , R 9 , and R 10 is H and R 11 , R 12 , R 13 , and R 14 Item 19. The compound according to item 18, wherein at least one of is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, and the methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogens.

[0227] Section 20.R 11 , R 12 , R 13 , and R 14 is H and R7 , R 8 , R 9 , and R 10 Item 19. The compound according to item 18, wherein at least one of is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, and the methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogens.

[0228] Section 21.R 7 , R 8 , R 9 , and R 10 21. The compound according to any one of items 1 to 20, wherein at least one of is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl.

[0229] Section 22.R 7 , R 8 , R 9 , and R 10 21. The compound according to item 20, wherein at least one of is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.

[0230] Section 23.R 7 and R 8 Both or R 9 and R 10 are both F or R 7 and R 8 Both or R 9 and R 10 Item 23. The compound according to item 22, wherein both of are methyl.

[0231] Section 24.R 11 , R 12 , R 13 , and R 1424. The compound according to any one of items 1 to 23, wherein at least one of is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl.

[0232] Section 25.R 11 , R 12 , R 13 , and R 14 25. The compound according to item 24, wherein at least one of is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.

[0233] Section 26.R 11 and R 12 Both or R 13 and R 14 are both F or R 11 and R 12 Both or R 13 and R 14 Item 26. The compound according to item 25, wherein both of are methyl.

[0234] Section 27.R 6 is as follows: [ka] Item 13. The compound according to any one of items 1 to 12, wherein

[0235] Item 28. The compound according to Item 27, wherein q, r, s, t, u, v, w, and x are each independently 0, 1, or 2.

[0236] Item 29. 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. The compound according to any one of items 27 and 28.

[0237] Section 30.R 15 , R 16 , R 17 , R 18, R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, wherein said methanoyl (-COH), carboxy (-COH), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogens.

[0238] Section 31.R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 one or more of R is H, or 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 and n is H.

[0239] Section 32.R 6 is as follows: [ka] 32. The compound according to any one of items 27 to 31, wherein

[0240] Section 33.R 6 is as follows: [ka] 33. The compound according to any one of items 27 to 32, wherein

[0241] Item 34. The compound according to any one of Items 1 to 33, wherein the compound is selected from compounds 1 to 64 listed in Examples 1 to 14 and Tables 1 to 10.

[0242] Item 35. The compound according to any one of items 1 to 34, wherein the compound is selected from compound 1, compound 5, compound 6, compound 8, compound 12, compound 14, compound 16, compound 35, compound 40, compound 44, compound 45, compound 46, compound 47, compound 51, and compound 55.

[0243] Item 36. The compound according to any one of items 1 to 35, wherein the compound is selected from compound 1, compound 5, compound 8, compound 12, compound 14, compound 16, compound 35, compound 44, compound 45, compound 46, compound 47, compound 51, and compound 55.

[0244] Item 37. A composition comprising a compound according to any one of items 1 to 36.

[0245] Item 38. The composition according to Item 37, wherein the amount of the compound is from about 0.0001% (based on the total composition weight) to about 99%.

[0246] Item 39. The composition of Item 37 or 38, further comprising a formulation component, adjuvant, or carrier.

[0247] Item 40. The composition according to any one of Items 37 to 39, further comprising a BCL2 inhibitor.

[0248] Item 41. The composition of any of Items 37 to 40, wherein the composition is used in combination with a second composition comprising a BCL2 inhibitor.

[0249] Clause 42. The composition of any of clauses 37 to 41, wherein the BCL2 comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0250] Clause 43. The composition of any of clauses 37 to 42, wherein the composition is used in combination with one or more chemotherapeutics, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof.

[0251] Item 44. The DNA methyltransferase / hypomethylating agent includes azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a fixed molar ratio of 5:1); and the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproic acid. and / or pracinostat; the purine nucleoside analogs (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab); the mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, cobimetinib, the CDK9 inhibitor includes alvocidib and / or voruciclib; the CDK8 inhibitor includes SEL120; the retinoic acid receptor agonist includes ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activator includes APR-246 (Eprenetapt); the smoothened receptor antagonist includes glasdegib; the ERK inhibitor includes ulixertinib, SCH772 984, lavoxertinib, MK-8353, and / or VTX-11e; the PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23 573), everolimus, bisertib (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, myricholant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor is tazemetostat.

[0252] Clause 45. A method for providing a compound to a subject, comprising one or more administrations of one or more compositions comprising a compound according to any one of clauses 1 to 36, wherein when there are multiple administrations, the compositions may be the same or different.

[0253] Item 46. The method of Item 45, wherein at least one of the one or more compositions comprises a compounding ingredient.

[0254] Item 47. The method according to Item 45 or Item 46, wherein at least one of the one or more compositions comprises a composition according to any one of Items 37 to 44.

[0255] Clause 48. The method of any of clauses 45 to 47, wherein at least one of the one or more administrations comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.

[0256] Clause 49. The method of any one of clauses 45 to 48, wherein, if there are multiple administrations, at least one composition used in at least one administration is different from the composition of at least one other administration.

[0257] Item 50. The method of any one of items 45 to 49, 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).

[0258] Clause 51. The method of any of clauses 45 to 50, wherein the subject is a mammal, preferably the subject is a human, a rodent, or a primate.

[0259] Clause 52. A method for treating a disease or disorder, comprising one or more administrations to a subject of one or more compositions comprising a compound according to any one of clauses 1 to 36, wherein the compositions, if administered multiple times, may be the same or different.

[0260] Clause 53. The method of clause 52, wherein the disease or disorder responds to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.

[0261] Item 54. The method according to Item 52 or 53, wherein at least one of the one or more compositions further comprises a formulation ingredient.

[0262] Item 55. The method of any one of Items 53 to 54, wherein at least one of the one or more compositions comprises a composition according to any one of Items 37 to 44.

[0263] Clause 56. The method of any of clauses 52 to 55, wherein at least one of the one or more administrations comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.

[0264] Clause 57. The method of any of clauses 52 to 56, wherein at least one of the one or more administrations comprises oral administration.

[0265] Clause 58. The method of any of clauses 52 to 57, wherein, if there are multiple administrations, at least one composition used in at least one administration is different from the composition in at least one other administration.

[0266] Item 59. The method of any of items 52 to 58, 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 (of the subject's body weight) to about 50 mg / kg (of the subject's body weight).

[0267] Clause 60. The method of any of clauses 52 to 59, wherein the subject is a mammal, preferably the subject is a human, rodent, or primate.

[0268] Paragraph 61. The method of any one of paragraphs 52 to 60, wherein the subject is in need of the treatment.

[0269] Paragraph 62. The method according to any one of paragraphs 52 to 61, wherein the method is for treating hematopoietic cancer.

[0270] Paragraph 63. The method of any of paragraphs 52 to 62, wherein the method is for treating myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML).

[0271] Clause 64. The method of any of clauses 52 to 62, wherein the method is for treating lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with a MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.

[0272] Clause 65. The method of any of clauses 52 to 61, wherein the disease or disorder is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof.

[0273] Clause 66. The method of clause 65, wherein the method is for treating one or more inflammatory or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof.

[0274] Paragraph 67. The method of any of paragraphs 52 to 63, wherein the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2, or the method is for treating AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or AML that is not driven by a FLT3 mutation but expresses IRAK4-Long.

[0275] Clause 68. The method of Clause 64, wherein the method is for treating DLBCL, and the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL.

[0276] Item 69. The method of Item 68, wherein the method further comprises administering a composition comprising a BTK inhibitor.

[0277] Item 70. The method of Item 69, wherein the BTK inhibitor comprises ibrutinib.

[0278] Clause 71. The method of any of clauses 52 to 70, wherein the subject is susceptible to AML and / or MDS and / or the method prevents or ameliorates future AML and / or MDS.

[0279] Paragraph 72. The method of any of paragraphs 52 to 71, wherein the method is performed after one or more of the following: development of a myelodysplastic syndrome, development of a myeloproliferative disorder, exposure to a chemical, exposure to ionizing radiation, or treatment for cancer.

[0280] Clause 73. The method of any one of clauses 52 to 71, wherein the method further comprises administering a composition comprising a BCL2 inhibitor, or wherein at least one of the compositions comprising a compound according to any one of clauses 1 to 36 further comprises a BCL2 inhibitor.

[0281] Clause 74. The method of clause 73, wherein the compound of any of clauses 1 to 36 and the BCL2 inhibitor may be administered together or separately in one or more administrations of one or more compositions.

[0282] Clause 75. The method of clause 73 or clause 74, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative, or analog thereof.

[0283] Clause 76. The method of any of clauses 52 to 75, wherein the method further comprises administration of one or more additional therapeutic agents selected from one or more chemotherapeutics, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof.

[0284] Item 77. The DNA methyltransferase / hypomethylating agent includes azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a fixed molar ratio of 5:1); and the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproic acid. and / or pracinostat; the purine nucleoside analogs (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab); the mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, cobimetinib, the CDK9 inhibitor includes alvocidib and / or voruciclib; the CDK8 inhibitor includes SEL120; the retinoic acid receptor agonist includes ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activator includes APR-246 (Eprenetapt); the smoothened receptor antagonist includes glasdegib; the ERK inhibitor includes ulixertinib, SCH772 984, lavoxertinib, MK-8353, and / or VTX-11e; the PI3K inhibitors include fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23 573), everolimus, bisertib (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, myricholant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor is tazemetostat.

[0285] Clause 78. A compound according to any one of clauses 1 to 36 for use in a method for treating a disease or disorder, the method comprising inhibiting at least one of IRAK and FLT3 by administering one or more compositions comprising the compound, and when there are multiple administrations, the compositions may be the same or different.

[0286] Item 79. A compound for use according to Item 78, wherein the disease or disorder responds to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.

[0287] Item 80. A compound for use according to Item 78 or 79, wherein at least one of the one or more compositions further comprises a formulating ingredient.

[0288] Item 81. A compound for use according to any one of items 78 to 80, wherein at least one of the one or more compositions comprises a composition according to any one of items 37 to 44.

[0289] Clause 82. The compound for use in any of clauses 78 to 81, wherein at least one of the one or more administrations comprises parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, transdermal, oral, sublingual, intranasal, or intramuscular administration.

[0290] Clause 83. The compound for use according to any of clauses 78 to 82, wherein at least one of said one or more administrations comprises oral administration.

[0291] Clause 84. A compound for use according to any of clauses 78 to 83, wherein, if there are multiple administrations, at least one composition used in at least one administration is different from the composition of at least one other administration.

[0292] Item 85. The compound for use of any of items 78 to 84, 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).

[0293] Paragraph 86. A compound for use according to any of paragraphs 78 to 84, wherein the subject is a mammal, preferably the subject is a human, a rodent, or a primate.

[0294] Paragraph 87. The compound for use according to any of paragraphs 78 to 86, wherein the subject is in need of treatment.

[0295] Paragraph 88. A compound for use according to any one of paragraphs 78 to 87, wherein the method is for treating hematopoietic cancer.

[0296] Paragraph 89. The compound for use of any of paragraphs 78 to 88, wherein the method is for treating MDS and / or AML.

[0297] Paragraph 90. The compound for use according to any of paragraphs 78 to 88, wherein the method is for treating at least one of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MYD88-mutated DLBCL, follicular lymphoma, or marginal zone lymphoma.

[0298] Paragraph 91. A compound for use according to any of paragraphs 78 to 87 for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof.

[0299] Clause 92. The compound for use of clause 91, wherein the method is for treating one or more inflammatory or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof.

[0300] Paragraph 93. The compound for use according to any of paragraphs 78 to 89, wherein the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2, or the method is for treating AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or AML that is not driven by a FLT3 mutation but expresses IRAK4-Long.

[0301] Paragraph 94. The compound for use of Paragraph 90, wherein the method is for treating DLBCL, and the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL.

[0302] Item 95. The compound for use of Item 94, wherein the method further comprises administering a composition comprising a BTK inhibitor.

[0303] Item 96. The compound for use according to Item 95, wherein the BTK inhibitor comprises ibrutinib.

[0304] Clause 97. A compound for use according to clauses 78 to 96, wherein the subject is susceptible to AML and / or MDS and / or the method prevents or ameliorates future AML and / or MDS.

[0305] Item 98. A compound for use according to any one of items 78 to 97, wherein the method is performed after one or more of the following: development of a myelodysplastic syndrome, development of a myeloproliferative disorder, exposure to a chemical, exposure to ionizing radiation, or treatment for cancer.

[0306] Clause 99. The compound for use of clauses 78 to 98, wherein the method further comprises administering a composition comprising a BCL2 inhibitor, or wherein at least one of the compositions comprising a compound according to any one of claims 1 to 36 further comprises a BCL2 inhibitor.

[0307] Item 100. A compound for use according to Item 99, wherein the compound according to any one of claims 1 to 36 and the BCL2 inhibitor may be administered together or separately in one or more administrations of one or more compositions.

[0308] Item 101. A compound for use according to item 99 or 100, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative, or analogue thereof.

[0309] Clause 102. The compound for use of clauses 78 to 101, wherein the method further comprises the administration of one or more additional therapeutic agents selected from one or more chemotherapeutics, DNA methyltransferase / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smoothened receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof.

[0310] Item 103. The DNA methyltransferase / hypomethylating agent includes azacitidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a fixed molar ratio of 5:1); and the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproate, the purine nucleoside analogs (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody drug conjugates include anti-CD33 (e.g., Ac225-lintuzumab, vadastuximab, gemtuzumab-ozogamicin) and / or anti-CD45 (e.g., I 131-apamistamab); the mAb / immunotherapies include anti-CD70 (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123xCD3)), anti-CTLA4 (e.g., ipilimumab), anti-PD1 / PDL1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 (e.g., 5F9 (magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, cobimetinib, the CDK9 inhibitors include alvocidib and / or voruciclib; the CDK8 inhibitors include SEL120; the retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (selective RARα agonist); the TP53 activators include APR-246 (Eprenetapt); the smoothened receptor antagonists include glasdegib; the ERK inhibitors include ulixertinib, SCH772984, The present invention relates to an ERK2 / MAPK1 inhibitor or an ERK1 / MAPK3 inhibitor, including lavoxertinib, MK-8353, and / or VTX-11e; the PI3K inhibitor includes fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and / or bimiralisib (PQR-309); the mTOR inhibitor includes bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), erlotinib (ERL-11), riboflavin (RI ... 103. A compound for use according to any one of claims 78 to 102, wherein the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or an antagonist comprising mifepristone, myricholant, and / or onapristone, and / or another binding ligand comprising vamorolone (VBP15); and / or the EZH2 inhibitor comprises tazemetostat.

[0311] Section 201. Formula (I): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof. (In the formula: R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halogen, hydroxy, oxo (=O), -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl; and The aryl may be substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-COH), nitro (-NO), -NH, -NHCH, -N(CH), cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SOH), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH, -CONHCH, -CON(CH), C-C alkyl, C-C perfluoroalkyl, C-C alkoxy, C-C haloalkoxy, or C-C alkyl substituted with cycloalkyl, and any two adjacent substituents may be bonded or fused to form a ring; R 6 teeth, [ka] Selected from R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogen and / or C-C alkyl; R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl, wherein said methanoyl (-COH), carboxy (-COH), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, cycloalkyl, spirofused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused-ring heteroaryl is optionally substituted with one or more halogen and / or C-C alkyl; m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, and q+r+s+t is at least 1 and u+v+w+x is at least 1.

[0312] Item 202. The compound of formula (I) has the formula (IIf): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; During the ceremony: R 20f is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(CH2) a -(C3-C6 cycloalkyl), and C3-C9 heterocyclyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and the C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, and =O, and any two adjacent substituents can be bonded or fused to form a ring; R21f , R 22f , and R 23f are each independently selected from H and halogen; R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are each independently selected from H, halogen, —OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; 202. The compound according to paragraph 201, wherein a is selected from 0, 1, 2, 3, 4, 5, and 6.

[0313] Section 203.R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb and one or more of the following are independently selected from halogen, -OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

[0314] Section 204.R 20f Item 204. The compound according to item 202 or 203, wherein is H.

[0315] Item 205: The compound according to Item 202 or 203, wherein at least one of the following (i) to (viii) applies: (i)R 20f is t-butyl, unsubstituted C3 cycloalkyl, pyrrolidinyl, -OCH3, -OCH2CH3, [ka] wherein b is 1 or 2; (ii)R 20f is as follows: [ka] where R 27fis as follows: [ka] Selected from; (iii)R 20f is as follows: [ka] where R 28f is =O and R 220fa and R 220fb are each -CH3, or R 220fa and R 220fb is bonded or condensed to form oxetanyl; (iv)R 21f , R 22f , and R 23f are H, respectively; (v)R 21f and R 23f are F and R, respectively. 22f is H; (vi)R 21f and R 23f are H and R, respectively. 22f is F; (vii)R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are H, respectively; (viii)R 25fa , R 25fb , R 26fa , and R 26fb are H and R, respectively. 24fa and / or R 24fb is selected from F, —CH3, and —CF3.

[0316] Item 206. The compound according to any one of items 202 to 205, wherein the compound is selected from the following: [ka] TIFF2024501658000145.tif152125TIFF2024501658000146.tif178125JPEG2024501658000147.jpg123124

[0317] Item 207. The compound of formula (I) has the formula (IIg): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; During the ceremony: the below described: [ka] is as follows: [ka] Selected from; R 20g is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, said C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and said C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -OH, and =O; R 21g , R 22g , and R 23g are each independently selected from H and halogen; R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gbare each independently selected from H, halogen, —OH, and C1-C6 alkyl.

[0318] Section 208.R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb 208. The compound according to paragraph 207, wherein one or more of are independently selected from halogen, —OH, and C1-C6 alkyl.

[0319] Section 209.R 20g Item 209. The compound according to item 207 or 208, wherein is H.

[0320] Item 210: A compound according to any one of Items 207 to 209, wherein at least one of the following (i) to (xi) applies: (i)R 20g is t-butyl, unsubstituted C3 cycloalkyl, [ka] wherein c is 1 or 2; (ii)R 20g is as follows: [ka] and R 29g is an unsubstituted C3 cycloalkyl, -CH3, [ka] Selected from; (iii)R 21g , R 22g , and R 23g are H, respectively; (iv)R 21g and R 23g are F and R, respectively. 22g is H; (v)R 21g and R 23g are H and R, respectively. 22g is F; (vi) The following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H; (vii) The following: [ka] is as follows: [ka] and R 24ga , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 24gb is F; (viii) The following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 25ga , R 26ga , R 26gb , R 27ga , and R 27gb Each of is H and R 25gb is -CH3; (ix) The following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb Each of is H; (x) The following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb Each of is H and R 27ga and / or R 27gb is F or -CH3; (xi) The following: [ka] is as follows: [ka] and R 24ga , R 24gb , R 27ga , R 27gb , R 26ga , R 28ga , and R 28gb Each of is H and R 26gb is F or -CH3.

[0321] Item 211. The compound according to any one of items 207 to 210, wherein the compound is selected from the following: [ka] TIFF2024501658000167.tif187125TIFF2024501658000168.tif152124TIFF2024501658000169.tif151124JPEG2024501658000170.jpg65124

[0322] Item 212. The compound of formula (I) has the formula (IIh): [ka] or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony: the below described: [ka] is as follows: [ka] Selected from; R 20h is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and —OH, and said C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R 21h , R 22h , and R 23h 202. The compound according to paragraph 201, wherein each is independently selected from H and halogen.

[0323] Section 213.R 20h 213. The compound according to item 212, wherein is H.

[0324] Item 214: The compound according to Item 212 or 213, which satisfies at least one of the following (i) to (v): (i)R 20h is as follows: [ka] Selected from; (ii)R 21h , R 22h , and R 23h are H, respectively; (iii)R 21h and R 23h are F and R, respectively. 22h is H; (iv)R 21h and R 23h are H and R, respectively. 22h is F; (v) The following: [ka] is as follows: [ka] is.

[0325] Item 215. The compound according to any one of items 212 to 214, wherein the compound is selected from the following: [ka]

[0326] Paragraph 216. The compound of any of paragraphs 201 to 215, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3.

[0327] Paragraph 217. The compound of any of paragraphs 201 to 216, wherein the compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3.

[0328] Item 218. The compound of any one of items 201 to 217, wherein the compound is an inhibitor of IRAK1 and IRAK4.

[0329] Item 219. The compound of any one of items 201 to 217, wherein the compound is an inhibitor of IRAK1, IRAK4, and FLT3.

[0330] Paragraph 220. The compound of any of paragraphs 216, 217, or 219, wherein the FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.

[0331] Item 221. The compound according to Item 220, wherein the mutant FLT3 is D835Y mutant FLT3 or F691L mutant FLT3.

[0332] Item 222. A composition comprising a compound according to any one of items 201 to 221, the composition further comprising a formulation component, adjuvant, or carrier.

[0333] Item 223. The composition is selected from the group consisting of chemotherapeutic agents, BCL2 inhibitors, immunomodulatory agents, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody drug conjugates, mAbs / immunotherapy, Plk inhibitors, MEK inhibitors, CDK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, smoothened receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, topoisomerase III inhibitors, topoisomerase II ... 223. The composition of claim 222, used in combination with one or more of an isomerase II inhibitor, an aminopeptidase / leukotriene A4 hydrolase inhibitor, a FLT3 / Axl / ALK inhibitor, a FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, a NEDD8 activator, an MDM2 inhibitor, a PLK1 inhibitor, an AuraA inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a Menin-KMT2A / MLL inhibitor, and a multikinase inhibitor.

[0334] Item 224. The composition of Item 223, wherein the composition is used in combination with a BCL2 inhibitor.

[0335] Item 225. The composition of Item 224, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

[0336] Paragraph 226. A method for treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of paragraphs 201 to 221 or a composition according to any one of paragraphs 222 to 225.

[0337] Clause 227. The method of clause 226, wherein the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of clause 1 and a formulation ingredient, adjuvant, or carrier.

[0338] Section 228.

[0339] 228. The method of paragraph 226 or 227, wherein 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.

[0340] Clause 229. The method of any of clauses 226 to 228, wherein the administration comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.

[0341] Item 230. The method of any one of Items 226 to 229, wherein 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).

[0342] Clause 231. The method of any of clauses 226 to 230, wherein the disease or disorder comprises a hematopoietic cancer.

[0343] Clause 232. The method of any of clauses 226 to 230, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML).

[0344] Clause 233. The method of any of clauses 226 to 230, wherein the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), myeloid carcinoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MYD88 mutated DLBCL, follicular lymphoma, or marginal zone lymphoma.

[0345] Clause 234. The method of any of clauses 226 to 230, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, renal cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactive IRAK1 and / or IRAK4, or a combination thereof.

[0346] Clause 235. The method of any of clauses 226 to 230, wherein the disease or disorder comprises one or more inflammatory or autoimmune diseases selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, or a combination thereof.

[0347] Item 236. The disease or disorder is (i) MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2; or (ii) The method of any of paragraphs 226 to 230, including AML with splicing factor mutations, AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or AML that is not driven by FLT3 mutations but expresses IRAK4-Long.

[0348] Item 237. The method of Item 236, wherein the MDS with splicing factor mutations comprises MDS with splicing factor mutations in U2AF1 or SF3B1, and the AML splicing factor mutations comprises AML with splicing factor mutations in U2AF1 or SF3B1.

[0349] Clause 238. The method of any of clauses 226 to 230, wherein the disease or disorder comprises DLBCL, and wherein the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL or the S219C MYD88 mutant (GCB) subtype of DLBCL.

[0350] Item 239. Further, the present invention relates to a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2 / MAPK1 or ERK1 / MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an agonist, an anti-cancer drug ... 239. The method of any of paragraphs 226 to 238, comprising administering to the subject one or more additional therapeutic agents selected from a minopeptidase / leukotriene A4 hydrolase inhibitor, a FLT3 / Axl / ALK inhibitor, a FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, a NEDD8 activator, an MDM2 inhibitor, a PLK1 inhibitor, an AuraA inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitor, an AKT1, 2, and / or 3 inhibitor, an ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitor, a farnesyltransferase inhibitor, a BRAF / MAP2K1 / MAP2K2 inhibitor, a Menin-KMT2A / MLL inhibitor, and a multikinase inhibitor.

[0351] Clause 240. The method of clause 239, wherein the additional therapeutic agent is a BCL2 inhibitor.

[0352] Item 241. The method of Item 240, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

[0353] Paragraph 242. The method of any of paragraphs 226 to 241, wherein the disease or disorder is a BCL2 inhibitor-resistant disease or disorder.

[0354] Clause 243. The method of any of clauses 226 to 241, wherein the disease or disorder is a venetoclax-resistant disease or disorder.

[0355] Item 244. The method of any one of Items 226 to 241, wherein the disease or disorder is an FLT3 inhibitor-resistant disease or disorder.

[0356] Clause 245. The method of any of clauses 226 to 241, wherein the disease or disorder is BCL2 inhibitor-resistant acute myeloid leukemia (AML).

[0357] Clause 246. The method of any of clauses 226 to 241, wherein the disease or disorder is venetoclax-resistant acute myeloid leukemia (AML).

[0358] Paragraph 247. The method of any of paragraphs 226 to 241, wherein the disease or disorder is FLT3 inhibitor-resistant acute myeloid leukemia (AML).

[0359] Paragraph 248. The method of any of paragraphs 226 to 241, wherein the disease or disorder is BCL2 inhibitor-resistant refractory acute myeloid leukemia (AML).

[0360] Clause 249. The method of any of clauses 226 to 241, wherein the disease or disorder is venetoclax-resistant refractory acute myeloid leukemia (AML).

[0361] Item 250. The method of any one of Items 226 to 241, wherein the disease or disorder is FLT3 inhibitor-resistant refractory acute myeloid leukemia (AML).

[0362] Clause 251. The method of any of clauses 226 to 241, wherein the disease or disorder is BCL2 inhibitor-resistant relapsed acute myeloid leukemia (AML).

[0363] Clause 252. The method of any of clauses 226 to 241, wherein the disease or disorder is venetoclax-resistant relapsed acute myeloid leukemia (AML).

[0364] Paragraph 253. The method of any of paragraphs 226 to 241, wherein the disease or disorder is FLT3 inhibitor-resistant relapsed acute myeloid leukemia (AML).

[0365] Clause 254. The method of clause 239, wherein the compound of any one of clauses 201 to 221 or the composition of any one of clauses 222 to 225 and the one or more further therapeutic agents are administered together in a single dose or composition.

[0366] Item 255. The method of claim 239, wherein the compound of any one of items 201 to 221 or the composition of any one of items 222 to 225 and the one or more additional therapeutic agents are administered separately as multiple doses or multiple compositions.

[0367] Paragraph 256. The method of any of paragraphs 226 to 256, wherein the disease or disorder is alleviated in the subject by inhibiting at least one of IRAK1, IRAK4, and FLT3.

[0368] Paragraph 257. The method of any of paragraphs 226 to 256, wherein the disease or disorder is alleviated in the subject by inhibiting at least two of IRAK1, IRAK4, and FLT3.

[0369] Paragraph 258. The method of any of paragraphs 226 to 255, wherein the disease or disorder is alleviated in the subject by inhibiting IRAK1 and IRAK4.

[0370] Paragraph 259. The method of any of paragraphs 226 to 255, wherein the disease or disorder is alleviated in the subject by inhibiting IRAK1, IRAK4, and FLT3.

[0371] Paragraph 260. The method of any of Paragraphs 256, 257, or 259, wherein the FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.

[0372] Paragraph 261. The method of Paragraph 260, wherein the mutant FLT3 is D835Y mutant FLT3 or F691L mutant FLT3. [Example]

[0373] The following non-limiting examples are provided to further illustrate embodiments of the disclosure disclosed herein. The techniques disclosed in the following examples represent approaches found to work well in the practice of the present disclosure and, therefore, can be considered to constitute examples of embodiments thereof, but will be understood by those skilled in the art. However, those skilled in the art will, in light of the present disclosure, understand that many changes can be made to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the disclosure.

[0374] List of abbreviations In the accompanying procedures and schemes, unless otherwise stated, the following abbreviations are used: Ac = acetate; aq, aq. = aqueous; Ar = aryl; BOC, Boc = t-butyloxycarbonyl; Bn = benzyl; BSA = bovine serum albumin; Bu = butyl, t-Bu = tert-butyl; BuLi, n-BuLi = n-butyllithium; CBZ, Cbz = benzyloxycarbonyl; conc, conc. = concentrated; c-Bu = cyclobutyl; c-Pr = cyclopropyl; Cy = cyclohexyl; DAST = (diethylamino)sulfur trifluoride; dba = dibenzylideneacetone; DCM = dichloromethane; DIAD = diisopropyl azodicarboxylate; DIBAL, DIBAL-H = diisobutylaluminum hydride; DIEA = diisopropylethylamine; DMA C,DMA = dimethylacetamide; DME = 1,2-dimethoxyethane; DMEM = Dulbecco's modified Eagle's medium; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; eq. = equivalents; EDC = N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide; EDTA = ethylenediaminetetraacetic acid; ESI = electrospray ionization; Et = ethyl acetate; EtOAc = ethyl acetate; EtOH = ethanol; FBS = fetal bovine serum; h,hr = hours; HATU = N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HOAc = acetic acid; HOAt = 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol; HOBt = 1H-benzotriazol-1-ol; HPLC = high-performance liquid chromatography; HTRF = homogenous time resolved fluorescence; IPA, i-PrOH = isopropanol; iPr = isopropyl; LAH = lithium aluminum hydride; LCMS = liquid chromatography-mass spectrometry; LHMDS = lithium bis(trimethylsilyl)amide; Me = methyl; MeOH = methanol; min, min.= minutes; μW = microwave; NaHMDS = sodium bis(trimethylsilyl)amide; NBS = 1-bromopyrrolidine-2,5-dione; NCS = 1-chloropyrrolidine-2,5-dione; NMP = N-methylpyrrolidinone; NMR = nuclear magnetic resonance; OMs, mesyl = methanesulfonyl; OXONE, OXONE = potassium peroxymonosulfate; PBS = phosphate-buffered saline; Pd2dba3 = tris(dibenzylidyneacetone)dipalladium; Pd / C = palladium on activated carbon; Ph = phenyl; PMB = 4-methoxybenzyl; PMBCl = 1-(chloromethyl)-4-methoxybenzene; Pr = propyl; Py = pyridyl; RT = room temperature; RuPhos Pd G3 = (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; sat. = saturated; TBAF = tetrabutylammonium fluoride; TBAI = tetrabutylammonium iodide; t-Bu = tert-butyl; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; prep TLC = preparative thin layer chromatography; Tosyl = toluenesulfonyl; triflate, OTf = trifluoromethanesulfonate; triflic = trifluoromethanesulfonic acid; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos Pd G2 or XPhos-PD-G2 = chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0375] General method Unless otherwise noted, all reactions were carried out in dry glassware under an atmosphere of dry nitrogen. The reaction temperatures indicated refer to the reaction bath temperature; room temperature (rt) is 25° C. Unless otherwise noted, all solvents were of anhydrous quality purchased from Aldrich Chemical Co. and used as received. Commercially available starting materials and reagents were purchased from commercial suppliers and used as received.

[0376] Analytical thin-layer chromatography (TLC) was performed using Sigma Aldrich TLC plates (5 × 20 cm, 60 Å, 250 μm). Visualization was achieved by irradiation under a UV lamp at 254 nm. Silica gel chromatography was performed on Biotage KP-Sil prepacked cartridges using forced flow (liquid) of the specified solvent system and using a Biotage SP-1 automated chromatography system. 1 H NMR spectra were recorded on a Varian Inova 400 MHz spectrometer. Chemical shifts are reported in ppm using the solvent resonance as the internal standard ( 1 For H, DMSO-d6 2.50 ppm. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, spt = septet, br = broad, m = multiplet), coupling constant, and number of protons. Low-resolution mass spectra (electrospray ionization) were obtained on an Agilent Technologies 6130 quadrupole spectrometer connected to an HPLC system. Unless otherwise noted, all LCMS ions listed are [M+H]. Where necessary, products were purified by semi-preparative HPLC using the indicated column and mobile phase. Sample purity was analyzed on an Agilent 1200 Series LC / MS equipped with a Luna® C18 reversed-phase (3 micron, 3 x 75 mm) column with a 7-minute gradient and a flow rate of 0.8-1.0 mL / min over an 8.5-minute run time (Method 1). Unless otherwise stated, the mobile phase was a mixture of acetonitrile (0.025% TFA) and HO (0.05% TFA) and the temperature was maintained at 50° C. The purity of the final compounds was determined to be >95% using a 3 μL injection, quantified by AUC at 220 and 254 nm (Agilent diode array detector). Example 1 Exemplary Synthetic Procedure #1 (Compounds 1-7) Compound 1, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-(1-methylcyclopropyl)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-amine [ka] Step A. 5-Bromo-N,N-bis(4-methoxybenzyl)pyridin-2-amine [ka]

[0377] To a stirred 0°C mixture of 5-bromopyrazin-2-amine (27.00 g, 155.2 mmol) and sodium hydride (15.52 g, 387.9 mmol, 60% purity) in N,N-dimethylacetamide (200 mL) was added 1-(chloromethyl)-4-methoxy-benzene (60.75 g, 387.9 mmol, 52.83 mL). The resulting reaction mixture was stirred at 0°C for 2 hours, then poured into water and extracted with ethyl acetate (3 × 300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2 × 250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0–15% ethyl acetate in petroleum ether) to provide the title compound. Step B. 5-Isopropenyl-N,N-bis[(4-methoxyphenyl)methyl]pyrazin-2-amine [ka]

[0378] To a solution of 5-bromo-N,N-bis[(4-methoxyphenyl)methyl]pyrazin-2-amine (60.00 g, 144.8 mmol) in toluene (250 mL), tetrahydrofuran (250 mL), and water (100 mL) was added potassium isopropenyltrifluoroborate (25.72 g, 173.8 mmol), cesium carbonate (141.56 g, 434.47 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.60 g, 14.48 mmol). The resulting mixture was heated at 80° C. for 2 hours, then cooled to room temperature, poured into water (200 mL), and extracted with ethyl acetate (2×200 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound: LCMS m / z 376.2 [M+H] + . Step CN,N-bis[(4-methoxyphenyl)methyl]-5-(1-methylcyclopropyl)pyrazin-2-amine [ka]

[0379] A solution of diethylzinc in hexane (1 M, 103.87 mL, 103.87 mmol) was added to dichloromethane (100 mL) at 0° C. Diiodomethane (46.37 g, 173.1 mmol, 13.97 mL) was added dropwise, and the resulting reaction mixture was stirred at 0° C. for 30 minutes. A solution of 5-isopropenyl-N,N-bis[(4-methoxyphenyl)methyl]pyrazin-2-amine (13.0 g, 34.6 mmol) in dichloromethane (50 mL) was added, and the reaction was stirred for 5 hours while warming to room temperature. The reaction mixture was then quenched by the addition of water (100 mL) and extracted with dichloromethane (2×200 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0-20% ethyl acetate in petroleum ether) to give the title compound: LCMS m / z 390.3 [M+H] + . Step D. 5-(1-methylcyclopropyl)pyrazin-2-amine [ka]

[0380] A solution of N,N-bis[(4-methoxyphenyl)methyl]-5-(1-methylcyclopropyl)pyrazin-2-amine (8.00 g, 20.5 mmol) in trifluoroacetic acid (100 mL) was stirred at room temperature for 5 hours. The reaction was then diluted with methanol (100 mL), and the resulting mixture was filtered and concentrated under reduced pressure. The residue thus obtained was basified to pH=8-9 by the addition of 1N aqueous sodium hydroxide at 0°C, and then extracted with ethyl acetate (2×20 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (2×15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound. LCMS m / z 150.0 [M+H] + . Step E. 6-(1-methylcyclopropyl)imidazo[1,2-a]pyrazine [ka]

[0381] To a solution of 5-(1-methylcyclopropyl)pyrazin-2-amine (1.50 g, 10.1 mmol) and 2-chloroacetaldehyde (19.73 g, 100.5 mmol, 16.17 mL, 40% purity) in ethyl alcohol (15 mL) was added sodium bicarbonate (1.44 g, 17.1 mmol). The resulting mixture was heated at 80 °C for 5 h, then cooled to room temperature, concentrated under reduced pressure, diluted with water (30 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (0–100% ethyl acetate in petroleum ether) to give the title compound. LCMS m / z 174.1 [M+H] + . Step F. 3-(6-Bromo-2-pyridyl)-6-(1-methylcyclopropyl)imidazo[1,2-a]pyrazine [ka]

[0382] A mixture of 6-(1-methylcyclopropyl)imidazo[1,2-a]pyrazine (0.901 g, 5.20 mmol), 2,6-dibromopyridine (3.69 g, 15.6 mmol), triphenylphosphine (0.136 g, 0.520 mmol), palladium acetate (0.117 g, 0.520 mmol), and potassium carbonate (2.15 g, 15.6 mmol) in ethyl alcohol (2 mL) and dioxane (4 mL) was purged with nitrogen and then heated at 100 °C under a nitrogen atmosphere for 10 h. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0-10% methanol in dichloromethane) to give the title compound. LCMS m / z 329.1 [M+H] + . Step G. tert-Butyl (3S,4S)-3-fluoro-4-[[6-[6-(1-methylcyclopropyl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate [ka]

[0383] A mixture of 3-(6-bromo-2-pyridyl)-6-(1-methylcyclopropyl)imidazo[1,2-a]pyrazine (0.501 g, 1.52 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (0.310 g, 1.52 mmol), cesium carbonate (1.24 g, 3.80 mmol), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.127 g, 0.152 mmol) in tetrahydrofuran (10 mL) was degassed, purged with nitrogen, and then heated at 80°C under a nitrogen atmosphere for 5 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated in vacuo to give the title compound: LCMS m / z 453.4 [M+H] + . Step H N-[(3S,4S)-4-fluoropyrrolidin-3-yl]-6-[6-(1-methylcyclopropyl)imidazo[1,2-a]pyrazin-3-yl]pyridin-2-amine [ka]

[0384] To a solution of tert-butyl (3S,4S)-3-fluoro-4-[[6-[6-(1-methylcyclopropyl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.400 g, 0.884 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (2.31 g, 20.3 mmol, 1.50 mL). The resulting mixture was stirred at room temperature for 2 hours, then filtered and concentrated under reduced pressure. The resulting crude product was purified by HPLC (Phenomenex Luna C18 column, 10 microns, 250 x 50 mm; 10-40% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 353.0 [M+H] + ; 1 H NMR (400 MHz,CD3OD) δ 9.61 (d, J = 1.3 Hz, 1 H), 9.09 (d, J = 1.1 Hz, 1 H), 8.41 (s, 1 H), 7.68 (t, J = 7.9 Hz, 1 H), 7.34 (d, J = 7.4 Hz, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 5.62 - 5.37 (m, 1 H), 5.01 - 4.96 (m, 1 H), 3.92 - 3.62 (m, 4 H), 1.60 (s, 3 H), 1.35 - 1.20 (m, 2 H), 1.00 - 0.84 (m, 2 H).

[0385] All compounds in Table 1 were prepared using the synthetic procedures described in Example 1. Further compounds prepared according to Example 1 [Table 1] Example 2 Exemplary Synthetic Procedure #2 (Compounds 8-15) Compound 8, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-amine [ka] Step A. 6-[1-(trifluoromethyl)vinyl]imidazo[1,2-a]pyrazine [ka]

[0386] A mixture of 6-bromoimidazo[1,2-a]pyrazine (2.00 g, 10.1 mmol), 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (2.47 g, 11.1 mmol), cesium carbonate (9.87 g, 30.3 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.739 g, 1.01 mmol) in toluene (40 mL) and water (15 mL) was purged with nitrogen and then heated at 110 °C under a nitrogen atmosphere for 10 hours. The reaction mixture was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 × 15 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0-100% ethyl acetate in petroleum ether) to give the title compound: LCMS m / z 214.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 9.04 (s, 1 H), 8.20 (s, 1 H), 7.78 - 7.65 (m, 2 H), 6.70 (q, J = 2.0 Hz, 1 H), 6.10 (d, J = 0.8 Hz, 1 H). Step B. 6-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyrazine [ka]

[0387] To a cooled solution of 6-[1-(trifluoromethyl)vinyl]imidazo[1,2-a]pyrazine (2.00 g, 9.38 mmol) and methyl(diphenyl)sulfonium tetrafluoroborate (2.27 g, 11.3 mmol) in tetrahydrofuran (30 mL) at 0°C was added a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 18.77 mL). The resulting mixture was stirred for 10 hours while warming to room temperature. The reaction was then quenched by the addition of water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0–100% ethyl acetate in petroleum ether) to give the title compound. LCMS m / z 228.1 [M+H] + . Step C. 3-(6-Bromo-2-pyridyl)-6-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyrazine [ka]

[0388] A mixture of 6-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyrazine (1.30 g, 5.72 mmol), 2,6-dibromopyridine (4.07 g, 17.2 mmol), triphenylphosphine (0.300 g, 1.14 mmol), palladium acetate (0.128 g, 0.572 mmol), potassium carbonate (2.37 g, 17.2 mmol), and 2,2-dimethylpropanoic acid (0.175 g, 1.72 mmol, 0.197 mL) in toluene (50 mL) was purged with nitrogen and then heated to 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0 to 100% ethyl acetate in petroleum ether) to provide the title compound. LCMS m / z 383.0 [M+H] + . Step D. tert-Butyl (3S,4S)-3-fluoro-4-[[6-[6-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate [ka]

[0389] A mixture of 3-(6-bromo-2-pyridyl)-6-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyrazine (0.060 g, 0.157 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (0.032 g, 0.157 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.013 g, 0.016 mmol), and cesium carbonate (0.128 g, 0.391 mmol) in tetrahydrofuran (3 mL) was purged with nitrogen and then heated at 80 °C under a nitrogen atmosphere for 5 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated in vacuo to give the title compound: LCMS m / z 507.3 [M+H] + Step E. 5-(tert-butyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine [ka]

[0390] To a solution of tert-butyl (3S,4S)-3-fluoro-4-[[6-[6-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.070 g, 0.138 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL). The resulting mixture was stirred at room temperature for 3 hours, then filtered and concentrated under reduced pressure. The crude product was purified by HPLC (Phenomenex Gemini-NX C18 column, 5 microns, 150 x 30 mm; 10-40% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 407.0 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 9.87 (s, 1 H), 9.07 (s, 1 H), 8.40 (s, 1 H), 7.67 (t, J = 7.9 Hz, 1 H), 7.38 (d, J = 7.5 Hz, 1 H), 6.66 (d, J = 8.3 Hz, 1 H), 5.63 - 5.35 (m, 1 H), 4.97 (br dd, J = 5.5, 12.6 Hz, 1 H), 3.92 - 3.62 (m, 4 H), 1.56 - 1.48 (m, 2 H), 1.47 - 1.38 (m, 2 H).

[0391] All compounds in Table 2 were prepared using the synthetic procedures described in Example 2. Further compounds prepared according to Example 2 [Table 2] Example 3 Exemplary Synthetic Procedure #3 (Compounds 16-26) Compound 16, 6-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3-yl)pyridin-2-amine [ka] Step A. 6-Vinylimidazo[1,2-a]pyrazine [ka]

[0392] A mixture of 6-bromoimidazo[1,2-a]pyrazine (10.0 g, 50.5 mmol), potassium vinyltrifluoroborate (16.91 g, 126.3 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (4.12 g, 5.05 mmol), and aqueous potassium carbonate (1.0 M, 152 mL, 152 mmol) in tetrahydrofuran (150 mL) was purged with nitrogen and then heated at 80 °C under a nitrogen atmosphere for 15 hours. The reaction mixture was then cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (2 × 150 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (2 × 75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0-10% methanol in dichloromethane) to give the title compound: LCMS m / z 146.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 9.21 - 8.78 (m, 1 H), 7.95 (s, 1 H), 7.73 (s, 1 H), 7.62 (s, 1 H), 6.66 (dd, J = 10.6, 17.0 Hz, 1 H), 6.27 (d, J = 16.9 Hz, 1 H), 5.43 (d, J = 10.7 Hz, 1 H). Step B. Imidazo[1,2-a]pyrazine-6-carbaldehyde [ka]

[0393] To a solution of 6-vinylimidazo[1,2-a]pyrazine (6.00 g, 41.3 mmol) in 1,4-dioxane (300 mL) and water (150 mL) was added sodium periodate (13.26 g, 62.00 mmol), 2,6-dimethylpyridine (8.86 g, 82.7 mmol), and osmium tetroxide (1.05 g, 4.13 mmol). The resulting reaction mixture was stirred at room temperature for 10 hours, then quenched by the addition of saturated aqueous sodium sulfite (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0–100% ethyl acetate in petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 10.21 - 9.98 (m, 1 H), 9.16 (s, 1 H), 8.81 (d, J = 1.5 Hz, 1 H), 8.02 - 7.77 (m, 2 H). Step C. 6-(Difluoromethyl)imidazo[1,2-a]pyrazine [ka]

[0394] To a cooled solution of imidazo[1,2-a]pyrazine-6-carbaldehyde (2.00 g, 13.6 mmol) in dichloromethane (60 mL) at 0°C was added diethylaminosulfur trifluoride (4.38 g, 27.2 mmol, 3.59 mL). The resulting reaction mixture was stirred at room temperature for 10 hours, then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel flash chromatography (0-100% ethyl acetate in petroleum ether) to give the title compound. LCMS m / z 170.2 [M+H] + . Step D. 3-(6-Bromo-2-pyridyl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine [ka]

[0395] A mixture of 6-(difluoromethyl)imidazo[1,2-a]pyrazine (1.00 g, 5.91 mmol), 2,6-dibromopyridine (4.20 g, 17.7 mmol), triphenylphosphine (0.310 g, 1.18 mmol), palladium acetate (0.133 g, 0.591 mmol), potassium carbonate (2.45 g, 17.7 mmol), and 2,2-dimethylpropanoic acid (0.181 g, 1.77 mmol) in toluene (40 mL) was purged with nitrogen and then heated to 100 °C under a nitrogen atmosphere for 10 h. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0 to 100% ethyl acetate in petroleum ether) to provide the title compound. Step E. 5-(tert-butyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine [ka]

[0396] A mixture of 3-(6-bromo-2-pyridyl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine (0.070 g, 0.215 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (0.044 g, 0.215 mmol), cesium carbonate (0.175 g, 0.538 mmol), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.018 g, 0.022 mmol) in tetrahydrofuran (5 mL) was degassed, purged with nitrogen, and then heated at 80°C under a nitrogen atmosphere for 5 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated in vacuo to give the title compound: LCMS m / z 449.2 [M+H] + . Step F. 6-[6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl]-N-[(3S,4S)-4-fluoropyrrolidin-3-yl]pyridin-2-amine [ka]

[0397] To a solution of tert-butyl (3S,4S)-3-[[6-[6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.100 g, 0.223 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL). The resulting reaction mixture was stirred at room temperature for 3 hours, then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Gemini-NX C18 column, 5 microns, 150 x 30 mm; 5-35% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 349.0 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 10.10 (d, J = 1.1 Hz, 1 H), 9.13 (s, 1 H), 8.45 (s, 1 H), 7.71 - 7.51 (m, 1 H), 7.40 (d, J = 7.5 Hz, 1 H), 7.10 - 6.72 (m, 1 H), 6.64 (d, J = 8.2 Hz, 1 H), 5.63 - 5.41 (m, 1 H), 4.95 - 4.88 (m, 1 H), 3.89 (dd, J = 6.1, 12.2 Hz, 1 H), 3.79 - 3.73 (m, 1 H), 3.72 - 3.60 (m, 2 H).

[0398] All compounds in Table 3 were prepared using the synthetic procedures described in Example 3. Further compounds prepared according to Example 3 [Table 3] JPEG2024501658000203.jpg50124 Example 4 Exemplary Synthetic Procedure #4 (Compounds 27-35) Compound 27, (R)-2-(3-(6-(pyrrolidin-3-ylamino)pyridin-2-yl)imidazo[1,2-a]pyrazin-6-yl)propan-2-ol [ka] Step A. 1-Imidazo[1,2-a]pyrazin-6-ylethanone [ka]

[0399] A mixture of 6-bromoimidazo[1,2-a]pyrazine (5.00 g, 25.3 mmol), tributyl(1-ethoxyvinyl)stannane (13.68 g, 37.87 mmol, 12.78 mL), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.85 g, 2.52 mmol), and copper iodide (0.721 g, 3.79 mmol) in acetonitrile (100 mL) was purged with nitrogen and then heated at 80° C. under a nitrogen atmosphere for 5 hours. The reaction was then cooled to room temperature. Hydrochloric acid (1.0 M, 25.25 mL) was added, and the reaction was stirred at room temperature for 2 hours. Saturated aqueous potassium fluoride (30 mL) was added, and the mixture was then cooled to 0°C, basified to pH 8-9 by the addition of saturated aqueous sodium hydroxide, and extracted with ethyl acetate (3 x 50 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (2 x 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0-100% ethyl acetate) to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ 9.15 (br s, 1 H), 8.94 (br s, 1 H), 8.03 - 7.81 (m, 2 H), 2.79 (s, 3 H). Step B. 5-Isopropenyl-N,N-bis[(4-methoxyphenyl)methyl]pyrazin-2-amine [ka]

[0400] To a cooled solution of 1-imidazo[1,2-a]pyrazin-6-ylethanone (0.901 g, 5.58 mmol) in dichloromethane (20 mL) at 0°C was added a solution of methylmagnesium bromide in diethyl ether (3 M, 9.31 mL). The resulting reaction mixture was stirred at 0°C for 1 hour, then quenched by the addition of water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0-100% ethyl acetate in petroleum ether) to give the title compound. LCMS m / z 178.2 [M+H] + . Step C. 2-(6-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-2-methylpropan-1-ol [ka]

[0401] A mixture of 2-imidazo[1,2-a]pyrazin-6-ylpropan-2-ol (0.300 g, 1.69 mmol), 2,6-dibromopyridine (1.20 g, 5.08 mmol), triphenylphosphine (0.089 g, 0.339 mmol), palladium acetate (0.038 g, 0.169 mmol), potassium carbonate (0.702 g, 5.08 mmol), and 2,2-dimethylpropanoic acid (0.052 g, 0.508 mmol) in toluene (5 mL) was purged with nitrogen and then heated at 100 °C under a nitrogen atmosphere for 10 h. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound. LCMS m / z 333.2 [M+H] + . Step D. tert-Butyl (3R)-3-[[6-[6-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate [ka]

[0402] A mixture of 2-[3-(6-bromo-2-pyridyl)imidazo[1,2-a]pyrazin-6-yl]propan-2-ol (0.030 g, 0.090 mmol), tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (0.017 g, 0.090 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.008 g, 0.009 mmol), and cesium carbonate (0.073 g, 0.225 mmol) in tetrahydrofuran (3 mL) was purged with nitrogen and then heated at 80°C under a nitrogen atmosphere for 3 hours. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound. LCMS m / z 439.2 [M+H] + . Step E. 2-[3-[6-[[(3R)-pyrrolidin-3-yl]amino]-2-pyridyl]imidazo[1,2-a]pyrazin-6-yl]propan-2-ol [ka]

[0403] To a solution of tert-butyl (3R)-3-[[6-[6-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.030 g, 0.068 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL). The resulting reaction mixture was stirred at room temperature for 2 hours, then filtered and concentrated under reduced pressure. The product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 microns, 75 x 30 mm; 6-36% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 339.1 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 10.20 (d, J = 1.3 Hz, 1 H), 9.06 (d, J = 1.3 Hz, 1 H), 8.40 (s, 1 H), 7.59 (dd, J = 7.6, 8.3 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 1 H), 6.58 (d, J = 8.2 Hz, 1 H), 4.96 - 4.88 (m, 1 H), 3.81 (dd, J = 5.8, 12.0 Hz, 1 H), 3.61 - 3.44 (m, 2 H), 3.36 (dd, J = 4.2, 11.9 Hz, 1 H), 2.56 - 2.44 (m, 1 H), 2.22 - 2.12 (m, 1 H), 1.65 (d, J = 9.0 Hz, 6H).

[0404] All compounds in Table 4 were prepared using the synthetic procedures described in Example 4. Further compounds prepared according to Example 4 [Table 4] JPEG2024501658000211.jpg99125Example 5 Exemplary Synthetic Procedure #5 (Compounds 36-42) Compound 36. N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-amine [ka] Step A. 6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazine [ka]

[0405] A mixture of 6-chloroimidazo[1,2-a]pyrazine (1.60 g, 10.4 mmol) and cesium carbonate (16.97 g, 52.09 mmol) in 2,2,2-trifluoroethanol (15 mL) was stirred at 100 °C for 16 h. The reaction mixture was then cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 × 20 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0–20% ethyl acetate in petroleum ether) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1 H), 8.46 (s, 1 H), 8.12 (s, 1 H), 7.87 (s, 1 H), 4.99 (q, J = 9.0 Hz, 2 H). Step B. 3-(6-Bromopyridin-2-yl)-6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazine [ka]

[0406] A mixture of 6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazine (1.00 g, 4.61 mmol), 2,6-dibromopyridine (3.27 g, 13.8 mmol), triphenylphosphine (0.121 g, 0.461 mmol), potassium carbonate (1.91 g, 13.8 mmol), and palladium acetate (0.103 g, 0.461 mmol) in 1,4-dioxane (10 mL) and ethyl alcohol (5 mL) was purged with nitrogen and then heated at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0 to 20% ethyl acetate in petroleum ether) to provide the title compound. Step C. tert-Butyl (3S,4S)-3-fluoro-4-[[6-[6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate [ka]

[0407] A mixture of 3-(6-bromo-2-pyridyl)-6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazine (0.060 g, 0.161 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (0.036 g, 0.177 mmol), cesium carbonate (0.131 g, 0.402 mmol), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.013 g, 0.016 mmol) in tetrahydrofuran (1 mL) was heated at 80° C. for 10 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to provide the title compound. LCMS m / z 497.2 [M+H] + . Step DN-[(3S,4S)-4-fluoropyrrolidin-3-yl]-6-[6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazin-3-yl]pyridin-2-amine [ka]

[0408] To a solution of tert-butyl (3S,4S)-3-fluoro-4-[[6-[6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.050 mg, 0.101 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL). The resulting reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 microns, 80 x 30 mm; 10-40% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 397.1 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 9.54 (s, 1 H), 8.86 (d, J = 1.1 Hz, 1 H), 8.40 (s, 1 H), 7.64 (t, J = 7.9 Hz, 1 H), 7.36 (d, J = 7.5 Hz, 1 H), 6.61 (d, J = 8.3 Hz, 1 H), 5.58 - 5.43 (m, 1 H), 4.94 (q, J = 8.7 Hz, 2 H), 4.89 (br s, 1 H), 3.89 (dd, J = 6.2, 12.8 Hz, 1 H), 3.78 - 3.74 (m, 1 H), 3.72 - 3.65 (m, 1 H), 3.65 - 3.59 (m, 1 H).

[0409] All compounds in Table 5 were prepared using the synthetic procedures described in Example 5. Further compounds prepared according to Example 5 [Table 5] Example 6 Exemplary Synthetic Procedure #6 (Compounds 43-55) Compound 43, (R)-6-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)-N-(piperidin-3-yl)pyridin-2-amine [ka] Step A. tert-Butyl (3R)-3-[[6-(6-chloroimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]piperidine-1-carboxylate [ka]

[0410] A mixture of 3-(6-bromo-2-pyridyl)-6-chloro-imidazo[1,2-a]pyrazine (1.00 g, 3.23 mmol), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (0.647 g, 3.23 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.270 g, 0.323 mmol), and cesium carbonate (3.16 g, 9.69 mmol) in tetrahydrofuran (20 mL) was purged with nitrogen and then heated at 80°C under a nitrogen atmosphere for 5 hours. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography (0-30% ethyl acetate in petroleum ether) to give the title compound: LCMS m / z 429.1 [M+H] + . Step B. tert-Butyl (3R)-3-[[6-[6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]piperidine-1-carboxylate [ka]

[0411] tert-Butyl (3R)-3-[[6-(6-chloroimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]piperidine-1-carboxylate (0.080 g, 0.187 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.039 g, 0.187 mmol), chloro(2-dicyclohexyl)pyrazole (0.039 g, 0.187 mmol), A mixture of 2-(2'-amino-1,1'-biphenyl)-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) (0.015 g, 0.019 mmol) and aqueous potassium phosphate (1.0 M, 0.560 mL, 0.560 mmol) in tetrahydrofuran (3 mL) was purged with nitrogen and then stirred at 90° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound. LCMS m / z 475.2 [M+H] + . Step C. 6-[6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl]-N-[(3R)-3-piperidyl]pyridin-2-amine [ka]

[0412] To a solution of tert-butyl (3R)-3-[[6-[6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]piperidine-1-carboxylate (0.065 g, 0.137 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL). The resulting reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting crude product was purified by HPLC (Phenomenex Gemini-NX C18 column, 5 microns, 150 x 30 mm; 2-32% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 375.2 [M+H]+ ; 1 H NMR (400 MHz, CD3OD) δ 9.64 (d, J = 1.3 Hz, 1 H), 9.09 (d, J = 1.3 Hz, 1 H), 8.29 (s, 1 H), 8.14 (s, 1 H), 7.96 (s, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 7.18 (d, J = 7.5 Hz, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 4.34 (td, J = 4.0, 7.8 Hz, 1 H), 3.97 (s, 3 H), 3.38 (dd, J = 3.3, 12.6 Hz, 1 H), 3.28 - 3.21 (m, 1H), 3.17 (dd, J = 8.4, 12.1 Hz, 1 H), 3.11 - 3.03 (m, 1 H), 2.28 - 2.17 (m, 1 H), 2.15 - 2.06 (m, 1 H), 1.90 - 1.73 (m, 2 H).

[0413] All compounds in Table 6 were prepared using the synthetic procedures described in Example 6. Further compounds prepared according to Example 6 [Table 6] JPEG2024501658000223.jpg185124 Example 7 Exemplary Synthetic Procedure #7 (Compounds 56-57) Compound 56, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-methoxyimidazo[1,2-a]pyrazin-3-yl)pyridin-2-amine [ka] Step A. (3S,4S)-tert-butyl 3-fluoro-4-((6-(6-methoxyimidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate [ka]

[0414] To a solution of tert-butyl (3S,4S)-3-[[6-(6-chloroimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.070 g, 0.162 mmol) in methanol (1 mL) was added sodium methoxide (0.087 g, 1.62 mmol). The resulting reaction mixture was heated at 80° C. for 16 hours, then cooled to room temperature, diluted with water (3 mL), and extracted with ethyl acetate (3×5 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound. LCMS m / z 429.2 [M+H] + . Step B N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-methoxyimidazo[1,2-a]pyrazin-3-yl)pyridin-2-amine [ka]

[0415] To a solution of tert-butyl (3S,4S)-3-fluoro-4-[[6-(6-methoxyimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.080 g, 0.187 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.23 g, 10.8 mmol, 0.800 mL). The resulting reaction was stirred at room temperature for 1 hour, then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 5 microns, 100 x 40 mm; 5-30% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 329.1 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ 9.37 (s, 1 H), 8.87 (d, J = 1.0 Hz, 1 H), 8.37 (s, 1 H), 7.66 (t, J = 7.9 Hz, 1 H), 7.35 (d, J = 7.4 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 5.59 - 5.40 (m, 1 H), 4.96 - 4.90 (m, 1 H), 4.03 (s, 3 H), 3.92 (dd, J = 6.1, 12.7 Hz, 1 H), 3.79 - 3.76 (m, 1 H), 3.72 - 3.57 (m, 2 H).

[0416] All compounds in Table 7 were prepared using the synthetic procedures described in Example 7. Further compounds prepared according to Example 7 [Table 7] Example 8 Exemplary Synthetic Procedure #8 (Compound 58) Compound 58, 6-(6-(2,2-difluoroethoxy)imidazo[1,2-a]pyrazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3-yl)pyridin-2-amine [ka] Step A. (3S,4S)-tert-butyl 3-((6-(6-(2,2-difluoroethoxy)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylate [ka]

[0417] To a cooled solution of 2,2-difluoroethanol (0.057 g, 0.693 mmol) in N,N-dimethylacetamide (2 mL) at 0° C. was added sodium hydride (0.017 g, 0.416 mmol, 60% purity). The resulting reaction mixture was removed from the cold bath and stirred for 30 minutes while warming to room temperature. A solution of tert-butyl (3S,4S)-3-[[6-(6-chloroimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.060 g, 0.139 mmol) in N,N-dimethylacetamide (1 mL) was then added, resulting in a mixture that was then heated at 80° C. for 12 hours. The reaction was then cooled to room temperature, diluted with water (3 mL), and extracted with ethyl acetate (3×5 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (4 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound: LCMS m / z 479.3 [M+H] + . Step B. 6-(6-(2,2-difluoroethoxy)imidazo[1,2-a]pyrazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3-yl)pyridin-2-amine [ka]

[0418] To a solution of tert-butyl (3S,4S)-3-[[6-[6-(2,2-difluoroethoxy)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.050 g, 0.105 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Xtimate C18 column, 3 microns, 100 x 30 mm; 1-31% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 379.2 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ 9.81 (d, J = 1.4 Hz, 1 H), 9.24 (d, J = 1.4 Hz, 1 H), 8.88 (s, 1 H), 7.75 (dd, J = 7.6, 8.4 Hz, 1 H), 7.43 (d, J = 7.5 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 6.03 (d, J = 2.5 Hz, 1 H), 5.59 - 5.41 (m, 1 H), 4.90 - 4.84 (m, 1 H), 4.75 (dt, J = 3.7, 14.0 Hz, 2 H), 3.94 (dd, J = 6.4, 12.8 Hz, 1 H), 3.82 - 3.76 (m, 1 H), 3.74 - 3.61 (m, 2 H). Example 9 Exemplary Synthetic Procedure #9 (Compounds 59-60) Compound 59, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-isopropoxyimidazo[1,2-a]pyrazin-3-yl)pyridin-2-amine [ka] Step A. tert-Butyl (3S,4S)-3-fluoro-4-[[6-(6-isopropoxyimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]pyrrolidine-1-carboxylate [ka]

[0419] A mixture of tert-butyl (3S,4S)-3-[[6-(6-chloroimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.060 g, 0.139 mmol), propan-2-ol (0.042 g, 0.693 mmol, 0.053 mL), sodium tert-butoxide (0.027 g, 0.277 mmol), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium-di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (0.011 g, 0.014 mmol) in toluene (2 mL) was purged with nitrogen and then heated at 80 °C under a nitrogen atmosphere for 16 hours. The reaction was then cooled to room temperature, filtered and concentrated in vacuo to give the title compound: LCMS m / z 457.2 [M+H] + . Step B N-[(3S,4S)-4-fluoropyrrolidin-3-yl]-6-(6-isopropoxyimidazo[1,2-a]pyrazin-3-yl)pyridin-2-amine [ka]

[0420] To a solution of tert-butyl (3S,4S)-3-fluoro-4-[[6-(6-isopropoxyimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.015 g, 0.033 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.232 g, 2.03 mmol, 0.150 mL). The resulting reaction was stirred at room temperature for 1 hour, then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Gemini-NX C18 column, 5 microns, 150 x 30 mm; 1-26% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 357.1 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ 9.34 (s, 1 H), 8.84 (s, 1 H), 8.34 (s, 1 H), 7.63 (t, J = 7.94 Hz, 1 H), 7.33 (d, J = 7.50 Hz, 1 H), 6.60 (d, J = 8.25 Hz, 1 H), 5.37 - 5.63 (m, 1 H), 5.20 (spt, J = 6.13 Hz, 1 H), 4.91 - 5.02 (m, 1 H), 3.90 (dd, J = 12.69, 6.07 Hz, 1 H), 3.74 - 3.80 (m, 1 H), 3.65 - 3.74 (m, 1 H), 3.60 - 3.65 (m, 1 H), 1.36 (t, J = 6.50 Hz, 6 H).

[0421] All compounds in Table 8 were prepared using the synthetic procedures described in Example 9. Further compounds prepared according to Example 9 [Table 8] Example 10 Exemplary Synthetic Procedure #10 (Compounds 61-62) Compound 61, 1-(3-(6-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)pyridin-2-yl)imidazo[1,2-a]pyrazin-6-yl)-3,3-dimethylpyrrolidin-2-one [ka] Step A. tert-Butyl (3S,4S)-3-((6-(6-(3,3-dimethyl-2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylate [ka]

[0422] tert-Butyl (3S,4S)-3-[[6-(6-chloroimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.020 g, 0.046 mmol), 3,3-dimethylpyrrolidin-2-one (0.010 g, 0.092 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6- A mixture of dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.004 g, 0.005 mmol) and sodium tert-butoxide (0.009 g, 0.092 mmol) in toluene (1 mL) was purged with nitrogen and then heated at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound. LCMS m / z 510.2 [M+H] + . Step B. 1-(3-(6-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)pyridin-2-yl)imidazo[1,2-a]pyrazin-6-yl)-3,3-dimethylpyrrolidin-2-one [ka]

[0423] To a solution of tert-butyl (3S,4S)-3-[[6-[6-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.060 g, 0.118 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.578 g, 5.06 mmol, 0.375 mL). The resulting reaction was stirred at room temperature for 1 hour, then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 5 microns, 100 x 40 mm; 1-30% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. LCMS m / z 410.2 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ 10.63 (s, 1 H), 8.97 (s, 1 H), 8.35 (s, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 1 H), 6.61 (d, J = 8.3 Hz, 1 H), 5.37 (br s, 1 H), 5.26 (br dd, J = 4.8, 13.1 Hz, 1 H), 4.20 - 4.01 (m, 2 H), 3.88 (br dd, J = 5.7, 12.5 Hz, 1 H), 3.81 - 3.55 (m, 3 H), 2.08 (t, J = 6.9 Hz, 2 H), 1.27 (d, J = 2.9 Hz, 6H).

[0424] All compounds in Table 9 were prepared using the synthetic procedures described in Example 10. Further compounds prepared according to Example 10 [Table 9] Example 11 Exemplary Synthetic Procedure #11 (Compound 63) Compound 63, 1-(3-(6-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)pyridin-2-yl)imidazo[1,2-a]pyrazin-6-yl)-4,4-dimethylpyrrolidin-2-one [ka] Step A. (3S,4S)-tert-butyl 3-((6-...

Claims

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

2. Formula (IIf): 【Chemistry 3】 or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; During the ceremony: R ２０ｆ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, -O-(CH ２ ) ａ - (C ３ -C ６ cycloalkyl), and C ３ -C ９ heterocyclyl, １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from -OH and halogen; ３ -C ６ Cycloalkyl is C １ -C ６ may be substituted with one or more substituents selected from alkyl and halogen; ３ -C ９ Heterocyclyl is halogen, C １ -C ６ Alkyl, C １ -C ６ may be substituted with one or more substituents selected from alkoxy, -OH, and =O, and any two adjacent substituents may be bonded or fused to form a ring; R ２１ｆ , R ２２ｆ , and R ２３ｆ are each independently selected from H and halogen; R ２４ｆａ , R ２４ｆｂ , R ２５ｆａ , R ２５ｆｂ , R ２６ｆａ , and R ２６ｆｂ are each independently H, a halogen, —OH, or C １ -C ６ Alkyl, and C １ -C ６ alkoxy, １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be optionally substituted with one or more halogen atoms; 2. The compound of claim 1, wherein a is selected from 0, 1, 2, 3, 4, 5, and 6, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof.

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

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

5. The compound according to claim 2 or 3, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, which satisfies at least one of the following (i) to (viii): (i) R ２０ｆ is t-butyl, unsubstituted C ３ Cycloalkyl, pyrrolidinyl, -OCH ３ , -OCH ２ CH ３ ,the below described: 【Chemistry 4】 wherein b is 1 or 2; (ii) R ２０ｆ below: 【Chemistry 5】 Wherein R ２７ｆ below: 【Chemistry 6】 Selected from: (iii) R ２０ｆ below: 【Chemistry 7】 Wherein R ２８ｆ is =O, and R ２２０ｆａ and R ２２０ｆｂ are each -CH ３ or R ２２０ｆａ and R ２２０ｆｂ is bonded or condensed to form oxetanyl; (iv) R ２１ｆ , R ２２ｆ , and R ２３ｆ are each H; (v) R ２１ｆ and R ２３ｆ are F and R, respectively. ２２ｆ is H; (vi) R ２１ｆ and R ２３ｆ are H and R ２２ｆ is F; (vii) R ２４ｆａ , R ２４ｆｂ , R ２５ｆａ , R ２５ｆｂ , R ２６ｆａ , and R ２６ｆｂ are each H; (viii) R ２５ｆａ , R ２５ｆｂ , R ２６ｆａ , and R ２６ｆｂ are H and R ２４ｆａ and / or R ２４ｆｂ is F, -CH ３ , and -CF ３ is selected from.

6. 6. The compound according to claim 2, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein the compound is selected from the following compounds: 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】

7. Formula (IIg): 【Chemistry 12】 or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof; During the ceremony: the below described: 【Chemistry 13】 below: 【Chemistry 14】 Selected from: R ２０ｇ is H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, and C ３ -C ９ heterocyclyl, １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from -OH and halogen; ３ -C ６ Cycloalkyl is C １ -C ６ may be substituted with one or more substituents selected from alkyl and halogen; ３ -C ９ Heterocyclyl is halogen, C １ -C ６ Alkyl, C ３ -C ６ optionally substituted with one or more substituents selected from -cycloalkyl, -OH, and =O; R ２１ｇ , R ２２ｇ , and R ２３ｇ are each independently selected from H and halogen; R ２４ｇａ , R ２４ｇｂ , R ２５ｇａ , R ２５ｇｂ , R ２６ｇａ , R ２６ｇｂ , R ２７ｇａ , R ２７ｇｂ , R ２８ｇａ , and R ２８ｇｂ are each independently H, a halogen, —OH, or C １ -C ６ 2. The compound of claim 1, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof, wherein R is selected from the group consisting of aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

8. R ２４ｇａ , R ２４ｇｂ , R ２５ｇａ , R ２５ｇｂ , R ２６ｇａ , R ２６ｇｂ , R ２７ｇａ , R ２７ｇｂ , R ２８ｇａ , and R ２８ｇｂ One or more of are independently selected from halogen, —OH, and C １ -C ６ 8. The compound of claim 7, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof, wherein R is selected from the group consisting of aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

9. R ２０ｇ is H, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof according to claim 7 or 8.

10. The compound according to any one of claims 7 to 9, wherein at least one of the following (i) to (xi) applies, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof: (i) R ２０ｇ is t-butyl, unsubstituted C ３ Cycloalkyl, such as: 【Chemistry 15】 wherein c is 1 or 2; (ii) R ２０ｇ below: 【Chemistry 16】 and R ２９ｇ is unsubstituted C ３ Cycloalkyl, -CH ３ ,the below described: 【Chemistry 17】 Selected from: (iii) R ２１ｇ , R ２２ｇ , and R ２３ｇ are each H; (iv) R ２１ｇ and R ２３ｇ are F and R, respectively. ２２ｇ is H; (v) R ２１ｇ and R ２３ｇ are H and R ２２ｇ is F; (vi) the following: 【Chemistry 18】 below: 【Chemistry 19】 and R ２４ｇａ , R ２４ｇｂ , R ２５ｇａ , R ２５ｇｂ , R ２６ｇａ , R ２６ｇｂ , R ２７ｇａ , and R ２７ｇｂ each of is H; (vii) the following: 【Chemistry 20】 below: 【Chemistry 21】 and R ２４ｇａ , R ２５ｇａ , R ２５ｇｂ , R ２６ｇａ , R ２６ｇｂ , R ２７ｇａ , and R ２７ｇｂ is H, and each of R ２４ｇｂ is F; (viii) the following: 【Chemical 22】 below: 【Chemistry 23】 and R ２４ｇａ , R ２４ｇｂ , R ２５ｇａ , R ２６ｇａ , R ２６ｇｂ , R ２７ｇａ , and R ２７ｇｂ is H, and each of R ２５ｇｂ is -CH ３ is; (ix) the following: 【Chemistry 24】 below: 【Chemistry 25】 and R ２４ｇａ , R ２４ｇｂ , R ２６ｇａ , R ２６ｇｂ , R ２７ｇａ , R ２７ｇｂ , R ２８ｇａ , and R ２８ｇｂ each of is H; (x) the following: 【Chemistry 26】 below: 【Chemical 27】 and R ２４ｇａ , R ２４ｇｂ , R ２６ｇａ , R ２６ｇｂ , R ２８ｇａ , and R ２８ｇｂ is H, and each of R ２７ｇａ and / or R ２７ｇｂ is F or -CH ３ is; (xi) the following: 【Chemistry 28】 below: 【Chemical 29】 and R ２４ｇａ , R ２４ｇｂ , R ２７ｇａ , R ２７ｇｂ , R ２６ｇａ , R ２８ｇａ , and R ２８ｇｂ is H, and each of R ２６ｇｂ is F or -CH ３ It is.

11. 11. The compound according to any one of claims 7 to 10, wherein the compound is selected from the following compounds: 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 【Chemical 34】

12. Formula (IIh): 【Chemistry 35】 or a salt, ester, solvate, optical isomer, geometric isomer, or isomeric salt thereof, During the ceremony: the below described: 【Chemical Formula 36】 below: 【Chemical 37】 Selected from: R ２０ｈ is H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and C ３ -C ６ cycloalkyl, wherein C １ -C ６ Alkyl and C １ -C ６ Each alkoxy may be substituted with one or more substituents selected from halogen and —OH; ３ -C ６ Cycloalkyl is C １ -C ６ optionally substituted with one or more substituents selected from alkyl and halogen; R ２１ｈ , R ２２ｈ , and R ２３ｈ are each independently selected from H and halogen, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, according to claim 1 .

13. R ２０ｈ is H, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof according to claim 12.

14. The compound according to claim 12 or 13, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, which satisfies at least one of the following (i) to (v): (i) R ２０ｈ below: 【Chemical 38】 Selected from: (ii) R ２１ｈ , R ２２ｈ , and R ２３ｈ are each H; (iii) R ２１ｈ and R ２３ｈ are F and R, respectively. ２２ｈ is H; (iv) R ２１ｈ and R ２３ｈ are H and R ２２ｈ is F; (v) the following: 【Chemical Formula 39】 below: 【Chemistry 40】 It is.

15. 15. The compound according to any one of claims 12 to 14, wherein the compound is selected from the following compounds: 【Chemistry 41】

16. The compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3; an inhibitor of at least two of IRAK1, IRAK4, and FLT3; an inhibitor of IRAK1 and IRAK4, or 16. The compound of any one of claims 1 to 15, or a salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative thereof, which is an inhibitor of IRAK1, IRAK4, and FLT3.

17. The FLT3 is selected from WT FLT3, activated FLT3, and mutant FLT3; 17. The compound or its salt, ester, solvate, optical isomer, geometric isomer, isomeric salt, prodrug, or derivative according to claim 16, wherein the mutated FLT3 is preferably D835Y mutated FLT3 or F691L mutated FLT3.

18. A composition comprising a compound according to any one of claims 1 to 17 or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, further comprising a compounding ingredient, adjuvant, or carrier.

19. A pharmaceutical composition for treating a disease or disorder in a subject, comprising a therapeutically effective amount of a compound as described in any one of claims 1 to 17 or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, or a composition as described in claim 18.

20. The pharmaceutical composition described in claim 19, for treating a disease or disorder responsive to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition.

21. The pharmaceutical composition of claim 19 or 20, administered parenterally, mucosally, intravenously, subcutaneously, topically, intradermally, orally, sublingually, intranasally, or intramuscularly to a subject in need thereof.

22. The pharmaceutical composition of any of claims 19 to 21, wherein the compound or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof is administered to a subject in need thereof in an amount of about 0.005 mg / kg (subject body weight) to about 1,000 mg / kg (subject body weight).

23. A pharmaceutical composition described in any of claims 19 to 22, wherein the disease or disorder includes hematopoietic cancer.

24. The disease or disorder is (i) myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, marginal zone lymphoma, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer at least one cancer selected from the group consisting of glioma, oral cancer, nasopharyngeal cancer, rectal cancer, stomach cancer, and uterine cancer; or (ii) one or more inflammatory or autoimmune diseases selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren's syndrome, ankylosing spondylitis, systemic sclerosis, and type 1 diabetes; Preferably, (a) the MDS is MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, and / or MDS with a mutation in isocitrate dehydrogenase 2, preferably, the MDS with a splicing factor mutation includes MDS with a splicing factor mutation in U2AF1 or SF3B1; or (b) the AML is an AML with a splicing factor mutation, an AML with enhanced expression and / or activity of IRAK4-Long relative to IRAK4-Short, and / or an AML that is not driven by FLT3 mutation but expresses IRAK4-Long, preferably the AML with a splicing factor mutation comprises an AML with a splicing factor mutation in U2AF1 or SF3B1; or (c) the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL or the S219C MYD88 mutant (GCB) subtype of DLBCL; 23. A pharmaceutical composition according to any one of claims 19 to 22.

25. The pharmaceutical composition is selected from the group consisting of a chemotherapeutic agent, a BCL2 inhibitor, an immunomodulatory agent, a BTK inhibitor, a DNA methyltransferase inhibitor / hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analog (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitor, an antibody drug conjugate, a mAb / immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, smoothened receptor antagonists, ERK inhibitors including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, PI3K inhibitors, mTOR inhibitors, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / Leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC, and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, AuraA inhibitors, Aurora kinase inhibitors, EGFR inhibitors, AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / 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, as an adjuvant and / or a combination agent for other therapies.

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

27. ​​A pharmaceutical composition described in any of claims 19 to 26, wherein the disease or disorder is a BCL2 inhibitor-resistant and / or FLT3 inhibitor-resistant disease or disorder.

28. The disease or disorder, BCL2 inhibitor-resistant acute myeloid leukemia (AML), Venetoclax-resistant AML, FLT3 inhibitor-resistant AML, Refractory AML resistant to BCL2 inhibitors, Refractory AML resistant to venetoclax, FLT3 inhibitor-resistant refractory AML, BCL2 inhibitor-resistant relapsed AML, relapsed venetoclax-resistant AML, and / or The pharmaceutical composition according to any one of claims 19 to 26, wherein the patient has relapsed AML resistant to an FLT3 inhibitor.

29. A compound according to any one of claims 1 to 17, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, or a composition according to claim 18, and The one or more additional therapeutic agents 26. The pharmaceutical composition of claim 25, administered in a single dose or together in a single composition to a subject in need thereof.

30. A compound according to any one of claims 1 to 17, or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, or a composition according to claim 18, and The one or more additional therapeutic agents 26. The pharmaceutical composition of claim 25, which is administered separately as multiple doses or multiple compositions to a subject in need thereof.

31. The disease or disorder is, in the subject, attenuated by inhibiting at least one of IRAK1, IRAK4, and FLT3; attenuated by inhibiting at least two of IRAK1, IRAK4, and FLT3; is attenuated by inhibiting IRAK1 and IRAK4, or 31. The pharmaceutical composition of any one of claims 19 to 30, wherein the condition is alleviated by inhibiting IRAK1, IRAK4, and FLT3.

32. The pharmaceutical composition of claim 31, wherein the FLT3 is selected from WT FLT3, activated FLT3, and mutant FLT3, and preferably the mutant FLT3 is D835Y mutant FLT3 or F691L mutant FLT3.

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